CA2112385A1 - Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor - Google Patents
Methods for making and administering a blinded oral dosage form and blinded oral dosage form thereforInfo
- Publication number
- CA2112385A1 CA2112385A1 CA002112385A CA2112385A CA2112385A1 CA 2112385 A1 CA2112385 A1 CA 2112385A1 CA 002112385 A CA002112385 A CA 002112385A CA 2112385 A CA2112385 A CA 2112385A CA 2112385 A1 CA2112385 A1 CA 2112385A1
- Authority
- CA
- Canada
- Prior art keywords
- capsule
- tableted
- medication
- dosage form
- plane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
- Y10T428/1348—Cellular material derived from plant or animal source [e.g., wood, cotton, wool, leather, etc.]
Abstract
The invention relates to a method for making and administering a blinded oral dosage form and the blinded oral dosage form therefor, used for disguising the indentity of tableted medications. The method includes making a blinded oral dosage form by placing a tableted medication within a capsule having a diameter greater than its height. The blinded oral dosage form is the combination of the above-described capsule and the tableted medication.
Description
! S'093/00073 2 l ~ 2 3~ ~ PCT/U592/05248 ~ET~OD~ FOR Na~ING ~ND ~D~INI~TE~ING A ~hIND~D
O~aL DOSAG~ FORM AND B~INDED ORAL DOSAGB FORM TH~FOR
B~CK~RO ~ O~ THE INVENTION
.
Field of the Invention:
The present invention relates to a method ~or making and administering a blinded oral dosage ~orm and the blinded oral dosage form therefor, used for disguising the identity of tableted medications~
..
Descriptio_ of~the_Prior ~rt:
~ Over the years, ~arious methods and d~vices have : bee~ used to compare one medication with another to determine the relative safety and/or e*~icacy of the medication~ I~ is a common pxactice to disguis~ the medications in order to prevent any prejudice from investig~torc~a*ministering~the drugs and subjects inge-~ting the~drugs. Disguising medications from investigators~administering:or subjects ingesting the medication is commonly referred to as "blinding".
0 I ~ Ta~lated m dications are nvrmally "blindPd" by placing~th~ medicati~.n in elongated cylindrical, i.e., ~ tubular,~ opague gelatin capsules along wi~h inactive : packing materials~ :In this way, none of the t~bleted ; medications can be identified by the in~estigators.
administaring the medication or 5ubjects ingesting the medica~ion~ However, conventional "blinding'l procedures using elongated cylindrical gelatin capsules ha~e :
~li238~
specific limitations when usiny certain ~ablets since the diameter of ~he tablet is o~ten very large in relation to the diameter of ~he capsule.
Elongated cylindrical~ or tubular, gelatin capsules may be purchaæed in standard sizes having a body portion and a cap portion. Th~ capsules typically ha~e an elongated cylindrical ~hape with rounded ends that faailitate the swallowi~g of the capsule. Standard el~nyated ayli~drical capsules may be purchased in various sizes. Howe~er, the diameter o~ the capsule is typically small in relation to the length or height of . the capsule~ ;
For example, E~ANCO Qualicaps~, which are t~pical of the industxy, are a~ailable in the following sizes:
000, 00, OEL, O, 1, ~, 3, 4 and 5. rrhe dimensions o~
th~se capsules are provided in the following ~able.
- DIMENSIONS OF ~LaNCO Q~ALICAP5~
-- . ,.~ _.
SIZECAP BOD~ CAP BODY FILL1 DIAMETER DIA~ETER LæNGTH L~NGTH LENGTH
~) (~ t~) (MM) (~) ~ _ . .
000 9.88 _ 9.5 13.1 _ ~.0 26.1 :Q~ 8.51 8.15 _11.7._ 20.2 23.5 : ': OE~ 7.63 7:.33:_ 12.0 20.7 2400 `~ O 7.63 7.33 _ 10.9 18.5 21.8 : : 1 ~.9~ 6~6Z ::9.~ 16.~ 19.5 : _ . _ ~ ~ _ I
~ S.3~ 6.~7 ~09 1501 ~7,~
I _ . ~ ~ ~
3 S.82 5~56 7.9 13.3 ~5.8 , . ~ ~ I
5.32 5.0~ 7.2 12~3 14.5 ~: - ~ , ~
5 4.9 4~67 6.0 9.1 11.7 _ 1FILL IæNGTH is the recommended ~illed joined length of ELAN~O POSILOR~ capsules which is controlled by the ~: location of the locking features on the cap and body.
~ .
O~aL DOSAG~ FORM AND B~INDED ORAL DOSAGB FORM TH~FOR
B~CK~RO ~ O~ THE INVENTION
.
Field of the Invention:
The present invention relates to a method ~or making and administering a blinded oral dosage ~orm and the blinded oral dosage form therefor, used for disguising the identity of tableted medications~
..
Descriptio_ of~the_Prior ~rt:
~ Over the years, ~arious methods and d~vices have : bee~ used to compare one medication with another to determine the relative safety and/or e*~icacy of the medication~ I~ is a common pxactice to disguis~ the medications in order to prevent any prejudice from investig~torc~a*ministering~the drugs and subjects inge-~ting the~drugs. Disguising medications from investigators~administering:or subjects ingesting the medication is commonly referred to as "blinding".
0 I ~ Ta~lated m dications are nvrmally "blindPd" by placing~th~ medicati~.n in elongated cylindrical, i.e., ~ tubular,~ opague gelatin capsules along wi~h inactive : packing materials~ :In this way, none of the t~bleted ; medications can be identified by the in~estigators.
administaring the medication or 5ubjects ingesting the medica~ion~ However, conventional "blinding'l procedures using elongated cylindrical gelatin capsules ha~e :
~li238~
specific limitations when usiny certain ~ablets since the diameter of ~he tablet is o~ten very large in relation to the diameter of ~he capsule.
Elongated cylindrical~ or tubular, gelatin capsules may be purchaæed in standard sizes having a body portion and a cap portion. Th~ capsules typically ha~e an elongated cylindrical ~hape with rounded ends that faailitate the swallowi~g of the capsule. Standard el~nyated ayli~drical capsules may be purchased in various sizes. Howe~er, the diameter o~ the capsule is typically small in relation to the length or height of . the capsule~ ;
For example, E~ANCO Qualicaps~, which are t~pical of the industxy, are a~ailable in the following sizes:
000, 00, OEL, O, 1, ~, 3, 4 and 5. rrhe dimensions o~
th~se capsules are provided in the following ~able.
- DIMENSIONS OF ~LaNCO Q~ALICAP5~
-- . ,.~ _.
SIZECAP BOD~ CAP BODY FILL1 DIAMETER DIA~ETER LæNGTH L~NGTH LENGTH
~) (~ t~) (MM) (~) ~ _ . .
000 9.88 _ 9.5 13.1 _ ~.0 26.1 :Q~ 8.51 8.15 _11.7._ 20.2 23.5 : ': OE~ 7.63 7:.33:_ 12.0 20.7 2400 `~ O 7.63 7.33 _ 10.9 18.5 21.8 : : 1 ~.9~ 6~6Z ::9.~ 16.~ 19.5 : _ . _ ~ ~ _ I
~ S.3~ 6.~7 ~09 1501 ~7,~
I _ . ~ ~ ~
3 S.82 5~56 7.9 13.3 ~5.8 , . ~ ~ I
5.32 5.0~ 7.2 12~3 14.5 ~: - ~ , ~
5 4.9 4~67 6.0 9.1 11.7 _ 1FILL IæNGTH is the recommended ~illed joined length of ELAN~O POSILOR~ capsules which is controlled by the ~: location of the locking features on the cap and body.
~ .
2 3~
93/00073 PCT/U~92/052 As listed, such capsule~ have a length to diameter ratio of well over two but less than three.
In contrast, tablçted medications commonly used in the pharmaceutical industry are manu~actured in ~arious shapes and size~. One co~mon shape us~d for tableted medications is the disk-shaped tablet. ~he diameter of these tablets is usually large in relation to the lenyth or height o~ the tablet. Consequently, when in~estigating or comparing medications, one of which i5 in a tab`let form, the investigator must obt~in a capsule large enough to facilitate the diameter o~ the largest tablet used in the study. That is, the cylindrical or tubular capsule into which the tableted medication must be placed for purposes of blinding, must have a larger diameter than the diameter of the tablet.
Alternatively, the tableted medication must be broken into small pieces or particles to plaae the medication into ~he capsule.
~:~ A standard elongated capsule having a diameter larger than the diameter:o~ the tablet~d medication has a length at least two tim~s longer than the diametex o~
the tableted~medication. For example, a table~ed m~dicatio~ having a:diamet~r o~ 9 millimeters would have to be encapsulated in an 000 E ~ CO Qualicap~. The fill length of the:ELANCO Qualicap~ is 26.1 millimet~rs.
Conse~uently, the st~ndard~ elongated cylindrical capsules are much longer than necessary. ~
Onei concern that arises`with respeck to the ~; : ingestion of m~dication is that the elongated ~ 30 cylindrical capsules large enough to encapsulate various ; : tableted ~edications;are so large that they are not as easily s~allowed as the~tablete~ medication itself~
This is especially:important when administering such medication to~ infants, ~children and the elderly who often have difficulty swallowing medication.
211238~
WOg3/00073 PCT/US9~/05.
Another concern that arises with respect to the ingestion of medication is that elongated cylindrical capsules can accidently be swallowQd sideways which causes the capsule to enter ~he esophagus lengthwise~
This produces difficulty ~n swallowing and significant discomfort to the subject ingesting the capsule. This is especially imporkant when c~lindrical-shaped capsules are presented to animals as it is sometimes necessary to push the capsule d~wn the throat o~ ~he animal.
Anoth~r concern that arises with respect to the ingestion of medication is that there are no readily available cylindrical capsules that may be used to encapsulate tableted medications ha~ing a large diam~,ter. For example, a tableted me~ication having a diameter of lO millimeters or more could not be : ~ encapsulated in even the larges~ ELANCO Qualicap~ which has a diameter o~ 9.5 millimeters. Tableted medications having a diameter of l0 millimeters or more are common.
~: Such medications are illustrated in the Ph~sician's Desk Re~erence~ 43rd Edition, Medical Economics Company, Inc., Oradell, New Jersey:(1989) and in The Familv Physician's Com~E~a um of~Druq_Therapy, Mc~raw-~ill Book ~:; Company, New~York (1988) both of which contain actual siza, full-color:reproductionsi of various medications available from~various manufacturers.
Of course, table~ed medications could be broken in~o smaller pieces or used:in smaller sizes; however, breakingi ableted;medicaitions ~r using ~hem in smaller ~: ~ : size~i affects the actual kinetics o~ medication. In : 30 pa~ticular,~ when tablets:are brok~n up into smaller sizes:there is more æurface area for dissolution and ::
: absorption~of~the medication. ~Furthermore, many tableted medications ha~a various coatings which will ~: be~me~ineffective if destroyed. Consequently, the ~: `
211 23',~j /o~o73 PCT/U~g2/~S~
integrity of the investigation or comparison is compromised when breaking up the tableted medicakions.
Thus, in the majority of research studies, a "double-dummy" approach is used when encapsulation is not practical. The "~ouble-dummy" approach could best be exemplified in a study in ~hich two or more tablets of Yarying size (for instance, one large and one small) are compared for safety or e~ficacy. When the larger of two tabletg is o* too great a diameter to be placed in~ide the standard ~longated ~apsule, it becomes necessary to produce placebos ~or both the large and small tabiets. The "double-dummy" procedure requires the subject to ingest two tablets (one active and one placebo). Therefore, when taking a large tablet as active medication, the subject must also take a smaller tablet as a placebo and vice versa. This method allows the investigator and the subject taking the medicine to be blinded as~o whether ~he Iarger tablet is an active medicati~n or, alternatively, a placebo.
: 20 ~any ~ariations o~ the "double-dummy~' procedure exist. Howev~r,:all variations requixe the expense o~
developing placebos identical to test medications or :: obtaining the~pla~ebo ~rom the manufacturer of the ::~ active product. :~urthermore, it should be noted that : 25 the use of tw~ or more:ta~lets in a ~'double-dummy"
`~ procedure requires the subj~ect to ingest several pills at each dosing period.: The ingestion of two or more : pills inherehtly results in a significant placebo effect :~ : which may increase (or, alterna~ively, decrease3 the 30: perceiyed ~fficacy (or:side ef~ect~ profile of thé study ~:: medication. In addition, ingesting m~ltiple pills may ~: affect the actual:kinetics o~ the study medication.
hile various unconventionally shaped capsules are ~ known In the art~ the aapsules are either not used to blind tableted~medications and/or are not con~enient for 21123Q~
W093/00~73 PCT/VS92/OS' blinding tableted medications. Such various unconventionally shaped capsules are disclosed in U.S.
Patents 46~,9gO; 710,060; 730,643; 1,087,~43; 1,148,621;
2,196,283; and 4~774,0g2~
U~S~ Patent 462,990 discloses a capsule consisting o~ a soluble shell or casing ~ormed integrally with a soluble partition to provide separated ~hambers for different kinds o~ medicine. This patent does not disclose a method for blinding tableted medications. In *act, the capsules are not suitable ~or blinding tableted medications since they are not constructed in a manner ~hat permits tableted medication Q~ various sizes and shapes to be placed ther~in.
U~ S n Patent 710,060 discloses a capsule in which one piece is provided with a double wall con~truction ,~
and the other piece a single wall construction. The ` patent mentions nothing with respect to placing a :~ tableted medication within the capsule.
: U~S. Patent 730,643 discloses a tableted medication con~ained within a gelatin casing~ The tableted medication is enclosed within the casing along with a liquid ingredient for introducing the solid and liquid simultane~usly. The d~vice shown in U~S~ Patent 730,643 ` i5 not acceptable for blinding procedures since the ~ : 25 casing con~aining the li~uid and solid ingreaients is :~ ~ formed with~various presses and dies resulti~g in an integrally formed-one piece~sphere.
U.S. Patent 3~,S36,074 discloses a tableted medication~within a~liquid~ imperYious frangible sac.
The tableted~medication is enclosed within the frangible sac along with a li~uid ingredient to assist in the swallowin~ of the tableted medica~ion. The device shown "~ iD U.S. Patent 3,536,074 is~not acceptable for blinding .:
prooedures since the frangib~e sa~ containing the liquid : : :
Y093~00073 2 1 1 2 ~ 8 -j PCT/~9~/052~
and solid ingredients is an integrally-formed one piece uni~.
'The devices disclosed in U.S~ Patents 730,643 and 3,536,074 are unacc~ptable ~or bl.inding studies since the m~nu~acture o~ such devices requires manu~acturing equipment for pla~ing the tablet and liquid within the capsule and ~or sealing the capsule.
The above-de~cribed methods and devices are intended to provide a means ~or "blinding" medications ~rom investigators and ~ubjects taking the medications.
However, as described abo~e, there are many disadvantage as~ociated with these methad~. Such disad~antages include the ~ack that elongated cylindrical or tubular shaped capsules readily available 15 to thos~ in the art are not aonvenient for disguising ~:~ man~ tableted medications due to their inability to contain many o~ the larger tableted medications and the unsatisfaatory nature of the alternative methods which are commonly utilized~
Thu~, thera remai~s a long elt need in the art for ~` : an impro~ed method and de~ice for "blinding" tableted : medications aontaining an active substance. S~ch method would facil.itate the imestigation of various medications to det~rmine thelr physislogical or pharmacolog~ical effect as well as to compare the safety and/or e~ficacy of the medications wikh other medications.
UM~ARY ~ E~ INVENTION
~: 3~ It is, ~herefore,: a primary object of the present inve~tion to provide an improved method for conducting a blinded study, an improY~d method for blinding a `~ tableted medication and an improved dos~ge form comprising a tableted medication within a capsule such 3~ that investigators analyæing such dosage form and :: :
2112~3~
W093/00073 ` PCT/US92/05' I
subjects ingesting such dosage ~orm cannot determine the identity o~ the medication they are administering or i~gesting.
~nother object of the present i~ntion is to provide a method ~or coating a tableted medication by encapsulating the tableted medication în a c~psule more readily adapted for tableted medications. ~'he method allows researchers and pharmacists to pro~ide medications with one or more desirable coatings wi~hout having to specially order the ~ableted medic~tion with the desired coating.
Still another object of the present invention is ta provide a covering for a tableted medication with~ut the need for special coating equipment, i~e. a capsule having a shape that can be more r~adily sw~llowed than a con~entional capsule that is large enough ta encapsulate the tableted medication.
Yet another ob~ect of the present in~ention is to pro~ide a method for coating a capsule w~h conventional tablet coa~ing apparatus and by co~entional tablet coating procedur~s.
Still another object of the present inven~ion i5 to provide a c`apsule having a shape that can be more r~adily ~wallowed than a convcntional capsule that is large enough to "encapsulate" a large tablet. The blinded oral dosage form of the present invention does ~ot need to be signi~icant1y larger ~han the tablet ` itself~ in both diameter~:and thickness, and could there~ore ~e as easily swa~lowed as the tablet itself.
Thus, the blinded oral dosage form o~ the present invention may ~e transported:through ~he esophagus more easily than~a readily available elongated cylin~rical capsule ~hat would be re~uired to disguise the same tablet.
~093/0~73 ~ 11 2 3 8 S PCT/USg2/05~
Consequently, another object of the present invention is to provide a blinded oral d~sage ~orm that is more easily swallowed by people who experience difficulty in swallowing capsules than a readily available elongated cylindrical capsule tha~ would be re~uired to disguise the same tablet~
Another object o~ the present invention is to pro~i~2 a blinded oral dosage ~orm that could be us~d for blinding co~ventional medications and which is resistant to tampering.
The ~ethod for conducting a blinded study comprises makiny a ~irst blinded oral dosage ~orm by placing a first composition within a capsule having a body portion and a cap portion suc~ that the diameter of the capsule is greater than its height when closed. The method also includes making a second blinded oral dosage form by placing a second co~position within a substantially identical capsule and then clo5ing the capsule. The `~ method also includes administering the ~irst blinded oral dosage form to a subj~ct and admini~tering the seco~d blinded oral dosage ~orm to the same subj~ct or to another subject.
~ Accor~ingly, the method ~or blinding a tableted :~ medication comprises placing the tab~eted medication :~5 within a capsule having a body portion and a cap portion such that the diameter of the capsule is greater than or equal to its height when clo ed.
Specifically, the method for blînding a tableted : medication c~mprises placing the ~ble~ed medication within a capsule having a body pc.. .ion and cap portion : and then closing the capsule, wherein the body portion comprises an open ~nd and an opposit~ly positioned closed end. The ~pen:end is de~ined by a circumferen~ial edge lying~in a first plane. The body portion is configured such that the greatest straight 2 1 ~ 2 3 8 ~
line distance connecting two points on the circumferential edge is greater than the perpendicular distance between the first plane and a second plane whi~h contact~ an outer surface o~ the closed end of the body portion and which is parallel to the first plane.
Preferably, the cap portion is configured similarly to the body portion. Even more preferably, the method includes the use o~ a cylindrical capsule having interlocking cylindrical body and cap poxtions.
The dosage form o~ the pr~sent invention comprises a capsule and, within the capsule, a tableted medication. The capsule has an interlocking body porkion and cap portion and a diameter greater than its height when closed.
More specifically, the dosage form comprises a capsule and, within the capsule:, a tableted medication, : wherein the capsule comprises an interlocking body portion and cap portion. The body portion comprises an open end and an oppositely positioned closed end. The open end is defined by a circumferential edge lying in a : first plane~. Thc body portion is con~igured such that the~greate~st straight line distance connecting-two points ~n the circumferential :edge is grea~er than the ~: perpendicular~;distance:between:the first plane and a second plane~which contacts an;outer surface of.the closed end~:of the body:portion~and which is parallel to the~first~plane. Prefcrably,~the cap portion is ¢onfigured~similarly to the body portion. Even more preferably,: the~dosage orm comprises a capsule and, within the~capsule,: a:tableted medication, wherein the capsule aompriscs interloc~ing cylindrical body and cap portio~s~
Even:more~ specif~ically,~thc dosage form of the pre~ent invcntion~compriscs the combination of a tableted medication and~a capsule, the capsule including a body portion and a cap portion. The cap portion and the body portion each are hollow and have an open end with means which interfit with one another so that the body portion and the cap pol~ion can be brought towar~s one another along an axis with their open ends ~acing one another and connected to one another to define khe capsul~.. The capsule has a cavity formed by ~he hollow body portion and the hollow cap portion and the tableted medication is disposed within the ca~ity. The capsule has ~ length or height as measured along the axis and a diameter as measured perpendicular to the ax~s, the height of the capsule being less than the diameter of the capsule as measured from an outer surface of the capsule.
B~IEF DESCRYPTION OF ~ DRAWINGS
The f~atures of the present inven~i~n will become app2rent fro~ the desaription, con~idered in conjunction with the drawings, in which like elements bear like reference numerals and wherein:
Figur~ _ _ perspective view of one embodiment of the capsule of the blinded oral dosage form o~-the present in~ention illustrating the capsule;
~ igure ~ is a perspectiv view of the capsule shown in Figure 1 illustrating two portions of the capsule separated from one another;
Figur~ 3 is a cro~s-sectional ~iew o~ the embodiment of the bli~ded oral dosage form illustrated in Fiyure t with a tableted medication encloscd within the capsule;
Figure 4 is a perspeative YieW of another em~odiment of the blinded oral dosage form employing a di~erent form of interlocking mechanism for interlocking the two portions; and W093/00~73 PCT/US92/05 Figures 5A and 5B are perspective ~iews of another embodiment of the blinded oral dosage form employing a different form of interlocking mechanism for interlocking khe two portiorl~.
DETAILED DESC~IPTION OF THE PREFERRED
EMBODIMENTS OF THE INV~N~ION
The following description of various embodiments of the dosage ~orm, me~hods of ma~ing the dosage ~orm and methods of administering the dosage fonm are merely illustrative of the present invention and they shQuld not be considered ~s limiting the scope of the invention in any way, as these illustrations and other ~quivalents thereof will become more apparent to thos~. versed in the art in the light of the present disclosure, and the a~companying claims.
The method ~or conducting a blinded study ~20 comprises makin~ a first blinded oral dosage form by placing a ~irst composition within a ~apsule having a body : poxtion and a cap portion such that the d~ameter of the ¢apsule is greater than its height when closed. The'method also includes making a ~econd blinded oral ~sage form by placing a second composition within a substantially identical capsule and then closin~ the capsule. ThP method also includes administering the first blinded oral dosage ~orm to a subject and administering the second blinded oral dosage form to the:same subject or to another subject.
3Q ~ Accordingly, t~e method ~or blinding a tableted mediGati~n comprises placing the tableted medication within a~capsule having a:~body portion and a cap portion such that the diameter of the~r~psule is greater than its height when : closed~ ~
~ The blinded oral dosage form of the present invention includes a:capsule having a body portion and a .
S13B~;TITUTE S~EET
93/0~073 ~ 1 1 2 3 8 S PCT/US92/05~
cap porkion which interlock to form an enclosed space or cavity re~erred ~o herein as the volume o~ the capsul~.
Prior to interlocking the cap por~ion with the body portion, one or more tableted medications are pl~ced within the body portion along with any ~esired non-toxic, pharmaceutically acceptable filler material sufficient to prevent substantial mo~ement of the tablet with the capsule. Optionally, only non-toxic, pharmaceutically acceptable filler material is placed with the capsule to ~orm a placebo~ Once the tablet or tablets and/or filler material is placed inside the body portion and th~ cap portion i~ $nterlocked with the body portion, the tablet or tablets and/or the ~îller material is blinded to persons administering and subjects ingesting the blinded or~l dosage form.
Referring initially to ~igure 1, the capsule includes a cap portion 15 and body portion 20 of the blinded oral dosage ~orm of the present invention produced in such a way to allow the cap po~tion 15 and body por~ion 20 to be combined b~ ~itting the one into the other with suf~iciently close toleranc~s to produce what is essentially a friction lock.
Generally, the capsule comprises a cross-sectional : dimension D and a height or length ~. The cross-sectional dimension D, when the capsul has ~ circular : cross~section:surface, is the diameter o~ the cross-section. In instances where the cro~s-sectional surface is not aircular, the cross--qectional dimension D ls the greatest straight line distance conne~ting two points on the edge of the cross-sectional surface. Preferably, how~ver, the croes-sectional surface is circular.
~; None~he.~ss,: as used`herein, the term "diameter" is ~he greatest straight line distance`connecting two points on the edge of the cross-sectional sur~:ace. This dis~ance is also referred ~o herein as the cross-sectional ' W093/00073 P~T/U~92/OS~
dimension D. The height or length ~ is the distance from the top of the capsule to the bottom of the capsule in a direction perpendicular to the cros~-sectional dimension D. Preferably, th~ cross-sectiQnal dimension D is greater than khe height or leng~h ~, preferably m~ch greater.
As sho~n in Figure Z, the cap portion 15 comprises an open end 25 and an oppositely positioned closed end 30. The open end is defined by a circumferential edge lQ 35 which lies in a first plane 40. Opposite the open end 25, there is a closed end 30 having a point or surface 45 touching but not intersecting a second plane 50 which is parallel to the first plane 40. The ~gxeatest straight line distance connecting any ~wo ;~ 15 points on the circum~erential ~dge 35 is greater than ~he perpendiaular distance between the first plane 40 and the second plane 50. That is, the aross-sectional dimension D i5 greater than the height ~ of the cap poxtion 15.
Like~ise, the body portion 20 comprises an open end : 55 and an oppositely positioned~closed end 60. The open end~is de~ined~by a circumferential edge 65 whi~h lies in a ir t plane 70. Opposite the ope~ end 55 there is a c}osed end~60 having:a point or surfa~e 75 touching :25 but not:intersecting a second plane 80 which is parallel ::~ to ~h~ first plane 70. The greatest straight line distance connecting:any:two;points on the circumfere~tial edge 65 is greater ~han the perpendicular distance between the first plane 70 and the second plane 80.~:That~is,~:the cross-sectional dimension D is greater than the hei~ht ~ of the body portion 20.
~` Tablets of various sizes and shapes along with suf~icien~ non-to~ic, pharma~eutically acceptable filler material (to avoid the tablet rattling within the ~: :
s ~093/~0073 2 1 1 ~ 3 8 S PCT/US92/05~48 capsule) may be placed within cap 15 or ~ody 20 portions; however, the largest tablet must be minimally smaller than the respecti~e opening in order for the tablet to be placed within the capsule. Opti~nally, only non~toxic, pharmaceutically acceptable ~iller material is placed wi~hin a capsule to form a placebo.
In addition, ~arious powdered medications or liquid medications could be placed within a capsule to ~o~m a comparative dosage ~orm.
Normally, ~or human applications, tablets have a diameter ranging ~rom about 2 to about 16 millimeters, preferably about 5 to about 12 millimeters, with a thickness ranging between about 1 and about lO
millimeters, preferably about 2 to about 7 millimeters.
Thus, ~or human applications, it is contemplated that the croæs-sectional dimension D, i.e., the greatest straight line distance b~tween two points on the circumferential edge of the cap or body portions of the capsule, could range from about 3 to about 18 millimeters, preferably about 3 to about 13 millimeters;
In addition, it is contemplated that the o~erall length or height E of ~ e capsule~ i.e~, the distance ~etween the point or surface 45 touching the second plane o~ the .
~` cap and the point or surface 75 touching the second plane of the~body when th~e body and cap are interlocked, could range from~about 3 to about ll millimeters, preferably about 3 to about 7 millimeters. However, the cross-sectional dimension~D should be greater than or equal to the~length or~hei~hk ~. Preferably, the cr~s-section~l dimension D is greater than the ength orheight ~. Even~more preferably, the cross-sectional ~ dimension D~is at~least;1.5;times greater than length or ;~` height ~. Most preferably, the cross-sectional ` dimensîon D is at~least~2.0 times greater than the length or height~
~ i~
: ~ :
211238~
WOg3/00073 P~T/US92~05~:
Another preferred embodiment o~ ~he in~ention for human applications would have a diameter D between about 4 and about 14 millimeters and a height or length ~
between about 3 and about a millimeters. In this way, tablets of normal size (3 to 13 millimeters in diameter and ~ to 7 millimeters in thickness) may be contained within the blinded oral dosage, allowing ~or pacXing materials to avoid movement of the tabl~t within the de~ice.
Another pre~erred embodiment of the blinded oral dosage of the present invention includes a capsule ha~ing a diametex D that is larger than the diameter o~
the standard elongated cylindrical capsules.
Speci~ically, this pre~erred embodiment has a diameter of at least about 10 millimeters, vr e~en a capsule ha~ing a diameter cf at least about 11 or about 12 millimeters. Such preferred capsules are par~icularly suitable for~encapsulating tableted medications having a diameter larger than the diameter o* standàrd elongated cylindrical capsules. Tableted medications having a ~: diameter o~ at lea t 10 millimeters include the 400 mg / dosage of Motrin~ brand ibuprofen tablets, the-500 mg : dosage of ~axi~um Strength Anacin~ brand analgesic (aspi~in~ca~feine).ta~lets, ~he 250 mg dosage o~
Wya~ycin~S~brand erythromycin~stearate tablets, the ~ 500 mg~dosage~of Aralen~:Phosphate brand chloroquine :~ ~ phosphate tablets, the 500 mg dosage of Toli~as~ brand ~ t~laza~i~e~tablets as well as many other wid21y : . available medications. Other tableted medications ha~ing a diameter o~ at least 10 millimeters are .
illustrated in~ the Ph~sician's~Desk Reference, 43rd Edition, ~edical Economics Company, Inc., Oradell, New Jersey ~198~ and in The Family Physician's Compendium }Yg_5b:3 DY~ McGraw-H~ill Book Company, New York (1988~ both of which~contain actual size, full-color :: :
.
2112 3 8 ~ PCT/US92/05248 reproductions of various medications avail~ble from a ~ariety of manufacturers.
The device illustrated in ~igure Z further in d udes a female ~riction portion 85 for placing on top o~ and 5 inkerlocking with the male friction portion so o~ the body portion of the device~ The female friction portion 8~ o* the device for the abo~e-described human applications may be between about 1 and ~bout 10 millimeters lo~g, preferably between about 1 and about 5 lO millimeters long. $he male ~riction portion 9o of the device may have dimensions similar to that o~ the female friction porti~n ~5.
As shown, th~ cap portion 15 and the body portion 20 of the capsule may have rounded closed ends. The 15 radius 95 o~ the cap portion or the radius loO of the body portion of the de~ice may be, ~or human appliaatiQns, be ween abou~ 1 and about 9 millimeters.
The radius is the distance ~rom th~ midpoint o~ the area de~ined by the circumferential edge to the inside 20 surface o~ the closed end o~ the respective portion.
:~ : The radiu~ is not uni~oxm in most instances ~rom the :~ midpoint of the area defined~by the circumferential edge to ~arious points:on the i~side sur~Sace of the closed end. That is, the distance from the midpoint to one 25 point on the inside~surface ~ay ~ot be the same as the :~ distance from the midpoint~to a dif~erent point on the inside surface~ Round~ed:closed ends are preferrad to f ' ' ! f~cilitate ease~of swallowing- ' . Figure 3 ~hows a top view with midline cut-away 30 illustrating:a cylindrical or disk-shaped blinded oral dvsage fonm complete with the tablet lO contained within the capsule~5. As sh~wn, there may be a certain amount of space 105 within the ca~ity formed by interlockin~
the cap portion and:~ody portion for placement of the 35 non-toxic, pharmaceutically acceptable filler material.
`
' W~93/00073 PCT/~S9~/05 The f.iller material may keep the tablet from rattling inside the capsule and gi~ing away its exlstence.
Optionally, only non-toxic, pharmaceutically acceptable ~iller material is placed within the capsule to form a placebo~
A preferred distance from the edge of the tablet to the inside edge of either the cap ox the body portion o~
~he device ~or the abo~e-described devices suitable for human applications may be from about 0.1 to about 6 millimeters. Preferably, one or more tablets occupy at least 20 percent of the enclosed space or cavity of the capsule. More preferably, on~ or more tab~ets occupy at least 35 percent of the enclosed space of the capsule.
Evan more preferably, one or more tablets occupy at least 50 percent of the enclosed space of the capsule.
Even more preferably, one or more kable~s occupy at least 75 percent of the ~nclosed space. ~ven mor~
preferably, one or more tablets occupy at least 90 percent o~ the enclosed spaceO
As the two parts of the capsule are placed together (covering the contents~, the friction produced by the close tolerances between th~ two segments shoul~ be suficient to keep the parts ~rom disassociating during transportation and normal use. In addition 9 it should be su~fi~iently difficult to open the product to inhibit ~ research su~jects or investigators from attempting to : determîne the con~ents.
While ~he above-described illustrations describe pre~erred ~mbodiments o~ the blinded oral dosage o~ the : 30 : present in~ention, it~should be notsd that the de~ice `~ ~ may be of any shape a~d size. Thus, the circumferential edge of either the cap portion or body portion o* the capsule could be circular, ellipsoidal, squareJ
rectangular, triangular or any other circumferential multi-sided shape as well as any ~ther circumferential ~0~3/00073 ~ 3 ~ ~ PCT/U592/05~8 curvilinear shape. Likewise, while the above illustrati~ns show rounded closed ends of the cap portion ~nd the body portion, the closed ends could have flat surfaces.
~ost preferablyr the capsules o~ the present invention are of a cylindrical or di~k shape with rounded ends~ However, by use o~ the term "cylindrical", when re~erring to the capsules of the present invention, it is meant that the capsules when assembled are "non-elongated"~ The phrase "non-elongated" when referring to the pre~rred cylindrical de~ices of the present invention, means that the diameter D o~ the de~ice is greater than or equal to the length or height ~, i.e., the straight line distance from end point to end point, o~ the capsule. More speci~ically, the preferred blinded oral dosage of the present invention has a non-elongated cylindrical shape wherein the ends of the cylinder are rounded or without edges as illustrated in Figure~ 1-5. In contrast, commercially available capsules are elongated. That is, the length or height o~ commercially available capsules is ~r~ater than ~he diameter. Typically, the length to diameter ratio of commercially available capsules is betwee~ two and three.
Thus9 as used herein, an "elongated cylindrical hape" refers:to the shape o~ standard cylindrical capsules widely used in manufacturing encapsulated ' medi¢ations. Such standard elongated cylindrical haped aapsules typically ha~a rounded ends and have a length or height longer than its diameter. Examples o~
~; medications available in cap~ules ha~ing an elongated cylindri¢al shape in~lude I~OBTD9 capsule-c, TRINSICON~
: capsules, VICONFORTE~ capsules, ~MOXII~ capsules, BACTOCILL~ capsules, CLOXAPEN~ apsules, DYCILI'ID
35 capsules, TIGAN~ capsules, DECONAMIME~ apsules, ~1~2~`;t) WO 93/00~73 PCI/l)S9~/05 MEXITI~ capsules, R-TUSSX capsules O MIDXIN~ c:apsules, ACTIFED0 capsules, SUDAFED~ capsules, ZOUIRAX~ capsules, BRONTRILX cap:~;ules, HYD~OCET0 capsules and MID:RIN~
capsules. Each of the above-listed capsules as well as o~hers are available ~ia various man~acturers as set forth in the hYs~cians Desk Reference, 43rd ~dition, ~edical Economics Compa~, Ina., Oradell , New Jersey (1989), The widely a~ailable elongated cylindrical capsules are also shown in Reminqton's Pharmaceutical Sciences, 18th Edition, on Page 1658 a~ Figure 89-34, Mack ' Publishing Company, Easton~ Pennsylvania (19gO).
: The widely available elongated cylindrical capsules are also a~ailable empty and ready f~r f illing .
15 Elongated cylindrical capsules available empty and ready for filling include the ELANCO QUALICAPS~ referred to abo~e.
In contrast to the elongated cylindrical capsules, the capsules o~ ~he present inve~tion have a length (i.e. height) to diameter ratio less than or equal to one. Nonetheless, the dimensions o~ the blinded oral dosage of the presen~ invention may be o~ any size depending on:the application, just so long as the height to diameter ratio does not exceed one. For example, when administering the blinded oral dosage of th~
present invention to large animals, such as cattle sr hors s, larger dosage forms may be required. Of course, logic dictates that the si~e o~ the blinded oral dosage form depends bo~h on the size of he tablet and ~he size of the subject ingesting the dosage. Thus, any variety of sizes are~applicable:to the present invention.
: However, the cross-sectional dimension D shoula be ~` greater than or equal to the leng~h or height H.
~: Preferably,~D is greater than the height H.
~:
: : .
2 l ~ ,J ?i ~
,t093/0oo73 P~ S92/05 The t~blets placed within the enclQsed ca~ity of the blinded oral dosage ~oxm o~ the invention may be any one of a wide variety of tableted medications. Tableted medications are medications that ha~e been pressed or S otherwise formed into a solid dosage form ready for ingestion. The tableked medication may be any number o~
a wide variety of shapes currently a~ailable to those skilled in the art. In this regard, manufacturers of tableted medications manu~acture such tablets in round or cylindrical shapes, sguare shape~, rectangular shapes, triangular shapes/ o~al shapes, spherical shapes, hexagonal shapes, trapezoidal shapes, etc.;
Accordingly, any su¢h tablet ox tablet shape is suitab~e for placiny within the cavity of the blinded oral dosage ~orm~
When the cap portion is engaged with the body portion of the instant dosage form, an ~nclosed cavity is formed such that the contents of the deYic~ are not exposed to external elements present during tranæportation and handling o~ the dosage forms. The volume o~ the capsule is the enclosed cavity ~ormed by the cap and body portions o~ the capsule. The-cap portion may engage the body porti~n via any locking mechanism k~own in the a~t. Locking mechanisms are particularly:important in research studi~s as they inhibit volunteers tas w~ll as researchers) from opening capsules and discovering their contents prior t~
`~ i 1administiation. They are also importan~ in simply kseping the`two halves o~ the product from falling apart durin~ storage, transportation or usageO
Locking mechanisms may include, for example, friction-type locki~g mechanisms as shown in Fi~ur~
and 2~ The ~riction ~type l~c~ing mechanism includes ~riction produced by the close tolerance between the 3S male and female segments of the capsule.
2 1 1 2 ~
W093/00073 PCT/U~92/05240 ~igure 4 is an illustration of another embodiment of the blinded oral dosage form showing a tonyue and groove locking mechanism. In this aonfiguration, the body portion 20 of the device has accordion-shaped ridges 110 permitting it to move into the cap portion lS
of the de~ice such that ik interlocks with one or more internal indentations 115. As shown, one or more internal indentations llS or ridges 110 may be used.
Optionally t the cap portion could contai~ the ridges and the body portion could contain the internal indentation~
of the locking mechanism~
If the male section has two or more internal indentations or ridges, any one of the ridges could be locked onto depending on the thickness of the tablet lS contained inside. This would allow the tablet-shaped : capsule to have one, two or more thickness~s to accommodate tablets of various thickness or even multipl~ tablets being encapsulated within the product.
Ob~iously, for any given study, all tablet-shaped capsules would be of identical thickness, with more or less filler present depending upon the space occupied py the tablet(s~ encapsulated.
The cro~s-section o~ the ridges or the internal indentation may have a profile which is curved or angular, and may range in shape, for example, from a single to a ~multiple radius design, or from a V-shape to a multi-angular shape, such as for example a square, rectangular, trapezoidal, etc. shapes. Examples ,of such tongue and groove-type locking mechanisms are illustrated in U.S. Patent 4,882,618.
As with the ~'tongue and groove" and "friction"
locking mechanisms, a "flexible lipl' could ~lso b~ used : as a means~of maintaining the integrity of a tablet-shaped capsule as described above. Fiqure~ S~
3s and SB provide an illustration of another embodiment of the .
SUBSTITUTE SHEE~
~112~5 ' 'NO93/00073 PCT/US92/052q8 oral dosage form of ~he invention containing a flexible lip txpe locking mechanism. In this ~orm, the cap portion 15 o~ ~he de~ice would fit over the body portion 20 o~ the de~ice or viae versa. Bo~h the cap and body portions of ~he device contain a portion of the "fl~xible lip" locking mechanism. ~ach portion o~ the locking mechanism is rounded on the edge in such a way as to allow the bod~ porti~n 20 o~ the locking mechanism (which is s~ightly smaller) to slip into the cap portion 15 o~ the locking mechanism~ The larger rounded edge o~
the cap portion 15 of the locking mechanism is suf~iciently flexible to expand and slip over t~e smaller but similarly rounded edge of the body portion 15 o~ the locking mechanism and due to the overla~, lock both segments together.
Additional locking mechanisms could incl~de screw-type locking mechanisms and external fasteners.
Accordinglyr any locking mechanism in existence for standard capsule shapes could be utilized for the blinded oral dosage o~ ~he present invention as long as it insures the;integrity o~ the dosage ~orm during no~mal h~ndling.
Additionally,~it is noted that each of the above-mentioned locking mechanisms may allow locking of the ` 25 ~apsules at ~arious thicknesses so tablets of various icknesses could be encapsulated along with fillers.
The blinded oral dosage form may also include ~axious wraps~or tapes conventionally used with standard gelati~ capsules to insur~ that the de~ice is not tampered with prior to administration. It may be ~;~ desired to apply à sealiDg band to an assembled dosage orm, to prevent~leakage in the case of any possible powder or liquid fillings, or to render the capsule tampér-evident or tamper resistant or for identification purposes. This may be a~hieved using known methods and .
211h3~3S
equipment, such as, ~or example, the Quali-Seal machine (Manu*acturing Chemist, Jan~ 1987, p. 27).
Preferably, the body and cap portions of the blinded oral dosage form of the present in~ention are made of a hard gelatin and could be manufactured on existing equipment with modifications to dies and other p~rts of those or similar machines. Optionally, the capsules o~ the present in~ention could be m~de of so~t gelatin or any other ma~erial used to make conventional capsules.
By wa~ o~ illustration, hard gelatin capsules may be made in two parts by dipping stainless steel pins into a molten gelatin solution, and all~wing the gelatin to set and dry. It is generally known that the gelatin film, as it dries, also undergoes shrinkage. The shrinkage depends on a number of factors such as the amount of water to be eliminated, the gelatin used, the : drying regime and the number and type of additi~es such as dyes, other colorants, opacifiers, plasticizers, viscosit~ builders or surfactants which may be included within the gelatin compositions o~ the present invention . Such pxocesses and compositions are-well ~own in the ~art, for example, see The Theory and ~ Practice of Industrial Pharmacy, 3rd Ed., Lea h Febiger, : 25 Philadelphia~(1986) and Reminaton's Pharmaceutical ; Sciences, 18th Edition, Mack Publishing Company, Easton, : Pennsylvania (1990)~
I ' In addition, the body~and cap portions of ~he blinded oral dosage~form may~be made of materials that :~: 30 are soluble in:alkaline intestinal secretions but substantially insoluble in~and resistant to acid secretions of the stoma~h.; Such~materials are commonly referred to as ha~ing enteric properties. The enteric dosage forms may be made, for~:example, by dip-molding : 35 using a homogeneous film-forming mixture comprising (1) ~ t 1'~
,,,................................... ., , ~
' yo 93/00073 PCr/US92/05248 gelatin and an ammonium salt o~ hydroxypropyl methylcelluose phthalate polymer, or ~2) hydroxypropyl methylcelluose and an ammonium sal~ of cellulose aceta te ph~halate pol~mer, or (3) gelatin and an ammonium salt o~ a copolymer of methacrylic acid and methacrylia acid ester optiQnally in co~binakion with additional ingredients such as plasticizers~ surfactants and coloring agen~s. The above compositions are described, ~or example, in more deti~il in U.S. Paten~ 4,138,013.
Likewise, many other ingestible materîals may be used to make the cap and body portions of the ~lindea oral dosage form of the present invention. Preferably, howe~er, the ca~sules are made o~ a hard gelatin composition.
Aæ a result o~ the non-elongated shape of the blinded oral dosage form, it is also suitable ~or coating with pharmaceutical grade materials in standard tablet coating bins (unlike a standard elongated shaped : capsule which does not tumble appropriately for coating : 20 purposes). me dosage forms of the present invention : may tumbl~ exactly like a standard tablet and may thereby coat as easily as any tablet depending sn the pa~ticular embodiment. Coatings (or multiple coatiny : layers) of~various degre~s o~ hardness, thickness or solubility~would be aesthetically pleasing and have standard pharmaceutical qualities regarding dissolution rate, ea~e of~swallowing and manu~ac~uring advantages.
Pref~rred embodiments of the blinded oral dosage form could be: coated by a standard tablet coating 30 proc:ess such as described,: for example, in :Reminqton's : Pharmaceutical Sciences, 18th Edition, ~hapter 90, ~: "Coatinq O* Pharmaceutical Dosage Forms", Mack Publishing Company, East~3n, Pennsylvania (19gO).
In addition~: to t~e above advantages, one or more 35 coatings may provide a: "tam~er proof" blinded oral 2 1 1 h 'J) ~
W~93~0~073 PCT/US92/05 dosage foxm as opening would break ~he coating. The broken coating material would be difficult, if not impossible, to restore to its original character and would be an obvious signal to khe investigaitors or 5 subj ects ingesting the device not to use the product.
The break could be made more ob~ious in many ways including use of layered coverings of different colorings, highly friable c~ating materials or unusual colors. The coating could also help maintain the inteyrity o~ the product during both research and commiercial use. ~lso, the coating may be used in conjunction with an external wrap or tamper resistant tape that protects the de~ice~ Additionally, it is also possible to utilize a number o* coating compounds or active agents in the coating ~omp~sition ko achieve a ~: desired e~fect. For instance, an enteric coating can be applied as one layer or in combination with another coating solutio~.
The method of the pxesent inYention includes 2Q pxeparing blinded ta~leted medications. ~n particular"
the method:includes~disgui~ng a tableted medication by plaaing the medication in a non-elongated ¢apsule, i.e., a capsule of ~he present:invention having a cross-, sectionial dimension D yreater than or egual ~o its length or height ~
This method pro~ides a~means ~or disguising ~: taibIeted:medications in~a qapsule more readily adapted for tableted~medications. Thus, standard elongated capsules which~are overly large in relation to the ~ tableted medications are not necessary. In fact, themethod includes disguising one~or more tablets that occupy at:least 20 percent, more pre~erably at least 35 percent, more preferably at least 50 percent~ more `:~ : preferably at least 75 percent or most preferably at.
:
21~ 238~
~093~00073 PCT/VS92/05 least 90 percent of the enclosed space or cavity of the capsule.
The method may further include placing one or more no~-toxic, pharmaceutically acceptable filler materials within the aavity o~ the capsule to prevent the tablet from rattling inside the capsule. ~his prevents researchers or subjects from distinguishing between capsules containing tabl~ts o~ various sizes, or between those containing tablets and those cQntaining non-tableted medications or fillers only ~i.e., placebos).Optionally, only non-toxic, pharmaceutically acceptable filler is placed within ~he capsules of the present invention to form a placebo. Suitable non-toxia, pharmaceutically acceptable filler material, including sugars and starchest: would be apparent to those skilled in the art.
Additionally, the method may fuxther include : applying one or more coatings covering the capsule.
Certain coatings may be applied either be~ore or after the tablet i8 placed within the capsule. I~ the case , ~: wherein the capsules are precoated, the method of the preserdt i~vention includes a:5imple and easy means for : encapsulating a tableted~medication to provide a desir~d .
coating without the need~to coat the tablet itself. In the case wherein the~capsules are coated after filling, :~ the closed:~capsule, unlike~standard elongated capsules, ~ may be coated according to co~ventional tablet coating ` tl~mbIe plrocesses and in conventional tablet coating ~:~ equipment. ; ~
: FU ~ ermore~, the~method of t~e present invention is :~ ~ particularly ~uitable *or comparing two dif~erent . :medications, i.e., one:tableted medication and another medication whi~h may or may not be tableted. Comparing :;: two different medications would include making a first : 35 ~ blinded oral dosage ~orm by disguising a first tahle~ed :~ :: : :
3 ~ '~
WOg3/0~073 PCT/US92/05 medication in a non-elongated capsule and making a second blinded oral dosage form by disguising a second medication (either tableted or not) in a non-elongated capsule having subs~antially the same size and shape as the ~irst blinded oral dosage ~orm.
Thus, the method o~ the present inYention further pro~ides a means for disguising or blinding one or more medications of differ~nt shapes and sizes, e~g., one large and one small, or even the same medication in different forms or amounts. The method in such case may include placing the large tableted medication in a capsule of the present in~ention of large enough size to hold the tableted medicatio* and placing a smaller tableted medication in a capsule identical to the capsule in which the larger tableted medication was placed. In this way, the person conducting the clinical ..
trial and the subject ing~sting t~e blinded oral dosage would not know what medication, form of medication or amount of medication was administered. By use of this method, two~medications o~ su stantially different siz~
or shape or~the same~medication in~di~ferent forms or amounts could be readily compared.
The method of the precent inventisn is also suitable for analyz~ing one~tableted medication as compared to a second dosa~e form which does not contain an e~fective medication. ~Analyzing sne tableted medication~may include making a first blînded oral dosage foxm by~disguising a;~irst tableted medication in a non-elongated capsule~and making a second blinded oral dosage form ha~ing;substantially the same size and shape as the first blinded~oral~dosage that does not contain an ef~ective medication, i.~e., a placebo.
From the~;*oregoing description, one of ordinary sk;ll in the art can easily~ascertain the essential ; 3S characteristics of the instant invention, and without : `
: :
: ~ :
!093~00073 21~ 2 ~ 3 ~ PCT/US92/05~
departing from the spirit and scope thereof, can make various change~ and/or modi~ications of the invention to adapt it to various usages and conditionæ~ As such, these changeæ and/or modifications are properly, e~uitably and int~nded to be~ within the full range of e~uivalents of the following claims.
I
`: ` : ::
:: : :
93/00073 PCT/U~92/052 As listed, such capsule~ have a length to diameter ratio of well over two but less than three.
In contrast, tablçted medications commonly used in the pharmaceutical industry are manu~actured in ~arious shapes and size~. One co~mon shape us~d for tableted medications is the disk-shaped tablet. ~he diameter of these tablets is usually large in relation to the lenyth or height o~ the tablet. Consequently, when in~estigating or comparing medications, one of which i5 in a tab`let form, the investigator must obt~in a capsule large enough to facilitate the diameter o~ the largest tablet used in the study. That is, the cylindrical or tubular capsule into which the tableted medication must be placed for purposes of blinding, must have a larger diameter than the diameter of the tablet.
Alternatively, the tableted medication must be broken into small pieces or particles to plaae the medication into ~he capsule.
~:~ A standard elongated capsule having a diameter larger than the diameter:o~ the tablet~d medication has a length at least two tim~s longer than the diametex o~
the tableted~medication. For example, a table~ed m~dicatio~ having a:diamet~r o~ 9 millimeters would have to be encapsulated in an 000 E ~ CO Qualicap~. The fill length of the:ELANCO Qualicap~ is 26.1 millimet~rs.
Conse~uently, the st~ndard~ elongated cylindrical capsules are much longer than necessary. ~
Onei concern that arises`with respeck to the ~; : ingestion of m~dication is that the elongated ~ 30 cylindrical capsules large enough to encapsulate various ; : tableted ~edications;are so large that they are not as easily s~allowed as the~tablete~ medication itself~
This is especially:important when administering such medication to~ infants, ~children and the elderly who often have difficulty swallowing medication.
211238~
WOg3/00073 PCT/US9~/05.
Another concern that arises with respect to the ingestion of medication is that elongated cylindrical capsules can accidently be swallowQd sideways which causes the capsule to enter ~he esophagus lengthwise~
This produces difficulty ~n swallowing and significant discomfort to the subject ingesting the capsule. This is especially imporkant when c~lindrical-shaped capsules are presented to animals as it is sometimes necessary to push the capsule d~wn the throat o~ ~he animal.
Anoth~r concern that arises with respect to the ingestion of medication is that there are no readily available cylindrical capsules that may be used to encapsulate tableted medications ha~ing a large diam~,ter. For example, a tableted me~ication having a diameter of lO millimeters or more could not be : ~ encapsulated in even the larges~ ELANCO Qualicap~ which has a diameter o~ 9.5 millimeters. Tableted medications having a diameter of l0 millimeters or more are common.
~: Such medications are illustrated in the Ph~sician's Desk Re~erence~ 43rd Edition, Medical Economics Company, Inc., Oradell, New Jersey:(1989) and in The Familv Physician's Com~E~a um of~Druq_Therapy, Mc~raw-~ill Book ~:; Company, New~York (1988) both of which contain actual siza, full-color:reproductionsi of various medications available from~various manufacturers.
Of course, table~ed medications could be broken in~o smaller pieces or used:in smaller sizes; however, breakingi ableted;medicaitions ~r using ~hem in smaller ~: ~ : size~i affects the actual kinetics o~ medication. In : 30 pa~ticular,~ when tablets:are brok~n up into smaller sizes:there is more æurface area for dissolution and ::
: absorption~of~the medication. ~Furthermore, many tableted medications ha~a various coatings which will ~: be~me~ineffective if destroyed. Consequently, the ~: `
211 23',~j /o~o73 PCT/U~g2/~S~
integrity of the investigation or comparison is compromised when breaking up the tableted medicakions.
Thus, in the majority of research studies, a "double-dummy" approach is used when encapsulation is not practical. The "~ouble-dummy" approach could best be exemplified in a study in ~hich two or more tablets of Yarying size (for instance, one large and one small) are compared for safety or e~ficacy. When the larger of two tabletg is o* too great a diameter to be placed in~ide the standard ~longated ~apsule, it becomes necessary to produce placebos ~or both the large and small tabiets. The "double-dummy" procedure requires the subject to ingest two tablets (one active and one placebo). Therefore, when taking a large tablet as active medication, the subject must also take a smaller tablet as a placebo and vice versa. This method allows the investigator and the subject taking the medicine to be blinded as~o whether ~he Iarger tablet is an active medicati~n or, alternatively, a placebo.
: 20 ~any ~ariations o~ the "double-dummy~' procedure exist. Howev~r,:all variations requixe the expense o~
developing placebos identical to test medications or :: obtaining the~pla~ebo ~rom the manufacturer of the ::~ active product. :~urthermore, it should be noted that : 25 the use of tw~ or more:ta~lets in a ~'double-dummy"
`~ procedure requires the subj~ect to ingest several pills at each dosing period.: The ingestion of two or more : pills inherehtly results in a significant placebo effect :~ : which may increase (or, alterna~ively, decrease3 the 30: perceiyed ~fficacy (or:side ef~ect~ profile of thé study ~:: medication. In addition, ingesting m~ltiple pills may ~: affect the actual:kinetics o~ the study medication.
hile various unconventionally shaped capsules are ~ known In the art~ the aapsules are either not used to blind tableted~medications and/or are not con~enient for 21123Q~
W093/00~73 PCT/VS92/OS' blinding tableted medications. Such various unconventionally shaped capsules are disclosed in U.S.
Patents 46~,9gO; 710,060; 730,643; 1,087,~43; 1,148,621;
2,196,283; and 4~774,0g2~
U~S~ Patent 462,990 discloses a capsule consisting o~ a soluble shell or casing ~ormed integrally with a soluble partition to provide separated ~hambers for different kinds o~ medicine. This patent does not disclose a method for blinding tableted medications. In *act, the capsules are not suitable ~or blinding tableted medications since they are not constructed in a manner ~hat permits tableted medication Q~ various sizes and shapes to be placed ther~in.
U~ S n Patent 710,060 discloses a capsule in which one piece is provided with a double wall con~truction ,~
and the other piece a single wall construction. The ` patent mentions nothing with respect to placing a :~ tableted medication within the capsule.
: U~S. Patent 730,643 discloses a tableted medication con~ained within a gelatin casing~ The tableted medication is enclosed within the casing along with a liquid ingredient for introducing the solid and liquid simultane~usly. The d~vice shown in U~S~ Patent 730,643 ` i5 not acceptable for blinding procedures since the ~ : 25 casing con~aining the li~uid and solid ingreaients is :~ ~ formed with~various presses and dies resulti~g in an integrally formed-one piece~sphere.
U.S. Patent 3~,S36,074 discloses a tableted medication~within a~liquid~ imperYious frangible sac.
The tableted~medication is enclosed within the frangible sac along with a li~uid ingredient to assist in the swallowin~ of the tableted medica~ion. The device shown "~ iD U.S. Patent 3,536,074 is~not acceptable for blinding .:
prooedures since the frangib~e sa~ containing the liquid : : :
Y093~00073 2 1 1 2 ~ 8 -j PCT/~9~/052~
and solid ingredients is an integrally-formed one piece uni~.
'The devices disclosed in U.S~ Patents 730,643 and 3,536,074 are unacc~ptable ~or bl.inding studies since the m~nu~acture o~ such devices requires manu~acturing equipment for pla~ing the tablet and liquid within the capsule and ~or sealing the capsule.
The above-de~cribed methods and devices are intended to provide a means ~or "blinding" medications ~rom investigators and ~ubjects taking the medications.
However, as described abo~e, there are many disadvantage as~ociated with these methad~. Such disad~antages include the ~ack that elongated cylindrical or tubular shaped capsules readily available 15 to thos~ in the art are not aonvenient for disguising ~:~ man~ tableted medications due to their inability to contain many o~ the larger tableted medications and the unsatisfaatory nature of the alternative methods which are commonly utilized~
Thu~, thera remai~s a long elt need in the art for ~` : an impro~ed method and de~ice for "blinding" tableted : medications aontaining an active substance. S~ch method would facil.itate the imestigation of various medications to det~rmine thelr physislogical or pharmacolog~ical effect as well as to compare the safety and/or e~ficacy of the medications wikh other medications.
UM~ARY ~ E~ INVENTION
~: 3~ It is, ~herefore,: a primary object of the present inve~tion to provide an improved method for conducting a blinded study, an improY~d method for blinding a `~ tableted medication and an improved dos~ge form comprising a tableted medication within a capsule such 3~ that investigators analyæing such dosage form and :: :
2112~3~
W093/00073 ` PCT/US92/05' I
subjects ingesting such dosage ~orm cannot determine the identity o~ the medication they are administering or i~gesting.
~nother object of the present i~ntion is to provide a method ~or coating a tableted medication by encapsulating the tableted medication în a c~psule more readily adapted for tableted medications. ~'he method allows researchers and pharmacists to pro~ide medications with one or more desirable coatings wi~hout having to specially order the ~ableted medic~tion with the desired coating.
Still another object of the present invention is ta provide a covering for a tableted medication with~ut the need for special coating equipment, i~e. a capsule having a shape that can be more r~adily sw~llowed than a con~entional capsule that is large enough ta encapsulate the tableted medication.
Yet another ob~ect of the present in~ention is to pro~ide a method for coating a capsule w~h conventional tablet coa~ing apparatus and by co~entional tablet coating procedur~s.
Still another object of the present inven~ion i5 to provide a c`apsule having a shape that can be more r~adily ~wallowed than a convcntional capsule that is large enough to "encapsulate" a large tablet. The blinded oral dosage form of the present invention does ~ot need to be signi~icant1y larger ~han the tablet ` itself~ in both diameter~:and thickness, and could there~ore ~e as easily swa~lowed as the tablet itself.
Thus, the blinded oral dosage form o~ the present invention may ~e transported:through ~he esophagus more easily than~a readily available elongated cylin~rical capsule ~hat would be re~uired to disguise the same tablet.
~093/0~73 ~ 11 2 3 8 S PCT/USg2/05~
Consequently, another object of the present invention is to provide a blinded oral d~sage ~orm that is more easily swallowed by people who experience difficulty in swallowing capsules than a readily available elongated cylindrical capsule tha~ would be re~uired to disguise the same tablet~
Another object o~ the present invention is to pro~i~2 a blinded oral dosage ~orm that could be us~d for blinding co~ventional medications and which is resistant to tampering.
The ~ethod for conducting a blinded study comprises makiny a ~irst blinded oral dosage ~orm by placing a first composition within a capsule having a body portion and a cap portion suc~ that the diameter of the capsule is greater than its height when closed. The method also includes making a second blinded oral dosage form by placing a second co~position within a substantially identical capsule and then clo5ing the capsule. The `~ method also includes administering the ~irst blinded oral dosage form to a subj~ct and admini~tering the seco~d blinded oral dosage ~orm to the same subj~ct or to another subject.
~ Accor~ingly, the method ~or blinding a tableted :~ medication comprises placing the tab~eted medication :~5 within a capsule having a body portion and a cap portion such that the diameter of the capsule is greater than or equal to its height when clo ed.
Specifically, the method for blînding a tableted : medication c~mprises placing the ~ble~ed medication within a capsule having a body pc.. .ion and cap portion : and then closing the capsule, wherein the body portion comprises an open ~nd and an opposit~ly positioned closed end. The ~pen:end is de~ined by a circumferen~ial edge lying~in a first plane. The body portion is configured such that the greatest straight 2 1 ~ 2 3 8 ~
line distance connecting two points on the circumferential edge is greater than the perpendicular distance between the first plane and a second plane whi~h contact~ an outer surface o~ the closed end of the body portion and which is parallel to the first plane.
Preferably, the cap portion is configured similarly to the body portion. Even more preferably, the method includes the use o~ a cylindrical capsule having interlocking cylindrical body and cap poxtions.
The dosage form o~ the pr~sent invention comprises a capsule and, within the capsule, a tableted medication. The capsule has an interlocking body porkion and cap portion and a diameter greater than its height when closed.
More specifically, the dosage form comprises a capsule and, within the capsule:, a tableted medication, : wherein the capsule comprises an interlocking body portion and cap portion. The body portion comprises an open end and an oppositely positioned closed end. The open end is defined by a circumferential edge lying in a : first plane~. Thc body portion is con~igured such that the~greate~st straight line distance connecting-two points ~n the circumferential :edge is grea~er than the ~: perpendicular~;distance:between:the first plane and a second plane~which contacts an;outer surface of.the closed end~:of the body:portion~and which is parallel to the~first~plane. Prefcrably,~the cap portion is ¢onfigured~similarly to the body portion. Even more preferably,: the~dosage orm comprises a capsule and, within the~capsule,: a:tableted medication, wherein the capsule aompriscs interloc~ing cylindrical body and cap portio~s~
Even:more~ specif~ically,~thc dosage form of the pre~ent invcntion~compriscs the combination of a tableted medication and~a capsule, the capsule including a body portion and a cap portion. The cap portion and the body portion each are hollow and have an open end with means which interfit with one another so that the body portion and the cap pol~ion can be brought towar~s one another along an axis with their open ends ~acing one another and connected to one another to define khe capsul~.. The capsule has a cavity formed by ~he hollow body portion and the hollow cap portion and the tableted medication is disposed within the ca~ity. The capsule has ~ length or height as measured along the axis and a diameter as measured perpendicular to the ax~s, the height of the capsule being less than the diameter of the capsule as measured from an outer surface of the capsule.
B~IEF DESCRYPTION OF ~ DRAWINGS
The f~atures of the present inven~i~n will become app2rent fro~ the desaription, con~idered in conjunction with the drawings, in which like elements bear like reference numerals and wherein:
Figur~ _ _ perspective view of one embodiment of the capsule of the blinded oral dosage form o~-the present in~ention illustrating the capsule;
~ igure ~ is a perspectiv view of the capsule shown in Figure 1 illustrating two portions of the capsule separated from one another;
Figur~ 3 is a cro~s-sectional ~iew o~ the embodiment of the bli~ded oral dosage form illustrated in Fiyure t with a tableted medication encloscd within the capsule;
Figure 4 is a perspeative YieW of another em~odiment of the blinded oral dosage form employing a di~erent form of interlocking mechanism for interlocking the two portions; and W093/00~73 PCT/US92/05 Figures 5A and 5B are perspective ~iews of another embodiment of the blinded oral dosage form employing a different form of interlocking mechanism for interlocking khe two portiorl~.
DETAILED DESC~IPTION OF THE PREFERRED
EMBODIMENTS OF THE INV~N~ION
The following description of various embodiments of the dosage ~orm, me~hods of ma~ing the dosage ~orm and methods of administering the dosage fonm are merely illustrative of the present invention and they shQuld not be considered ~s limiting the scope of the invention in any way, as these illustrations and other ~quivalents thereof will become more apparent to thos~. versed in the art in the light of the present disclosure, and the a~companying claims.
The method ~or conducting a blinded study ~20 comprises makin~ a first blinded oral dosage form by placing a ~irst composition within a ~apsule having a body : poxtion and a cap portion such that the d~ameter of the ¢apsule is greater than its height when closed. The'method also includes making a ~econd blinded oral ~sage form by placing a second composition within a substantially identical capsule and then closin~ the capsule. ThP method also includes administering the first blinded oral dosage ~orm to a subject and administering the second blinded oral dosage form to the:same subject or to another subject.
3Q ~ Accordingly, t~e method ~or blinding a tableted mediGati~n comprises placing the tableted medication within a~capsule having a:~body portion and a cap portion such that the diameter of the~r~psule is greater than its height when : closed~ ~
~ The blinded oral dosage form of the present invention includes a:capsule having a body portion and a .
S13B~;TITUTE S~EET
93/0~073 ~ 1 1 2 3 8 S PCT/US92/05~
cap porkion which interlock to form an enclosed space or cavity re~erred ~o herein as the volume o~ the capsul~.
Prior to interlocking the cap por~ion with the body portion, one or more tableted medications are pl~ced within the body portion along with any ~esired non-toxic, pharmaceutically acceptable filler material sufficient to prevent substantial mo~ement of the tablet with the capsule. Optionally, only non-toxic, pharmaceutically acceptable filler material is placed with the capsule to ~orm a placebo~ Once the tablet or tablets and/or filler material is placed inside the body portion and th~ cap portion i~ $nterlocked with the body portion, the tablet or tablets and/or the ~îller material is blinded to persons administering and subjects ingesting the blinded or~l dosage form.
Referring initially to ~igure 1, the capsule includes a cap portion 15 and body portion 20 of the blinded oral dosage ~orm of the present invention produced in such a way to allow the cap po~tion 15 and body por~ion 20 to be combined b~ ~itting the one into the other with suf~iciently close toleranc~s to produce what is essentially a friction lock.
Generally, the capsule comprises a cross-sectional : dimension D and a height or length ~. The cross-sectional dimension D, when the capsul has ~ circular : cross~section:surface, is the diameter o~ the cross-section. In instances where the cro~s-sectional surface is not aircular, the cross--qectional dimension D ls the greatest straight line distance conne~ting two points on the edge of the cross-sectional surface. Preferably, how~ver, the croes-sectional surface is circular.
~; None~he.~ss,: as used`herein, the term "diameter" is ~he greatest straight line distance`connecting two points on the edge of the cross-sectional sur~:ace. This dis~ance is also referred ~o herein as the cross-sectional ' W093/00073 P~T/U~92/OS~
dimension D. The height or length ~ is the distance from the top of the capsule to the bottom of the capsule in a direction perpendicular to the cros~-sectional dimension D. Preferably, th~ cross-sectiQnal dimension D is greater than khe height or leng~h ~, preferably m~ch greater.
As sho~n in Figure Z, the cap portion 15 comprises an open end 25 and an oppositely positioned closed end 30. The open end is defined by a circumferential edge lQ 35 which lies in a first plane 40. Opposite the open end 25, there is a closed end 30 having a point or surface 45 touching but not intersecting a second plane 50 which is parallel to the first plane 40. The ~gxeatest straight line distance connecting any ~wo ;~ 15 points on the circum~erential ~dge 35 is greater than ~he perpendiaular distance between the first plane 40 and the second plane 50. That is, the aross-sectional dimension D i5 greater than the height ~ of the cap poxtion 15.
Like~ise, the body portion 20 comprises an open end : 55 and an oppositely positioned~closed end 60. The open end~is de~ined~by a circumferential edge 65 whi~h lies in a ir t plane 70. Opposite the ope~ end 55 there is a c}osed end~60 having:a point or surfa~e 75 touching :25 but not:intersecting a second plane 80 which is parallel ::~ to ~h~ first plane 70. The greatest straight line distance connecting:any:two;points on the circumfere~tial edge 65 is greater ~han the perpendicular distance between the first plane 70 and the second plane 80.~:That~is,~:the cross-sectional dimension D is greater than the hei~ht ~ of the body portion 20.
~` Tablets of various sizes and shapes along with suf~icien~ non-to~ic, pharma~eutically acceptable filler material (to avoid the tablet rattling within the ~: :
s ~093/~0073 2 1 1 ~ 3 8 S PCT/US92/05~48 capsule) may be placed within cap 15 or ~ody 20 portions; however, the largest tablet must be minimally smaller than the respecti~e opening in order for the tablet to be placed within the capsule. Opti~nally, only non~toxic, pharmaceutically acceptable ~iller material is placed wi~hin a capsule to form a placebo.
In addition, ~arious powdered medications or liquid medications could be placed within a capsule to ~o~m a comparative dosage ~orm.
Normally, ~or human applications, tablets have a diameter ranging ~rom about 2 to about 16 millimeters, preferably about 5 to about 12 millimeters, with a thickness ranging between about 1 and about lO
millimeters, preferably about 2 to about 7 millimeters.
Thus, ~or human applications, it is contemplated that the croæs-sectional dimension D, i.e., the greatest straight line distance b~tween two points on the circumferential edge of the cap or body portions of the capsule, could range from about 3 to about 18 millimeters, preferably about 3 to about 13 millimeters;
In addition, it is contemplated that the o~erall length or height E of ~ e capsule~ i.e~, the distance ~etween the point or surface 45 touching the second plane o~ the .
~` cap and the point or surface 75 touching the second plane of the~body when th~e body and cap are interlocked, could range from~about 3 to about ll millimeters, preferably about 3 to about 7 millimeters. However, the cross-sectional dimension~D should be greater than or equal to the~length or~hei~hk ~. Preferably, the cr~s-section~l dimension D is greater than the ength orheight ~. Even~more preferably, the cross-sectional ~ dimension D~is at~least;1.5;times greater than length or ;~` height ~. Most preferably, the cross-sectional ` dimensîon D is at~least~2.0 times greater than the length or height~
~ i~
: ~ :
211238~
WOg3/00073 P~T/US92~05~:
Another preferred embodiment o~ ~he in~ention for human applications would have a diameter D between about 4 and about 14 millimeters and a height or length ~
between about 3 and about a millimeters. In this way, tablets of normal size (3 to 13 millimeters in diameter and ~ to 7 millimeters in thickness) may be contained within the blinded oral dosage, allowing ~or pacXing materials to avoid movement of the tabl~t within the de~ice.
Another pre~erred embodiment of the blinded oral dosage of the present invention includes a capsule ha~ing a diametex D that is larger than the diameter o~
the standard elongated cylindrical capsules.
Speci~ically, this pre~erred embodiment has a diameter of at least about 10 millimeters, vr e~en a capsule ha~ing a diameter cf at least about 11 or about 12 millimeters. Such preferred capsules are par~icularly suitable for~encapsulating tableted medications having a diameter larger than the diameter o* standàrd elongated cylindrical capsules. Tableted medications having a ~: diameter o~ at lea t 10 millimeters include the 400 mg / dosage of Motrin~ brand ibuprofen tablets, the-500 mg : dosage of ~axi~um Strength Anacin~ brand analgesic (aspi~in~ca~feine).ta~lets, ~he 250 mg dosage o~
Wya~ycin~S~brand erythromycin~stearate tablets, the ~ 500 mg~dosage~of Aralen~:Phosphate brand chloroquine :~ ~ phosphate tablets, the 500 mg dosage of Toli~as~ brand ~ t~laza~i~e~tablets as well as many other wid21y : . available medications. Other tableted medications ha~ing a diameter o~ at least 10 millimeters are .
illustrated in~ the Ph~sician's~Desk Reference, 43rd Edition, ~edical Economics Company, Inc., Oradell, New Jersey ~198~ and in The Family Physician's Compendium }Yg_5b:3 DY~ McGraw-H~ill Book Company, New York (1988~ both of which~contain actual size, full-color :: :
.
2112 3 8 ~ PCT/US92/05248 reproductions of various medications avail~ble from a ~ariety of manufacturers.
The device illustrated in ~igure Z further in d udes a female ~riction portion 85 for placing on top o~ and 5 inkerlocking with the male friction portion so o~ the body portion of the device~ The female friction portion 8~ o* the device for the abo~e-described human applications may be between about 1 and ~bout 10 millimeters lo~g, preferably between about 1 and about 5 lO millimeters long. $he male ~riction portion 9o of the device may have dimensions similar to that o~ the female friction porti~n ~5.
As shown, th~ cap portion 15 and the body portion 20 of the capsule may have rounded closed ends. The 15 radius 95 o~ the cap portion or the radius loO of the body portion of the de~ice may be, ~or human appliaatiQns, be ween abou~ 1 and about 9 millimeters.
The radius is the distance ~rom th~ midpoint o~ the area de~ined by the circumferential edge to the inside 20 surface o~ the closed end o~ the respective portion.
:~ : The radiu~ is not uni~oxm in most instances ~rom the :~ midpoint of the area defined~by the circumferential edge to ~arious points:on the i~side sur~Sace of the closed end. That is, the distance from the midpoint to one 25 point on the inside~surface ~ay ~ot be the same as the :~ distance from the midpoint~to a dif~erent point on the inside surface~ Round~ed:closed ends are preferrad to f ' ' ! f~cilitate ease~of swallowing- ' . Figure 3 ~hows a top view with midline cut-away 30 illustrating:a cylindrical or disk-shaped blinded oral dvsage fonm complete with the tablet lO contained within the capsule~5. As sh~wn, there may be a certain amount of space 105 within the ca~ity formed by interlockin~
the cap portion and:~ody portion for placement of the 35 non-toxic, pharmaceutically acceptable filler material.
`
' W~93/00073 PCT/~S9~/05 The f.iller material may keep the tablet from rattling inside the capsule and gi~ing away its exlstence.
Optionally, only non-toxic, pharmaceutically acceptable ~iller material is placed within the capsule to form a placebo~
A preferred distance from the edge of the tablet to the inside edge of either the cap ox the body portion o~
~he device ~or the abo~e-described devices suitable for human applications may be from about 0.1 to about 6 millimeters. Preferably, one or more tablets occupy at least 20 percent of the enclosed space or cavity of the capsule. More preferably, on~ or more tab~ets occupy at least 35 percent of the enclosed space of the capsule.
Evan more preferably, one or more tablets occupy at least 50 percent of the enclosed space of the capsule.
Even more preferably, one or more kable~s occupy at least 75 percent of the ~nclosed space. ~ven mor~
preferably, one or more tablets occupy at least 90 percent o~ the enclosed spaceO
As the two parts of the capsule are placed together (covering the contents~, the friction produced by the close tolerances between th~ two segments shoul~ be suficient to keep the parts ~rom disassociating during transportation and normal use. In addition 9 it should be su~fi~iently difficult to open the product to inhibit ~ research su~jects or investigators from attempting to : determîne the con~ents.
While ~he above-described illustrations describe pre~erred ~mbodiments o~ the blinded oral dosage o~ the : 30 : present in~ention, it~should be notsd that the de~ice `~ ~ may be of any shape a~d size. Thus, the circumferential edge of either the cap portion or body portion o* the capsule could be circular, ellipsoidal, squareJ
rectangular, triangular or any other circumferential multi-sided shape as well as any ~ther circumferential ~0~3/00073 ~ 3 ~ ~ PCT/U592/05~8 curvilinear shape. Likewise, while the above illustrati~ns show rounded closed ends of the cap portion ~nd the body portion, the closed ends could have flat surfaces.
~ost preferablyr the capsules o~ the present invention are of a cylindrical or di~k shape with rounded ends~ However, by use o~ the term "cylindrical", when re~erring to the capsules of the present invention, it is meant that the capsules when assembled are "non-elongated"~ The phrase "non-elongated" when referring to the pre~rred cylindrical de~ices of the present invention, means that the diameter D o~ the de~ice is greater than or equal to the length or height ~, i.e., the straight line distance from end point to end point, o~ the capsule. More speci~ically, the preferred blinded oral dosage of the present invention has a non-elongated cylindrical shape wherein the ends of the cylinder are rounded or without edges as illustrated in Figure~ 1-5. In contrast, commercially available capsules are elongated. That is, the length or height o~ commercially available capsules is ~r~ater than ~he diameter. Typically, the length to diameter ratio of commercially available capsules is betwee~ two and three.
Thus9 as used herein, an "elongated cylindrical hape" refers:to the shape o~ standard cylindrical capsules widely used in manufacturing encapsulated ' medi¢ations. Such standard elongated cylindrical haped aapsules typically ha~a rounded ends and have a length or height longer than its diameter. Examples o~
~; medications available in cap~ules ha~ing an elongated cylindri¢al shape in~lude I~OBTD9 capsule-c, TRINSICON~
: capsules, VICONFORTE~ capsules, ~MOXII~ capsules, BACTOCILL~ capsules, CLOXAPEN~ apsules, DYCILI'ID
35 capsules, TIGAN~ capsules, DECONAMIME~ apsules, ~1~2~`;t) WO 93/00~73 PCI/l)S9~/05 MEXITI~ capsules, R-TUSSX capsules O MIDXIN~ c:apsules, ACTIFED0 capsules, SUDAFED~ capsules, ZOUIRAX~ capsules, BRONTRILX cap:~;ules, HYD~OCET0 capsules and MID:RIN~
capsules. Each of the above-listed capsules as well as o~hers are available ~ia various man~acturers as set forth in the hYs~cians Desk Reference, 43rd ~dition, ~edical Economics Compa~, Ina., Oradell , New Jersey (1989), The widely a~ailable elongated cylindrical capsules are also shown in Reminqton's Pharmaceutical Sciences, 18th Edition, on Page 1658 a~ Figure 89-34, Mack ' Publishing Company, Easton~ Pennsylvania (19gO).
: The widely available elongated cylindrical capsules are also a~ailable empty and ready f~r f illing .
15 Elongated cylindrical capsules available empty and ready for filling include the ELANCO QUALICAPS~ referred to abo~e.
In contrast to the elongated cylindrical capsules, the capsules o~ ~he present inve~tion have a length (i.e. height) to diameter ratio less than or equal to one. Nonetheless, the dimensions o~ the blinded oral dosage of the presen~ invention may be o~ any size depending on:the application, just so long as the height to diameter ratio does not exceed one. For example, when administering the blinded oral dosage of th~
present invention to large animals, such as cattle sr hors s, larger dosage forms may be required. Of course, logic dictates that the si~e o~ the blinded oral dosage form depends bo~h on the size of he tablet and ~he size of the subject ingesting the dosage. Thus, any variety of sizes are~applicable:to the present invention.
: However, the cross-sectional dimension D shoula be ~` greater than or equal to the leng~h or height H.
~: Preferably,~D is greater than the height H.
~:
: : .
2 l ~ ,J ?i ~
,t093/0oo73 P~ S92/05 The t~blets placed within the enclQsed ca~ity of the blinded oral dosage ~oxm o~ the invention may be any one of a wide variety of tableted medications. Tableted medications are medications that ha~e been pressed or S otherwise formed into a solid dosage form ready for ingestion. The tableked medication may be any number o~
a wide variety of shapes currently a~ailable to those skilled in the art. In this regard, manufacturers of tableted medications manu~acture such tablets in round or cylindrical shapes, sguare shape~, rectangular shapes, triangular shapes/ o~al shapes, spherical shapes, hexagonal shapes, trapezoidal shapes, etc.;
Accordingly, any su¢h tablet ox tablet shape is suitab~e for placiny within the cavity of the blinded oral dosage ~orm~
When the cap portion is engaged with the body portion of the instant dosage form, an ~nclosed cavity is formed such that the contents of the deYic~ are not exposed to external elements present during tranæportation and handling o~ the dosage forms. The volume o~ the capsule is the enclosed cavity ~ormed by the cap and body portions o~ the capsule. The-cap portion may engage the body porti~n via any locking mechanism k~own in the a~t. Locking mechanisms are particularly:important in research studi~s as they inhibit volunteers tas w~ll as researchers) from opening capsules and discovering their contents prior t~
`~ i 1administiation. They are also importan~ in simply kseping the`two halves o~ the product from falling apart durin~ storage, transportation or usageO
Locking mechanisms may include, for example, friction-type locki~g mechanisms as shown in Fi~ur~
and 2~ The ~riction ~type l~c~ing mechanism includes ~riction produced by the close tolerance between the 3S male and female segments of the capsule.
2 1 1 2 ~
W093/00073 PCT/U~92/05240 ~igure 4 is an illustration of another embodiment of the blinded oral dosage form showing a tonyue and groove locking mechanism. In this aonfiguration, the body portion 20 of the device has accordion-shaped ridges 110 permitting it to move into the cap portion lS
of the de~ice such that ik interlocks with one or more internal indentations 115. As shown, one or more internal indentations llS or ridges 110 may be used.
Optionally t the cap portion could contai~ the ridges and the body portion could contain the internal indentation~
of the locking mechanism~
If the male section has two or more internal indentations or ridges, any one of the ridges could be locked onto depending on the thickness of the tablet lS contained inside. This would allow the tablet-shaped : capsule to have one, two or more thickness~s to accommodate tablets of various thickness or even multipl~ tablets being encapsulated within the product.
Ob~iously, for any given study, all tablet-shaped capsules would be of identical thickness, with more or less filler present depending upon the space occupied py the tablet(s~ encapsulated.
The cro~s-section o~ the ridges or the internal indentation may have a profile which is curved or angular, and may range in shape, for example, from a single to a ~multiple radius design, or from a V-shape to a multi-angular shape, such as for example a square, rectangular, trapezoidal, etc. shapes. Examples ,of such tongue and groove-type locking mechanisms are illustrated in U.S. Patent 4,882,618.
As with the ~'tongue and groove" and "friction"
locking mechanisms, a "flexible lipl' could ~lso b~ used : as a means~of maintaining the integrity of a tablet-shaped capsule as described above. Fiqure~ S~
3s and SB provide an illustration of another embodiment of the .
SUBSTITUTE SHEE~
~112~5 ' 'NO93/00073 PCT/US92/052q8 oral dosage form of ~he invention containing a flexible lip txpe locking mechanism. In this ~orm, the cap portion 15 o~ ~he de~ice would fit over the body portion 20 o~ the de~ice or viae versa. Bo~h the cap and body portions of ~he device contain a portion of the "fl~xible lip" locking mechanism. ~ach portion o~ the locking mechanism is rounded on the edge in such a way as to allow the bod~ porti~n 20 o~ the locking mechanism (which is s~ightly smaller) to slip into the cap portion 15 o~ the locking mechanism~ The larger rounded edge o~
the cap portion 15 of the locking mechanism is suf~iciently flexible to expand and slip over t~e smaller but similarly rounded edge of the body portion 15 o~ the locking mechanism and due to the overla~, lock both segments together.
Additional locking mechanisms could incl~de screw-type locking mechanisms and external fasteners.
Accordinglyr any locking mechanism in existence for standard capsule shapes could be utilized for the blinded oral dosage o~ ~he present invention as long as it insures the;integrity o~ the dosage ~orm during no~mal h~ndling.
Additionally,~it is noted that each of the above-mentioned locking mechanisms may allow locking of the ` 25 ~apsules at ~arious thicknesses so tablets of various icknesses could be encapsulated along with fillers.
The blinded oral dosage form may also include ~axious wraps~or tapes conventionally used with standard gelati~ capsules to insur~ that the de~ice is not tampered with prior to administration. It may be ~;~ desired to apply à sealiDg band to an assembled dosage orm, to prevent~leakage in the case of any possible powder or liquid fillings, or to render the capsule tampér-evident or tamper resistant or for identification purposes. This may be a~hieved using known methods and .
211h3~3S
equipment, such as, ~or example, the Quali-Seal machine (Manu*acturing Chemist, Jan~ 1987, p. 27).
Preferably, the body and cap portions of the blinded oral dosage form of the present in~ention are made of a hard gelatin and could be manufactured on existing equipment with modifications to dies and other p~rts of those or similar machines. Optionally, the capsules o~ the present in~ention could be m~de of so~t gelatin or any other ma~erial used to make conventional capsules.
By wa~ o~ illustration, hard gelatin capsules may be made in two parts by dipping stainless steel pins into a molten gelatin solution, and all~wing the gelatin to set and dry. It is generally known that the gelatin film, as it dries, also undergoes shrinkage. The shrinkage depends on a number of factors such as the amount of water to be eliminated, the gelatin used, the : drying regime and the number and type of additi~es such as dyes, other colorants, opacifiers, plasticizers, viscosit~ builders or surfactants which may be included within the gelatin compositions o~ the present invention . Such pxocesses and compositions are-well ~own in the ~art, for example, see The Theory and ~ Practice of Industrial Pharmacy, 3rd Ed., Lea h Febiger, : 25 Philadelphia~(1986) and Reminaton's Pharmaceutical ; Sciences, 18th Edition, Mack Publishing Company, Easton, : Pennsylvania (1990)~
I ' In addition, the body~and cap portions of ~he blinded oral dosage~form may~be made of materials that :~: 30 are soluble in:alkaline intestinal secretions but substantially insoluble in~and resistant to acid secretions of the stoma~h.; Such~materials are commonly referred to as ha~ing enteric properties. The enteric dosage forms may be made, for~:example, by dip-molding : 35 using a homogeneous film-forming mixture comprising (1) ~ t 1'~
,,,................................... ., , ~
' yo 93/00073 PCr/US92/05248 gelatin and an ammonium salt o~ hydroxypropyl methylcelluose phthalate polymer, or ~2) hydroxypropyl methylcelluose and an ammonium sal~ of cellulose aceta te ph~halate pol~mer, or (3) gelatin and an ammonium salt o~ a copolymer of methacrylic acid and methacrylia acid ester optiQnally in co~binakion with additional ingredients such as plasticizers~ surfactants and coloring agen~s. The above compositions are described, ~or example, in more deti~il in U.S. Paten~ 4,138,013.
Likewise, many other ingestible materîals may be used to make the cap and body portions of the ~lindea oral dosage form of the present invention. Preferably, howe~er, the ca~sules are made o~ a hard gelatin composition.
Aæ a result o~ the non-elongated shape of the blinded oral dosage form, it is also suitable ~or coating with pharmaceutical grade materials in standard tablet coating bins (unlike a standard elongated shaped : capsule which does not tumble appropriately for coating : 20 purposes). me dosage forms of the present invention : may tumbl~ exactly like a standard tablet and may thereby coat as easily as any tablet depending sn the pa~ticular embodiment. Coatings (or multiple coatiny : layers) of~various degre~s o~ hardness, thickness or solubility~would be aesthetically pleasing and have standard pharmaceutical qualities regarding dissolution rate, ea~e of~swallowing and manu~ac~uring advantages.
Pref~rred embodiments of the blinded oral dosage form could be: coated by a standard tablet coating 30 proc:ess such as described,: for example, in :Reminqton's : Pharmaceutical Sciences, 18th Edition, ~hapter 90, ~: "Coatinq O* Pharmaceutical Dosage Forms", Mack Publishing Company, East~3n, Pennsylvania (19gO).
In addition~: to t~e above advantages, one or more 35 coatings may provide a: "tam~er proof" blinded oral 2 1 1 h 'J) ~
W~93~0~073 PCT/US92/05 dosage foxm as opening would break ~he coating. The broken coating material would be difficult, if not impossible, to restore to its original character and would be an obvious signal to khe investigaitors or 5 subj ects ingesting the device not to use the product.
The break could be made more ob~ious in many ways including use of layered coverings of different colorings, highly friable c~ating materials or unusual colors. The coating could also help maintain the inteyrity o~ the product during both research and commiercial use. ~lso, the coating may be used in conjunction with an external wrap or tamper resistant tape that protects the de~ice~ Additionally, it is also possible to utilize a number o* coating compounds or active agents in the coating ~omp~sition ko achieve a ~: desired e~fect. For instance, an enteric coating can be applied as one layer or in combination with another coating solutio~.
The method of the pxesent inYention includes 2Q pxeparing blinded ta~leted medications. ~n particular"
the method:includes~disgui~ng a tableted medication by plaaing the medication in a non-elongated ¢apsule, i.e., a capsule of ~he present:invention having a cross-, sectionial dimension D yreater than or egual ~o its length or height ~
This method pro~ides a~means ~or disguising ~: taibIeted:medications in~a qapsule more readily adapted for tableted~medications. Thus, standard elongated capsules which~are overly large in relation to the ~ tableted medications are not necessary. In fact, themethod includes disguising one~or more tablets that occupy at:least 20 percent, more pre~erably at least 35 percent, more preferably at least 50 percent~ more `:~ : preferably at least 75 percent or most preferably at.
:
21~ 238~
~093~00073 PCT/VS92/05 least 90 percent of the enclosed space or cavity of the capsule.
The method may further include placing one or more no~-toxic, pharmaceutically acceptable filler materials within the aavity o~ the capsule to prevent the tablet from rattling inside the capsule. ~his prevents researchers or subjects from distinguishing between capsules containing tabl~ts o~ various sizes, or between those containing tablets and those cQntaining non-tableted medications or fillers only ~i.e., placebos).Optionally, only non-toxic, pharmaceutically acceptable filler is placed within ~he capsules of the present invention to form a placebo. Suitable non-toxia, pharmaceutically acceptable filler material, including sugars and starchest: would be apparent to those skilled in the art.
Additionally, the method may fuxther include : applying one or more coatings covering the capsule.
Certain coatings may be applied either be~ore or after the tablet i8 placed within the capsule. I~ the case , ~: wherein the capsules are precoated, the method of the preserdt i~vention includes a:5imple and easy means for : encapsulating a tableted~medication to provide a desir~d .
coating without the need~to coat the tablet itself. In the case wherein the~capsules are coated after filling, :~ the closed:~capsule, unlike~standard elongated capsules, ~ may be coated according to co~ventional tablet coating ` tl~mbIe plrocesses and in conventional tablet coating ~:~ equipment. ; ~
: FU ~ ermore~, the~method of t~e present invention is :~ ~ particularly ~uitable *or comparing two dif~erent . :medications, i.e., one:tableted medication and another medication whi~h may or may not be tableted. Comparing :;: two different medications would include making a first : 35 ~ blinded oral dosage ~orm by disguising a first tahle~ed :~ :: : :
3 ~ '~
WOg3/0~073 PCT/US92/05 medication in a non-elongated capsule and making a second blinded oral dosage form by disguising a second medication (either tableted or not) in a non-elongated capsule having subs~antially the same size and shape as the ~irst blinded oral dosage ~orm.
Thus, the method o~ the present inYention further pro~ides a means for disguising or blinding one or more medications of differ~nt shapes and sizes, e~g., one large and one small, or even the same medication in different forms or amounts. The method in such case may include placing the large tableted medication in a capsule of the present in~ention of large enough size to hold the tableted medicatio* and placing a smaller tableted medication in a capsule identical to the capsule in which the larger tableted medication was placed. In this way, the person conducting the clinical ..
trial and the subject ing~sting t~e blinded oral dosage would not know what medication, form of medication or amount of medication was administered. By use of this method, two~medications o~ su stantially different siz~
or shape or~the same~medication in~di~ferent forms or amounts could be readily compared.
The method of the precent inventisn is also suitable for analyz~ing one~tableted medication as compared to a second dosa~e form which does not contain an e~fective medication. ~Analyzing sne tableted medication~may include making a first blînded oral dosage foxm by~disguising a;~irst tableted medication in a non-elongated capsule~and making a second blinded oral dosage form ha~ing;substantially the same size and shape as the first blinded~oral~dosage that does not contain an ef~ective medication, i.~e., a placebo.
From the~;*oregoing description, one of ordinary sk;ll in the art can easily~ascertain the essential ; 3S characteristics of the instant invention, and without : `
: :
: ~ :
!093~00073 21~ 2 ~ 3 ~ PCT/US92/05~
departing from the spirit and scope thereof, can make various change~ and/or modi~ications of the invention to adapt it to various usages and conditionæ~ As such, these changeæ and/or modifications are properly, e~uitably and int~nded to be~ within the full range of e~uivalents of the following claims.
I
`: ` : ::
:: : :
Claims (63)
1. A method for conducting a blinded study comprising:
(a) placing a first non-toxic, pharmaceutically acceptable composition within a capsule having a body portion and a cap portion, said capsule having a diameter greater than or equal to its height when closed, and then closing said capsule, to form a first blinded oral dosage form;
(b) placing a second non-toxic, pharmaceutically acceptable composition within a substantially identical capsule, and then closing said capsule, to form a second blinded oral dosage form, (c) administering said first blinded oral dosage form to a subject; and (d) administering said second blinded oral dosage form to said subject or to another subject.
(a) placing a first non-toxic, pharmaceutically acceptable composition within a capsule having a body portion and a cap portion, said capsule having a diameter greater than or equal to its height when closed, and then closing said capsule, to form a first blinded oral dosage form;
(b) placing a second non-toxic, pharmaceutically acceptable composition within a substantially identical capsule, and then closing said capsule, to form a second blinded oral dosage form, (c) administering said first blinded oral dosage form to a subject; and (d) administering said second blinded oral dosage form to said subject or to another subject.
2. The method as claimed in Claim 1, wherein said first non-toxic, pharmaceutically acceptable composition comprises a tableted medication.
3. The method as claimed in Claim 2, wherein said second non-toxic, pharmaceutically acceptable composition comprises a tableted medication.
4. The method as claimed in Claim 3, wherein the first tableted medication comprises an active ingredient which is different from the active ingredient in the second tableted medication.
5. The method as claimed in Claim 3, wherein the first tableted medication comprises the same active ingredient as in the second tableted medication, but the dosage levels are different.
6. The method as claimed in Claim 2, wherein said second non-toxic, pharmaceutically acceptable composition comprises a non-tableted medication.
7. The method as claimed in Claim 2, wherein said second dosage form is a placebo.
8. The method as claimed in Claim 2, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
9. The method as claimed in Claim 8, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
10. The method as claimed in Claim 1, further comprising applying one or more coatings to the closed capsule of each of said blinded oral dosage forms.
11. The method as claimed in Claim 2 wherein said first non-toxic, pharmaceutically acceptable composition further comprises a non-toxic, pharmaceutically acceptable filler material.
12. The method as claimed in Claim 1, wherein said body and cap portions are interlocking.
13. The method as claimed in Claim 2, wherein said body and cap portions have a diameter of at least 10 millimeters.
14. A method for blinding a tableted medication comprising placing said tableted medication within a capsule having a body portion and a cap portion, said WO 93/00073 PCT/US92/052??
capsule having a diameter greater than or equal to its height when closed, and then closing said capsule.
capsule having a diameter greater than or equal to its height when closed, and then closing said capsule.
15. The method as claimed in Claim 14, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
16. The method as claimed in Claim 15, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
17. The method as claimed in Claim 14, further comprising applying one or more coatings to the closed capsule.
18. The method as claimed in Claim 14, further comprising adding a non-toxic, pharmaceutically acceptable filler material prior to closing said capsule.
19. The method as claimed in Claim 14, wherein said body and cap portions are interlocking.
20. The method as claimed in Claim 14, wherein said body and cap portions have a diameter of at least 10 millimeters.
21. A method for blinding a tableted medication comprising placing said tableted medication within a capsule having a body portion and cap portion, said body portion comprising an open end and an oppositely positioned closed end, said open end being defined by a circumferential edge said circumferential edge lying in a first plane, said body portion being configured such that the greatest straight line distance connecting two points on said circumferential edge is greater than the perpendicular distance between said first plane and a second plane which contacts an outer surface of the closed end of the body portion and which is parallel to the first plane; and then closing said capsule.
22. The method as claimed in Claim 21, wherein said body and cap portions are interlocking.
23. The method as claimed in Claim 21, wherein said cap portion comprises an open end and an oppositely positioned closed end, said open end being defined by a circumferential edge, said circumferential edge lying in a first plane, said cap portion being configured such that the greatest straight line distance connecting two points on said circumferential edge of said body portion is greater than the perpendicular distance between said second plane of said body portion and a second plane of the cap portion which contacts an outer surface of the closed end of the cap portion and which is parallel to the first plane of the cap portion.
24. The method as claimed in Claim 21, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
25. The method as claimed in Claim 24, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
26. The method as claimed in Claim 21, further comprising applying one or more coatings to the closed capsule.
27. The method as claimed in Claim 21, further comprising adding non-toxic, pharmaceutically acceptable filler material prior to closing said capsule.
28. The method as claimed in Claim 21, wherein said greatest straight line distance is at least 10 millimeters.
29. A method for blinding a tableted medication comprising placing said tableted medication within a cylindrical capsule having interlocking cylindrical body and cap portions, said body portion comprising an open end and an oppositely positioned closed end, said open end being defined by a circumferential edge, said circumferential edge lying in a first plane, said body portion being configured such that the greatest straight line distance connecting two points on said circumferential edge is greater than the perpendicular distance between said first plane and a second plane which contacts an outer surface of the closed end of the body portion and which is parallel to the first plane;
and then closing the capsule.
and then closing the capsule.
30. The method as claimed in Claim 29, wherein said cap portion comprises an open end and a closed end, said open end being defined by a circumferential edge, said circumferential edge lying in a first plane, said cap portion being configured such that the greatest straight line distance connecting two points on said circumferential edge of said body portion is greater than the perpendicular distance between said second plane of said body portion and a second plane of the cap portion which contacts an outer surface of the closed end of the cap portion and which is parallel to the first plane of the cap portion.
31. The method as claimed in Claim 30, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
32. The method as claimed in Claim 31, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
33. The method as claimed in Claim 29, further comprising applying one or more coatings to the closed capsule.
34. A dosage form comprising a capsule and, within said capsule, a tableted medication, said capsule having an interlocking body portion and cap portion, said capsule having a diameter greater than or equal to its height when closed.
35. The dosage form as claimed in Claim 34, wherein the volume of the closed capsule which is unoccupied by the tableted medication is occupied by a quantity of non-toxic, pharmaceutically acceptable filler material sufficient to prevent substantial movement the tablet within the capsule.
36. The dosage form as claimed in Claim 35, wherein said filler material occupies substantially all of the volume of the closed capsule which is unoccupied by the tableted medication.
37. The dosage form as claimed in Claim 34, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
WO 93/00073 PCT/US92/052??
WO 93/00073 PCT/US92/052??
38. The dosage form as claimed in Claim 37, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
39. The dosage form as claimed in Claim 34, having a diameter of at least 10 millimeters.
40. A dosage form comprising a capsule and, within said capsule, a tableted medication, said capsule comprising an interlocking body portion and cap portion, said body portion comprising an open end and an oppositely positioned closed end, said open and being defined by a circumferential edge, said circumferential edge lying in a first plane, said body portion being configured such that the greatest straight line distance connecting two points on said circumferential edge is greater than the perpendicular distance between said first plane and a second plane which contacts an outer surface of the closed end of the body portion and which is parallel to the first plane.
41. The dosage form as claimed in Claim 40, wherein said cap portion comprises an open end and an oppositely positioned closed end, said open end being defined by a circumferential edge, said circumferential edge lying in a first plane, said cap portion being configured such that the greatest straight line distance connecting two points on said circumferential edge of said body portion is greater than the perpendicular distance between said second plane of said body portion and a second plane of the cap portion which contacts an outer surface of the closed end of the cap portion and which is parallel to the first plane of the cap portion.
42. The dosage form as claimed in Claim 40, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
43. The dosage form as claimed in Claim 42, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
44. The dosage form as claimed in Claim 40, wherein the shape of said circumferential edge is round, oval, triangular, square or other multi-sided shape.
45. The dosage form as claimed in Claim 40, wherein said greatest straight line distance is at least 10 millimeters.
46. The dosage form as claimed in Claim 40, further comprising one or more coatings on said capsule.
47. The dosage form as claimed in Claim 40, wherein said capsule further comprises a locking means.
48. The dosage form as claimed in Claim 47, wherein said locking means is a friction-type locking means, tongue and groove-type locking means, curved lip-type locking means, or screw-type locking means.
49. A dosage form comprising a capsule and, within said capsule, a tableted medication, said capsule comprising interlocking cylindrical body and cap portions, said body portion comprising an open end and an oppositely positioned closed end, said open end being defined by a circumferential edge, said circumferential edge lying in a first plane, said body portion being configured such that the greatest straight line distance connecting two points on said circumferential edge is greater than the perpendicular distance between said first plane and a second plane which contacts an outer surface of the closed end of the body portion and which is parallel to the first plane.
50. The dosage form as claimed in Claim 49, wherein said cap portion comprises an open end and an oppositely positioned closed end, said open end being defined by a circumferential edge, said circumferential edge lying in a first plane, said cap portion being configured such that the greatest straight line distance connecting two points on said circumferential edge of said body portion is greater than the perpendicular distance between said second plane of said body portion and a second plane of the cap portion which contacts an outer surface of the closed end of the cap portion and which is parallel to the first plane of the cap portion.
51. The dosage form as claimed in Claim 50, wherein said closed end of said body portion is rounded.
52. The dosage form as claimed in Claim 50, wherein said tableted medication occupies at least 35 percent of the volume of the closed capsule.
53. The dosage form as claimed in Claim 50, wherein said tableted medication occupies at least 50 percent of the volume of the closed capsule.
54. The dosage form as claimed in Claim 50, wherein the shape of said circumferential edge is round or oval.
55. The dosage form as claimed in Claim 50, wherein said closed end of said body portion and said closed end of said cap portion are rounded.
56. The dosage form as claimed in Claim 50, wherein said capsule is coated with one or more coatings.
57. The dosage form as claimed in Claim 50, wherein said capsule further comprises a locking means.
58. The dosage form as claimed in Claim 57 J
wherein said locking means is a friction-type locking means, tongue and groove-type locking means, curved lip-type locking means, or screw-type locking means.
wherein said locking means is a friction-type locking means, tongue and groove-type locking means, curved lip-type locking means, or screw-type locking means.
59. A dosage form comprising a tableted medication within a capsule, the capsule including a body portion and a cap portion, said cap portion and said body portion being hollow and having an open end, said body portion and said cap portion having means which interfit with one another so that said body portion and said cap portion can be brought towards one another along an axis with their open ends facing one another and connected to one another to define the capsule, the capsule having a cavity formed by the hollow body portion and the hollow cap portion and said tableted medication being disposed within the cavity, said capsule having a height as measured along said axis and a diameter as measured perpendicular to said axis, the height of the capsule being less than the diameter of the capsule as measured from an outer surface of the capsule.
60. The dosage form as claimed in Claim 59, wherein said cap portion and said body portion define an WO 93/00073 PCT/US92/052??
enclosed space or cavity and said tablet occupies at least 35 percent of the volume of the enclosed space or cavity of the closed capsule.
enclosed space or cavity and said tablet occupies at least 35 percent of the volume of the enclosed space or cavity of the closed capsule.
61. The dosage form as claimed in Claim 60, wherein said one tablet occupies at least 50 percent of the volume of the closed capsule.
62. The dosage form as claimed in Claim 59, wherein said capsule is coated with one or more coatings.
63. The dosage form as claimed in Claim 59, wherein said capsule further comprises one or more non-toxic, pharmaceutically acceptable filler materials.
Applications Claiming Priority (2)
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|---|---|---|---|
| US722,155 | 1991-06-27 | ||
| US07/722,155 US5314696A (en) | 1991-06-27 | 1991-06-27 | Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor |
Publications (1)
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|---|---|
| CA2112385A1 true CA2112385A1 (en) | 1993-01-07 |
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| CA002112385A Abandoned CA2112385A1 (en) | 1991-06-27 | 1992-06-26 | Methods for making and administering a blinded oral dosage form and blinded oral dosage form therefor |
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| EP (1) | EP0591421A4 (en) |
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| CA (1) | CA2112385A1 (en) |
| WO (1) | WO1993000073A1 (en) |
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| US4743248A (en) * | 1986-08-11 | 1988-05-10 | Alza Corporation | Dosage form for delivering acid sensitive beneficial agent |
| EP0275468B1 (en) * | 1986-12-20 | 1991-02-06 | Roche Diagnostics GmbH | Pharmaceutical compositions containing clodronate, and process for their preparation |
| US4820524A (en) * | 1987-02-20 | 1989-04-11 | Mcneilab, Inc. | Gelatin coated caplets and process for making same |
| US4973480A (en) * | 1987-03-25 | 1990-11-27 | K.V. Pharmaceutical Co. | Tamper evident pharmaceutical capsule |
| US4857313A (en) * | 1987-05-28 | 1989-08-15 | Warner-Lambert Company | Transdermal drug delivery device comprising copolymers of N-morpholinoethyl methacrylate and 2-hydroxylmethacrylate |
| US4795644A (en) * | 1987-08-03 | 1989-01-03 | Merck & Co., Inc. | Device for pH independent release of drugs through the Donnan-like influence of charged insoluble resins |
| US4886668A (en) * | 1987-09-24 | 1989-12-12 | Merck & Co., Inc. | Multiparticulate controlled porosity osmotic pump |
| US4978521A (en) * | 1990-01-03 | 1990-12-18 | John Duncan Blue | Color coded flavored dentifrice toothpowders |
| US5089270A (en) * | 1990-05-15 | 1992-02-18 | L. Perrigo Company | Capsule-shaped tablet |
| US5260069A (en) * | 1992-11-27 | 1993-11-09 | Anda Sr Pharmaceuticals Inc. | Pulsatile particles drug delivery system |
-
1991
- 1991-06-27 US US07/722,155 patent/US5314696A/en not_active Expired - Lifetime
-
1992
- 1992-06-26 JP JP5501595A patent/JPH06508633A/en active Pending
- 1992-06-26 EP EP92914751A patent/EP0591421A4/en not_active Withdrawn
- 1992-06-26 CA CA002112385A patent/CA2112385A1/en not_active Abandoned
- 1992-06-26 AU AU22940/92A patent/AU672754B2/en not_active Ceased
- 1992-06-26 WO PCT/US1992/005248 patent/WO1993000073A1/en not_active Application Discontinuation
-
1994
- 1994-04-15 US US08/228,254 patent/US5558878A/en not_active Expired - Lifetime
-
1995
- 1995-06-07 US US08/487,511 patent/US5576019A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US5558878A (en) | 1996-09-24 |
| JPH06508633A (en) | 1994-09-29 |
| AU672754B2 (en) | 1996-10-17 |
| US5576019A (en) | 1996-11-19 |
| WO1993000073A1 (en) | 1993-01-07 |
| EP0591421A1 (en) | 1994-04-13 |
| US5314696A (en) | 1994-05-24 |
| EP0591421A4 (en) | 1997-05-07 |
| AU2294092A (en) | 1993-01-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |