CA1277913C - Oral pharmaceutical composition - Google Patents
Oral pharmaceutical compositionInfo
- Publication number
- CA1277913C CA1277913C CA000511153A CA511153A CA1277913C CA 1277913 C CA1277913 C CA 1277913C CA 000511153 A CA000511153 A CA 000511153A CA 511153 A CA511153 A CA 511153A CA 1277913 C CA1277913 C CA 1277913C
- Authority
- CA
- Canada
- Prior art keywords
- cellulose
- composition according
- mucosa
- granules
- drug
- 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.)
- Expired - Fee Related
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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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Abstract
ABSTRACT
A sustained release, oral pharmaceutical composition in solid unit dosage form, for application to the mucosa of the oral or nasal cavity, comprises compressed, mucosa adhesive cellulose, coated granules, the granules comprising a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
Preferably the composition is in the form of a buccal tablet, especially a kidney shaped buccal tablet. Preferred materials are morphine as the drug, hydroxypropyl cellulose as the mucosa adhesive cellulose, cetostearyl alcohol as the aliphatic alcohol and hydroxyethyl cellulose as the water soluble cellulose.
The composition has enhanced adherent properties (to the mucosa) and prolongs the bioavailability of the drug.
A sustained release, oral pharmaceutical composition in solid unit dosage form, for application to the mucosa of the oral or nasal cavity, comprises compressed, mucosa adhesive cellulose, coated granules, the granules comprising a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
Preferably the composition is in the form of a buccal tablet, especially a kidney shaped buccal tablet. Preferred materials are morphine as the drug, hydroxypropyl cellulose as the mucosa adhesive cellulose, cetostearyl alcohol as the aliphatic alcohol and hydroxyethyl cellulose as the water soluble cellulose.
The composition has enhanced adherent properties (to the mucosa) and prolongs the bioavailability of the drug.
Description
~2r79~3 ORAL PHARMACEUTICAL COMPOSITION
The present invent;on relates to a sustained release, oral pharmaceutical composition and, in particular, to an oral vehicle adapted for application to the mucosa of the oral or nasal cavity, especially within the buccal cavity.
The administration of drugs using oral vehicles retained in the buccal cavity is known. Such administration is generally effected by inserting an oral vehicle (e.g. a tablet) containing a drug into the buccal cavity of the patient's mouth and then pressing the vehicle against the mucosa of the cheek or the gum until it adheres.
Absorption of the drug in the vehicle generally occurs directly through the mucosa at the inner surface of the cheek and/or gum into the pat;ent's bloodstream. In some cases, however, the drug may be absorbed gastr;cally or enterally by the absorpt;on of drug contained in swallowed saliva.
2û
The buccal method of drug admin;strat;on has considerable advantages over administration by, for example, swallowing a tablet or injection. One advantage is that administration can be discontinued at any time (e.g. when undesired effects arising from the administration are identified) simply by removing the remainder of the vehicle. Another advantage, ovor-oral administration, is that first pass, drug metabolism may b avoided.
A particular problem associated with the buccal administration of drugs, ho~ever, is that the oral vehicle containing the drug tends, after a period, to become detached from the mucosa. At best this can be merely inconvenient, at worst it may lead to the patient swallow;ng the veh;cle.
~27 79~3 It is an object of the present invention to provide a sustained release, oral pharmaceutical composition having improved properties of adherence to the mucosa within the oral or nasal, especially buccal cavity.
It is a further object of the present invention to provide an oral vehicle prepared from the improved composition and shaped to facilitate attachment within the buccal cavity.
Further objects and advantages of the present invention will become apparent from the following detailed description thereof.
According to the present invention, therefore, there is provided a sustained release, oral pharmaceutical composition in solid unit dosage form, for application to the mucosa of the oral or nasal cavity, comprising compressed, mucosa-adhesive cellulose coated granules, the granules comprising a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
Preferably the solid unit dosage form is an oral vehicle for attachment within the buccal cavity.
. ~ .
It is an important feature of the present invention that the granules used to prepare the solid unit dosage form (e.g.
tablet) comprise extragranular mucosa-adhesive cellulose which improves the attachment of the dosage form to the oral or nasal mucosa, especially within the buccal cavity.
Preferably the extragranular, mucosa adhesive cellulose is applied to the granules in the form of a powdered solid rather than a solution. This allows greater control over the water content of the granules, avoids swelling of the lZ~9i3 granules and also avoids an unnecessary drying step.
The present inventors have surprisingly found that by employing extragranular cellulose adhesive, especially powdered adhesive, the adherent properties of the resulting dosage form are significantly greater than those of a dosage form having intragranular adhesive only.
The mucosa adhesive cellulose may be, for example, a carboxyalkyl cellulose, such as sodium carboxymethyl cellulose or a hydroxyalkyl cellulose, such as hydroxypropylmethyl cellulose. Preferably, however, hydroxypropyl cellulose (HPC), espec;ally that sold by the Hercules Powder Company as Klucel HF (Trade Mark), is the mucosa adhesive material.
Preferably, the mucosa adhesive cellulose is a high molecular weight material having a number average molecular weight above 200,000, especially above 500,000.
Surprisingly, when HPC is employed as the adhesive in the present formulation ;t is found to give the dosage form adhesive properties superior to those ach;eved using previously preferred adhesives, such as Karaya gum and acrylic acid polymers (e.g. carbopol gel) or mixtures of these adhesives with other knovn binders.
The concentration of extragranular adhesive cellulose (as a proportion of the total dosage form weight) is preferably between 2X and 15X (w/w), especially between 4X and 10X (w/w).
Prior to compression, the granules coated with mucosa-adhesive cellulose will, preferably, have a granule size of less than ~oOOr.
, ~
4 12~79~3 The higher aliphatic alcohol is an aliphatic alcohol containing from 8 to 18 carbon atoms which is optionally substituted by a further aliphatic group containing from 8 to ~ 18 carbon atoms. Suitable alcohols include lauryl alcohol, myristyl alcohol, stearyl alcohol, or, which is preferred, cetyl alcohol and cetostearyl alcohol. The higher aliphatic aLcohol, together with the water soluble hydroxyalkyl cellulose, serves to control the release of the drug from the composition. The level of alcohol in the composition will therefore be determined by the rate of drug release required.
GeneralLy, however, the composition will contain between 5X
and 35X ~w/w), espec;ally 10% and 30% (w/w), (as a proportion of the total dosage form weight) of the higher aliphatic alcohol.
The hydroxyaLkyl cellulose is a hydroxy lower alkyl ether of cellulose and is preferably selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxypropylmethyl cellulose, with hydroxyethyl cellulose (for example Natrosol 250 HX, Trade Mark, Hercules Powder Company) being particularly preferred. The hydroxyalkyl cellulose, together with the higher aliphatic alcohol, serves to control the release of the drug from the composition. The level of hydroxyalkyl cellulose in the composition will therefore be determined by the rate of drug release required.
Preferably the composition will contain between 2% and 15X
~w/u), as a proportion of the total dosage form weight, of the hydroxyalkyl cellulose.
It should be noted that when the water-soluble hydroxyalkyl cellulose used in the present composition is also the composition's mucosa adhesive, then the amount of hydroxyalkyl cellulose present in each dosage form is at least the sum of the hydroxyalkyl cellulose added as water-soluble hydroxyalkyl . .
. 1Z779i3 cellulose and the hydroxyalkyl cellulose added as extra-granular adhes;ve.
The drug employed in the present composition is preferably absorbable through the oral or nasal mucosa. In some instances, however, drugs that are absorbed gastrically and/or enterically (rather than via the mucosal route) may be employed. In a still further instance, the drug may be one that acts locally in the mouth, for example in the treatment of mouth ulcers. Suitable medicaments will be well known to those skilled in the pharmaceutical art. Listed below are certain of the drug categories within which are classed a number of the drugs that may be employed in the present composition.
(a) Analgesic agents; e.g. morphine, or analogues thereof, phenazocine, pentazocine, buprenorphine;
(b) Anti-inflammatory agents; e.g. ibuprofen, indomethacin, acetaminophen, phenacetin, aspirin, aminopyrine, sulpyrine, phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, colchicine, probenecid, ethenzamide, salicylamide, ketoprofen, flurbiprofen, diclofenac, clidanac, alclofenac, sulindac, piroxicam;
(c) Antihistamines, e.g. clemastine fumarate, mepyramine, diphenylhydramine hydrochloride, dexchlorpheniramine maleate;
(d) Topical anaesthetics, e.g. benzocaine, procaine, lidocaine;
(e) Vasodilators, e.g. nitroglycerin, nifedipine, papaverine, isosorbide dinitrate, diltiazem, nicardipine;
. ~
`~` 6 1 2 ~ 9 1 3 (f) Antitussives and expectorants, such as codeine phosphate and isoproterenol hydrochloride;
(g) Hormones; e.g. insulin, vasopressin and heparin;
(h) Diuretics, e.g. ethacrynic acid and bendrofLuazide;
(i) Anti/hypotensives, e.g. propranolol and clon;dine;
(j) Anti-neoplastic agents, e.g~ cytarabine and doxorubicin;
(k) Antidiabetic drugs, e.g. chlorpropamide and glibenclamide;
5 (l) Bronchodilators, such as albuterol (salbutamol), ipratropiumbromide;
(m) Antiarrythm;c agents, e.g. verapamil;
(n) Ant;-inflammatory steroids, e.g. hydrocortisone, prednisone, prednisolone, triamc;nolone, dexamethasone, betamethasone;
(o) Antib;ot;cs or Fung;c;des, e.g. tetracyclines, Z5 leucomyc;ns, fradiomycins, pen;c;ll;ns, cephalospor;ns, erythromycins;
tp) Chemotherapeutic agents, e.g. sulphathiazole, nitrofurazone, clotr;mazole;
~q) Card;ac ton;cs, e.g. digital;s, digoxin;
~r) Oral antiseptics, e.g. chlorhexidine, hexylresorc;nol, dequalin;um chloride and ethacridine;
7 1~779~3 ~s) Antiasthmatics, e.g. disodium cromoglycate;
(t) Drugs acting on the central nervous system, e.g. diazepam - and estazolam;
(u~ Anti-epileptics, e.g. phenytoin, meprobamate and nitrazepam;
(v) Anticholinergics, e.g. scopolamine;
(w) Muscle Relaxants e.g. baclofen, dentrolene sodium, cyclobenzaprine hydrochloride;
(x) Beta-blocker, e.g. pindolol;
~y) Antiarteriosclerotic agents, e.g. clofibrate, pentoxifylline;
(z) Drugs for treatment of ulcers, e.g. cimetidine, ranitidine;
Other, e.g. nicotine.
It will be apprec;ated that the drug may be added to the present composition not only in ;ts free form, but also as a s;mple pharmacolog;cally acceptable der;vat;ve, such as an ethor, an ester, an amide, an acetal, a salt and the like. In so~e cases, such derivatives may actually be preferred.
Particularly preferred drugs for use in the present composition are morph;ne, n;fed;pine, phenazocine, verapamil and salbutamol.
These drugs can be used either singly or as a mixture of two i2779~3 _ 8 or more. The amount of drug to be blended in a solid dosage unit will generally be enough to maintain a therapeutic level of the drug in the bloodstream for a predetermined period~
In addition to the constituents discussed above, the present pharmaceutical composition may also contain certain of the known excipients, such as lubricants, binders, vehicles, colouring agents, taste controlling agents and odour controlling agents, that are employed to improve the appearance, odour or taste of pharmaceutical preparations.
In a particularly preferred embodiment of the present composition, the granules contain between 2% and 15X (w/w), especially between 4% and 10X (w/w), of a binder to improve the binding and strength of the dosage form. Suitable binders include starch, dextrin, tragacanth, ge~atin, polyvinylpyrrolidone, polyvinylalcohol or, which is especially preferred, a mucosa adhesive cellulose such as a carboxyalkyl cellulose or a hydroxyalkyl cellulose especially sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose or, most especially, hydroxypropyl cellulose. Compositions according to this invention having both extragranular adhesive cellulose and intragranular adhesive cellulose (as binder) have been found to exhibit particularly good qualities of adhesion and strength.
It should be noted that when the same cellulosic material ;s used in the present composition as the water soluble hydroxyalkyl cellulose, the extragranular mucosa adhesive 3û cellulose and the binder, then the amount of cellulosic material present in each dosage form is at least the sum of that added as water-soluble hydroxyalkyl cellulose and that added as binder and extragranular adhesive.
~ ~.
9 - ~9~
The present composition is prepared by compressing mucosa-adhesive cellulose coated granules of a mixture of a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
The mucosa-adhesive cellulose coated granules may be prepared in a number of ways. For example, the drug may f;rst be incorporated in the higher alcohol or the cellulosic material prior to blending this with the remainder of the granules' constituents. Alternatively, and preferably, the drug may first be mixed with both the water soluble hydroxyalkyl cellulose and a binder before this mixture is blended with the higher alcohol.
The hydration of the water soluble hydroxyalkyl cellulose is effected at any convenient stage during the mixing of the granules' ingredients. It must be carried out carefully since excess;ve hydrat;on of the hydroxyalkyl cellulose results in an unmanageable granular mass, whilst insufficient hydration results in an erratic and inferior release rate of medicament from the f;nal compos;t;on. The degree of hydrat;on ;s ;n pract;ce preferably that obta;ned by the add;t;on of a quantity of water between 1 and 5, espec;ally, 2 and 3 times, the dry weight of the water soluble hydroxyalkyl cellulose.
Once the granules' ingredients have been mixed and hydrated they are then granulated and s;eved to afford granules of a suitable granule s;ze, preferably less than 1000~m. F;nally the granules are mixed with extragranular mucosa adhesive cellulose to form mucosa adhes;ve cellulose coated granules.
It ;s ;mportant to note that the above methods and processes of granule formation are merely illustrative. Other preparations of the present mucosa adhesive coated granules ~Z779~3 , 10 will be immediately apparent to those skilled in this art.
The compressed granules may be formed into any suitable oral - dosage form by the use of, for example, a punch, die or press.
In order to facilitate the use of the present composition in the mucosal, especially buccal, administration of drugs, however, there is provided, in a further aspect of the present invention, a kidney-shaped oral vehicle adapted to fit closely the shape of the buccal cavity. Such an oral vehicle may be prepared using kidney shaped punches and dies.
Oral dosage units according to the present invention in the form of kidney-shaped oral veh;cles have been found to be part;cularly convenient in the mucosal, especially buccal, administration of the drugs. It has been found that most patients may eat and drink freely whilst the kidney shaped oral vehicle is in position.
Sustained release, oral pharmaceutical compositions and oral vehicles according to this invention, as well as processes for preparing both compositions and vehicles, will now be described by way of example only.
A kidney-shaped oral vehicle according to this invention is particularly exemplified by reference to Figure 1 in which a plan, a side elevation and a rear elevation is shown.
Figure 2 shows the morphine plasma level achieved (as a function of time) by four patients using three morphine sulphate formulations.
figure 3 shows the morphine plasma levels achieved (as a function of time) by nine patients using a buccal morphine tablet prior to surgery.
1 1 1~77913 ExamDle 1 The following ingredients were used to prepare one thousand tablets (200 mg total weight, 10 mg of morphine sulphate).
Inaredient % Weiaht (am) Morphine Sulphate 7.5 10.0 Mannitol 25.0 50.0 actose (Anhydrous) 15.0 35.0 Hydroxyethyl cellulose 13.3 26.6 ~Natrosol 250 HX) Hydroxypropyl cellulose 12.5 25.0 (Klucel HF) Cetostearyl Alcohol 26.7 53.4 Water q.s. q.s. (approx. 65 9.) The morphine sulphate, mannitol, lactose, hydroxyethyl cellulose and hydroxypropyl cellulose (159., added as a binder~ were dry blended until thoroughly mixed. The mixture was then hydrated (approx. 659.) until a wet granular mass was obtained. The hydrated mater;al was then partially dried in a Fluid Bed Dryer (FBD) at 600C, granulated and sieved through a 12 mesh screen. The granulated material was then completely dried ;n the FBD at 6ûC, regranulated and sieved through a 16 mesh screen.
To the warmed morphine sulphate containing granules was added molten cetostearyl alcohol and the whole was mixed thoroughly.
This m;xture was allowed to cool ;n the a;r, regranulated and s;eved through a 16 mesh screen.
12- ~277913 The extragranular hydroxyproPyl cellulose (109.) was then added and m;xed with the granules, until at least a substantial proportion of the granules had a coating of hydroxypropyL cellulose.
s Finally the coated granules were compressed and formed, using a kidney-shaped punch, into kidney-shaped tablets.
This process afforded one thousand 20û mg. tablets, each containing 10 mg. of morphine sulphate.
If desired the tablets could then be coated using standard procedures.
ExamDle 2 The method of Example 1 was followed except that the amount of morph;ne sulphate employed was increased to 20 9. and the amount of lactose employed was reduced to 25 9.
ExamDle 3 The method of Example 1 was followed except that the amount of morphine sulphate employed was increased to 30 9. and the amount of lactose employed was decreased to 15 9.
ExamDle 4 Tho method of Example 1 was followed except that sodium carboxymethyl cellulose replaced hydroxypropyl cellulose as the mucosa adhesive cellulose and binder.
ExamDle s The method of Example 1 was followed except that morphine ~ 13- 1~3 sulphate was replaced by nitroglycerin (5g.), added as a 1 in 10 blend of nitroglycerine and lactose, the amount of anhydrous lactose being reduced to zero.
ExamDle 6 The following ingredients were used to prepare one thousand tablets (200 mg. total weight, 2û mg. n;fedipine).
10 Inaredient /.Weiaht (am) Nifedipine (micronised) 10 20 Xylitol 25 50 Anhydrous Lactose 42.7585.5 Hydroxyethyl cellulose 15(Natrosol 250HX) 3.25 6.5 A Hydroxypropyl cellulose (Klucel HF) 10 20 Sodium carboxymethyl cellulose (Blanose 7MFD) 2.5 5 20 Cetostearyl alcohol 6.5 13 Water 25 The nifedipine, xylitoL, lactose, hydroxyethyl cellulose and hydroxypropyl cellulose (159, added as a binder) were dry Z5 blended until thoroughly mixed. The mixture was then hydrated (approx. 25ml.) until a wet granular mass was obtained. The hydrated material was then partially dried in a Fluid Bed Dry-r ~FBD) at 6onc~ granulated and sieved through a 12 mesh screen. The granulated material was then completely dried in the FBD at 60UC, regranulated and sieved through a 16 mesh screen.
To the warmed nifedipine containing granules was added molten cetostearyl alcohol and the whole was mixed thoroughly. This ~r~d~ Inar~
14. 1Z~7913 mixture was allowed to cool in the air regranulated and sieved through a 16 mesh screen.
The extragranular hydroxypropyl cellulose (59) and sodium carboxymethyl cellulose (59) was then added and mixed with the granules until at least a substantial proportion of the granules had a coating of hydroxypropyl cellulose.
Finally the coated granules were compressed and formed using a k;dney-shaped punch ;nto k;dney-shaped tablets.
This process afforded one thousand 200mg. tablets each contain;ng 20mg. of n;fedipine.
ExamDle 7 The method of Example 6 was repeated w;th the following ingredients Inoredient XWeiqht (q.) Buprenorphine 0.25 0.5 Anhydrous Laçtose 24.75 49.5 Hydroxyethyl cellulose (Natrosol 250 HX) 12.5 25 Cetostearyl alcohol 25 50 Xylito~ 25 50 Hydroxypropyl cellulose ~ingragranular) (klucel HF) 7.5 15 Hydroxypropyl cellulose (extragranular) 2.5 5 Sodium carboxymethyl cellulose (extragranular) (Blanose 7MFD)2.5 5 Water 60 This process afforded one thousand 200 mg. tablets each 1~779~3 containing 0.5 mg. of buprenorphine.
Examole 8 S The method of Example 6 was repeated with the following ingredients, Inaredient %Weiqht (a) Phenazocine hydrobromide 5 10 10 Anhydrous Lactose 10 20 Hydroxyethyl cellulose (Natrosol 250 HX~ 15 30 Cetostearyl alcohol 30 60 Mannitol 27.5 55 15 Hydroxypropyl cellulose (intragranular) (klucel HF) 7.5 15 Hydroxypropyl cellulose (extragranular) 5 10 Water 70 Th;s process afforded one thousand 200 mg. tablets, each containing 10 mg. of phenazocine hydrobrom;de.
Referring to F;gure 1, a kidney-shaped oral veh;cle accord;ng to this invention (1) has a convex side (2) and a concave side ~3)~ Both the upper portion (4) and the lower portion (5) of the vehicle are rounded.
In use the oral vehicle ;s placed ;n the buccal cav;ty of a pat;ent, w;th the concave s;de (3) uppermost.
16~ 3 CLINICAL TRIALS
A comparat;ve s;ngle dose pharmacok;net;c study of three morph;ne sulphate preparat;ons, namely morph;ne sulphate 5 10 mg. buccal tablets (prepared as descr;bed ;n Example 1), morph;ne sulphate liquid 10 mg, and a sustained release morphine sulphate oral tablet 10mg ~orally administered MST
CONTINUS tablet) was conducted using four patients for each preparat;on. Morphine levels in plasma were determined using 10 a l;qu;d-solid extraction followed by radio immuno-assay.
The results are given in Figure 2.
From th;s Figure it can be seen that the bioavailability of morph;ne sulphate ;s s;gn;f;cantly prolonged us;ng the present 15 buccal tablets, compared w;th the b;oavailability achieved by e;ther a l;quid morphine formulat;on or an orally administered sustained release morphine formulation.
A single dose pharmacokinetic study of morph;ne sulphate J 20 buccal tablets, 10 mg and 20 mg, was conducted us;ng n;ne patients. The tablet was placed in position in the buccal cavity four hours prior to ~aparoscopy. Morphine leveLs in plasma were determined using an ESE/RIA method. Results are given in Figure 3. Again the prolonged nature of the morphine 25 sulphate bioavailability is apparent from this Figure.
PRODUCT ~DHERENCE TO MUCOSA
Placebo tablots, prepared as described in Example 1, but with 30 morphine sulphate replaced by lactose (10.Ogm) were used to ; determine the adherence of tablets, prepared according to this invention, to the oral mucosa.
'.
~ The trial was carried out using nine volunteers. One tablet ~. ' . ::
1~77~9~3 was put ;n place in the buccal cavity tw;ce da;ly (at 12 hour ;ntervals), using both sides of the mouth alternatively, over a seven day period.
Subjects were asked to record the duration of each tablet in the buccal cavity. Results are given in the Table.
Table Tablet Duration (hr) Subject Night Day 1 12 9.7 2 12 8.0 3 12 7.2 4 12 5.9 12 11.0 6 12 8.5 7 12 1û.9 8 12 8.6 9 12Subject found tablets unacceptable Average 12 8.4
The present invent;on relates to a sustained release, oral pharmaceutical composition and, in particular, to an oral vehicle adapted for application to the mucosa of the oral or nasal cavity, especially within the buccal cavity.
The administration of drugs using oral vehicles retained in the buccal cavity is known. Such administration is generally effected by inserting an oral vehicle (e.g. a tablet) containing a drug into the buccal cavity of the patient's mouth and then pressing the vehicle against the mucosa of the cheek or the gum until it adheres.
Absorption of the drug in the vehicle generally occurs directly through the mucosa at the inner surface of the cheek and/or gum into the pat;ent's bloodstream. In some cases, however, the drug may be absorbed gastr;cally or enterally by the absorpt;on of drug contained in swallowed saliva.
2û
The buccal method of drug admin;strat;on has considerable advantages over administration by, for example, swallowing a tablet or injection. One advantage is that administration can be discontinued at any time (e.g. when undesired effects arising from the administration are identified) simply by removing the remainder of the vehicle. Another advantage, ovor-oral administration, is that first pass, drug metabolism may b avoided.
A particular problem associated with the buccal administration of drugs, ho~ever, is that the oral vehicle containing the drug tends, after a period, to become detached from the mucosa. At best this can be merely inconvenient, at worst it may lead to the patient swallow;ng the veh;cle.
~27 79~3 It is an object of the present invention to provide a sustained release, oral pharmaceutical composition having improved properties of adherence to the mucosa within the oral or nasal, especially buccal cavity.
It is a further object of the present invention to provide an oral vehicle prepared from the improved composition and shaped to facilitate attachment within the buccal cavity.
Further objects and advantages of the present invention will become apparent from the following detailed description thereof.
According to the present invention, therefore, there is provided a sustained release, oral pharmaceutical composition in solid unit dosage form, for application to the mucosa of the oral or nasal cavity, comprising compressed, mucosa-adhesive cellulose coated granules, the granules comprising a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
Preferably the solid unit dosage form is an oral vehicle for attachment within the buccal cavity.
. ~ .
It is an important feature of the present invention that the granules used to prepare the solid unit dosage form (e.g.
tablet) comprise extragranular mucosa-adhesive cellulose which improves the attachment of the dosage form to the oral or nasal mucosa, especially within the buccal cavity.
Preferably the extragranular, mucosa adhesive cellulose is applied to the granules in the form of a powdered solid rather than a solution. This allows greater control over the water content of the granules, avoids swelling of the lZ~9i3 granules and also avoids an unnecessary drying step.
The present inventors have surprisingly found that by employing extragranular cellulose adhesive, especially powdered adhesive, the adherent properties of the resulting dosage form are significantly greater than those of a dosage form having intragranular adhesive only.
The mucosa adhesive cellulose may be, for example, a carboxyalkyl cellulose, such as sodium carboxymethyl cellulose or a hydroxyalkyl cellulose, such as hydroxypropylmethyl cellulose. Preferably, however, hydroxypropyl cellulose (HPC), espec;ally that sold by the Hercules Powder Company as Klucel HF (Trade Mark), is the mucosa adhesive material.
Preferably, the mucosa adhesive cellulose is a high molecular weight material having a number average molecular weight above 200,000, especially above 500,000.
Surprisingly, when HPC is employed as the adhesive in the present formulation ;t is found to give the dosage form adhesive properties superior to those ach;eved using previously preferred adhesives, such as Karaya gum and acrylic acid polymers (e.g. carbopol gel) or mixtures of these adhesives with other knovn binders.
The concentration of extragranular adhesive cellulose (as a proportion of the total dosage form weight) is preferably between 2X and 15X (w/w), especially between 4X and 10X (w/w).
Prior to compression, the granules coated with mucosa-adhesive cellulose will, preferably, have a granule size of less than ~oOOr.
, ~
4 12~79~3 The higher aliphatic alcohol is an aliphatic alcohol containing from 8 to 18 carbon atoms which is optionally substituted by a further aliphatic group containing from 8 to ~ 18 carbon atoms. Suitable alcohols include lauryl alcohol, myristyl alcohol, stearyl alcohol, or, which is preferred, cetyl alcohol and cetostearyl alcohol. The higher aliphatic aLcohol, together with the water soluble hydroxyalkyl cellulose, serves to control the release of the drug from the composition. The level of alcohol in the composition will therefore be determined by the rate of drug release required.
GeneralLy, however, the composition will contain between 5X
and 35X ~w/w), espec;ally 10% and 30% (w/w), (as a proportion of the total dosage form weight) of the higher aliphatic alcohol.
The hydroxyaLkyl cellulose is a hydroxy lower alkyl ether of cellulose and is preferably selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxypropylmethyl cellulose, with hydroxyethyl cellulose (for example Natrosol 250 HX, Trade Mark, Hercules Powder Company) being particularly preferred. The hydroxyalkyl cellulose, together with the higher aliphatic alcohol, serves to control the release of the drug from the composition. The level of hydroxyalkyl cellulose in the composition will therefore be determined by the rate of drug release required.
Preferably the composition will contain between 2% and 15X
~w/u), as a proportion of the total dosage form weight, of the hydroxyalkyl cellulose.
It should be noted that when the water-soluble hydroxyalkyl cellulose used in the present composition is also the composition's mucosa adhesive, then the amount of hydroxyalkyl cellulose present in each dosage form is at least the sum of the hydroxyalkyl cellulose added as water-soluble hydroxyalkyl . .
. 1Z779i3 cellulose and the hydroxyalkyl cellulose added as extra-granular adhes;ve.
The drug employed in the present composition is preferably absorbable through the oral or nasal mucosa. In some instances, however, drugs that are absorbed gastrically and/or enterically (rather than via the mucosal route) may be employed. In a still further instance, the drug may be one that acts locally in the mouth, for example in the treatment of mouth ulcers. Suitable medicaments will be well known to those skilled in the pharmaceutical art. Listed below are certain of the drug categories within which are classed a number of the drugs that may be employed in the present composition.
(a) Analgesic agents; e.g. morphine, or analogues thereof, phenazocine, pentazocine, buprenorphine;
(b) Anti-inflammatory agents; e.g. ibuprofen, indomethacin, acetaminophen, phenacetin, aspirin, aminopyrine, sulpyrine, phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, colchicine, probenecid, ethenzamide, salicylamide, ketoprofen, flurbiprofen, diclofenac, clidanac, alclofenac, sulindac, piroxicam;
(c) Antihistamines, e.g. clemastine fumarate, mepyramine, diphenylhydramine hydrochloride, dexchlorpheniramine maleate;
(d) Topical anaesthetics, e.g. benzocaine, procaine, lidocaine;
(e) Vasodilators, e.g. nitroglycerin, nifedipine, papaverine, isosorbide dinitrate, diltiazem, nicardipine;
. ~
`~` 6 1 2 ~ 9 1 3 (f) Antitussives and expectorants, such as codeine phosphate and isoproterenol hydrochloride;
(g) Hormones; e.g. insulin, vasopressin and heparin;
(h) Diuretics, e.g. ethacrynic acid and bendrofLuazide;
(i) Anti/hypotensives, e.g. propranolol and clon;dine;
(j) Anti-neoplastic agents, e.g~ cytarabine and doxorubicin;
(k) Antidiabetic drugs, e.g. chlorpropamide and glibenclamide;
5 (l) Bronchodilators, such as albuterol (salbutamol), ipratropiumbromide;
(m) Antiarrythm;c agents, e.g. verapamil;
(n) Ant;-inflammatory steroids, e.g. hydrocortisone, prednisone, prednisolone, triamc;nolone, dexamethasone, betamethasone;
(o) Antib;ot;cs or Fung;c;des, e.g. tetracyclines, Z5 leucomyc;ns, fradiomycins, pen;c;ll;ns, cephalospor;ns, erythromycins;
tp) Chemotherapeutic agents, e.g. sulphathiazole, nitrofurazone, clotr;mazole;
~q) Card;ac ton;cs, e.g. digital;s, digoxin;
~r) Oral antiseptics, e.g. chlorhexidine, hexylresorc;nol, dequalin;um chloride and ethacridine;
7 1~779~3 ~s) Antiasthmatics, e.g. disodium cromoglycate;
(t) Drugs acting on the central nervous system, e.g. diazepam - and estazolam;
(u~ Anti-epileptics, e.g. phenytoin, meprobamate and nitrazepam;
(v) Anticholinergics, e.g. scopolamine;
(w) Muscle Relaxants e.g. baclofen, dentrolene sodium, cyclobenzaprine hydrochloride;
(x) Beta-blocker, e.g. pindolol;
~y) Antiarteriosclerotic agents, e.g. clofibrate, pentoxifylline;
(z) Drugs for treatment of ulcers, e.g. cimetidine, ranitidine;
Other, e.g. nicotine.
It will be apprec;ated that the drug may be added to the present composition not only in ;ts free form, but also as a s;mple pharmacolog;cally acceptable der;vat;ve, such as an ethor, an ester, an amide, an acetal, a salt and the like. In so~e cases, such derivatives may actually be preferred.
Particularly preferred drugs for use in the present composition are morph;ne, n;fed;pine, phenazocine, verapamil and salbutamol.
These drugs can be used either singly or as a mixture of two i2779~3 _ 8 or more. The amount of drug to be blended in a solid dosage unit will generally be enough to maintain a therapeutic level of the drug in the bloodstream for a predetermined period~
In addition to the constituents discussed above, the present pharmaceutical composition may also contain certain of the known excipients, such as lubricants, binders, vehicles, colouring agents, taste controlling agents and odour controlling agents, that are employed to improve the appearance, odour or taste of pharmaceutical preparations.
In a particularly preferred embodiment of the present composition, the granules contain between 2% and 15X (w/w), especially between 4% and 10X (w/w), of a binder to improve the binding and strength of the dosage form. Suitable binders include starch, dextrin, tragacanth, ge~atin, polyvinylpyrrolidone, polyvinylalcohol or, which is especially preferred, a mucosa adhesive cellulose such as a carboxyalkyl cellulose or a hydroxyalkyl cellulose especially sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose or, most especially, hydroxypropyl cellulose. Compositions according to this invention having both extragranular adhesive cellulose and intragranular adhesive cellulose (as binder) have been found to exhibit particularly good qualities of adhesion and strength.
It should be noted that when the same cellulosic material ;s used in the present composition as the water soluble hydroxyalkyl cellulose, the extragranular mucosa adhesive 3û cellulose and the binder, then the amount of cellulosic material present in each dosage form is at least the sum of that added as water-soluble hydroxyalkyl cellulose and that added as binder and extragranular adhesive.
~ ~.
9 - ~9~
The present composition is prepared by compressing mucosa-adhesive cellulose coated granules of a mixture of a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
The mucosa-adhesive cellulose coated granules may be prepared in a number of ways. For example, the drug may f;rst be incorporated in the higher alcohol or the cellulosic material prior to blending this with the remainder of the granules' constituents. Alternatively, and preferably, the drug may first be mixed with both the water soluble hydroxyalkyl cellulose and a binder before this mixture is blended with the higher alcohol.
The hydration of the water soluble hydroxyalkyl cellulose is effected at any convenient stage during the mixing of the granules' ingredients. It must be carried out carefully since excess;ve hydrat;on of the hydroxyalkyl cellulose results in an unmanageable granular mass, whilst insufficient hydration results in an erratic and inferior release rate of medicament from the f;nal compos;t;on. The degree of hydrat;on ;s ;n pract;ce preferably that obta;ned by the add;t;on of a quantity of water between 1 and 5, espec;ally, 2 and 3 times, the dry weight of the water soluble hydroxyalkyl cellulose.
Once the granules' ingredients have been mixed and hydrated they are then granulated and s;eved to afford granules of a suitable granule s;ze, preferably less than 1000~m. F;nally the granules are mixed with extragranular mucosa adhesive cellulose to form mucosa adhes;ve cellulose coated granules.
It ;s ;mportant to note that the above methods and processes of granule formation are merely illustrative. Other preparations of the present mucosa adhesive coated granules ~Z779~3 , 10 will be immediately apparent to those skilled in this art.
The compressed granules may be formed into any suitable oral - dosage form by the use of, for example, a punch, die or press.
In order to facilitate the use of the present composition in the mucosal, especially buccal, administration of drugs, however, there is provided, in a further aspect of the present invention, a kidney-shaped oral vehicle adapted to fit closely the shape of the buccal cavity. Such an oral vehicle may be prepared using kidney shaped punches and dies.
Oral dosage units according to the present invention in the form of kidney-shaped oral veh;cles have been found to be part;cularly convenient in the mucosal, especially buccal, administration of the drugs. It has been found that most patients may eat and drink freely whilst the kidney shaped oral vehicle is in position.
Sustained release, oral pharmaceutical compositions and oral vehicles according to this invention, as well as processes for preparing both compositions and vehicles, will now be described by way of example only.
A kidney-shaped oral vehicle according to this invention is particularly exemplified by reference to Figure 1 in which a plan, a side elevation and a rear elevation is shown.
Figure 2 shows the morphine plasma level achieved (as a function of time) by four patients using three morphine sulphate formulations.
figure 3 shows the morphine plasma levels achieved (as a function of time) by nine patients using a buccal morphine tablet prior to surgery.
1 1 1~77913 ExamDle 1 The following ingredients were used to prepare one thousand tablets (200 mg total weight, 10 mg of morphine sulphate).
Inaredient % Weiaht (am) Morphine Sulphate 7.5 10.0 Mannitol 25.0 50.0 actose (Anhydrous) 15.0 35.0 Hydroxyethyl cellulose 13.3 26.6 ~Natrosol 250 HX) Hydroxypropyl cellulose 12.5 25.0 (Klucel HF) Cetostearyl Alcohol 26.7 53.4 Water q.s. q.s. (approx. 65 9.) The morphine sulphate, mannitol, lactose, hydroxyethyl cellulose and hydroxypropyl cellulose (159., added as a binder~ were dry blended until thoroughly mixed. The mixture was then hydrated (approx. 659.) until a wet granular mass was obtained. The hydrated mater;al was then partially dried in a Fluid Bed Dryer (FBD) at 600C, granulated and sieved through a 12 mesh screen. The granulated material was then completely dried ;n the FBD at 6ûC, regranulated and sieved through a 16 mesh screen.
To the warmed morphine sulphate containing granules was added molten cetostearyl alcohol and the whole was mixed thoroughly.
This m;xture was allowed to cool ;n the a;r, regranulated and s;eved through a 16 mesh screen.
12- ~277913 The extragranular hydroxyproPyl cellulose (109.) was then added and m;xed with the granules, until at least a substantial proportion of the granules had a coating of hydroxypropyL cellulose.
s Finally the coated granules were compressed and formed, using a kidney-shaped punch, into kidney-shaped tablets.
This process afforded one thousand 20û mg. tablets, each containing 10 mg. of morphine sulphate.
If desired the tablets could then be coated using standard procedures.
ExamDle 2 The method of Example 1 was followed except that the amount of morph;ne sulphate employed was increased to 20 9. and the amount of lactose employed was reduced to 25 9.
ExamDle 3 The method of Example 1 was followed except that the amount of morphine sulphate employed was increased to 30 9. and the amount of lactose employed was decreased to 15 9.
ExamDle 4 Tho method of Example 1 was followed except that sodium carboxymethyl cellulose replaced hydroxypropyl cellulose as the mucosa adhesive cellulose and binder.
ExamDle s The method of Example 1 was followed except that morphine ~ 13- 1~3 sulphate was replaced by nitroglycerin (5g.), added as a 1 in 10 blend of nitroglycerine and lactose, the amount of anhydrous lactose being reduced to zero.
ExamDle 6 The following ingredients were used to prepare one thousand tablets (200 mg. total weight, 2û mg. n;fedipine).
10 Inaredient /.Weiaht (am) Nifedipine (micronised) 10 20 Xylitol 25 50 Anhydrous Lactose 42.7585.5 Hydroxyethyl cellulose 15(Natrosol 250HX) 3.25 6.5 A Hydroxypropyl cellulose (Klucel HF) 10 20 Sodium carboxymethyl cellulose (Blanose 7MFD) 2.5 5 20 Cetostearyl alcohol 6.5 13 Water 25 The nifedipine, xylitoL, lactose, hydroxyethyl cellulose and hydroxypropyl cellulose (159, added as a binder) were dry Z5 blended until thoroughly mixed. The mixture was then hydrated (approx. 25ml.) until a wet granular mass was obtained. The hydrated material was then partially dried in a Fluid Bed Dry-r ~FBD) at 6onc~ granulated and sieved through a 12 mesh screen. The granulated material was then completely dried in the FBD at 60UC, regranulated and sieved through a 16 mesh screen.
To the warmed nifedipine containing granules was added molten cetostearyl alcohol and the whole was mixed thoroughly. This ~r~d~ Inar~
14. 1Z~7913 mixture was allowed to cool in the air regranulated and sieved through a 16 mesh screen.
The extragranular hydroxypropyl cellulose (59) and sodium carboxymethyl cellulose (59) was then added and mixed with the granules until at least a substantial proportion of the granules had a coating of hydroxypropyl cellulose.
Finally the coated granules were compressed and formed using a k;dney-shaped punch ;nto k;dney-shaped tablets.
This process afforded one thousand 200mg. tablets each contain;ng 20mg. of n;fedipine.
ExamDle 7 The method of Example 6 was repeated w;th the following ingredients Inoredient XWeiqht (q.) Buprenorphine 0.25 0.5 Anhydrous Laçtose 24.75 49.5 Hydroxyethyl cellulose (Natrosol 250 HX) 12.5 25 Cetostearyl alcohol 25 50 Xylito~ 25 50 Hydroxypropyl cellulose ~ingragranular) (klucel HF) 7.5 15 Hydroxypropyl cellulose (extragranular) 2.5 5 Sodium carboxymethyl cellulose (extragranular) (Blanose 7MFD)2.5 5 Water 60 This process afforded one thousand 200 mg. tablets each 1~779~3 containing 0.5 mg. of buprenorphine.
Examole 8 S The method of Example 6 was repeated with the following ingredients, Inaredient %Weiqht (a) Phenazocine hydrobromide 5 10 10 Anhydrous Lactose 10 20 Hydroxyethyl cellulose (Natrosol 250 HX~ 15 30 Cetostearyl alcohol 30 60 Mannitol 27.5 55 15 Hydroxypropyl cellulose (intragranular) (klucel HF) 7.5 15 Hydroxypropyl cellulose (extragranular) 5 10 Water 70 Th;s process afforded one thousand 200 mg. tablets, each containing 10 mg. of phenazocine hydrobrom;de.
Referring to F;gure 1, a kidney-shaped oral veh;cle accord;ng to this invention (1) has a convex side (2) and a concave side ~3)~ Both the upper portion (4) and the lower portion (5) of the vehicle are rounded.
In use the oral vehicle ;s placed ;n the buccal cav;ty of a pat;ent, w;th the concave s;de (3) uppermost.
16~ 3 CLINICAL TRIALS
A comparat;ve s;ngle dose pharmacok;net;c study of three morph;ne sulphate preparat;ons, namely morph;ne sulphate 5 10 mg. buccal tablets (prepared as descr;bed ;n Example 1), morph;ne sulphate liquid 10 mg, and a sustained release morphine sulphate oral tablet 10mg ~orally administered MST
CONTINUS tablet) was conducted using four patients for each preparat;on. Morphine levels in plasma were determined using 10 a l;qu;d-solid extraction followed by radio immuno-assay.
The results are given in Figure 2.
From th;s Figure it can be seen that the bioavailability of morph;ne sulphate ;s s;gn;f;cantly prolonged us;ng the present 15 buccal tablets, compared w;th the b;oavailability achieved by e;ther a l;quid morphine formulat;on or an orally administered sustained release morphine formulation.
A single dose pharmacokinetic study of morph;ne sulphate J 20 buccal tablets, 10 mg and 20 mg, was conducted us;ng n;ne patients. The tablet was placed in position in the buccal cavity four hours prior to ~aparoscopy. Morphine leveLs in plasma were determined using an ESE/RIA method. Results are given in Figure 3. Again the prolonged nature of the morphine 25 sulphate bioavailability is apparent from this Figure.
PRODUCT ~DHERENCE TO MUCOSA
Placebo tablots, prepared as described in Example 1, but with 30 morphine sulphate replaced by lactose (10.Ogm) were used to ; determine the adherence of tablets, prepared according to this invention, to the oral mucosa.
'.
~ The trial was carried out using nine volunteers. One tablet ~. ' . ::
1~77~9~3 was put ;n place in the buccal cavity tw;ce da;ly (at 12 hour ;ntervals), using both sides of the mouth alternatively, over a seven day period.
Subjects were asked to record the duration of each tablet in the buccal cavity. Results are given in the Table.
Table Tablet Duration (hr) Subject Night Day 1 12 9.7 2 12 8.0 3 12 7.2 4 12 5.9 12 11.0 6 12 8.5 7 12 1û.9 8 12 8.6 9 12Subject found tablets unacceptable Average 12 8.4
Claims (22)
1. A sustained release, oral pharmaceutical composition in solid unit dosage form, for application to the mucosa of the oral or nasal cavity, comprising compressed, mucosa adhesive cellulose coated granules, the granules comprising a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose.
2. A composition according to claim 1 wherein the granules are coated with a powdered mucosa adhesive cellulose.
3. A composition according to claim 1 wherein the mucosa adhesive cellulose comprises a carboxyalkyl cellulose or a hydroxyalkyl cellulose.
4. A composition according to claim 3 wherein the mucosa adhesive cellulose comprises sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose or hydroxypropyl cellulose.
5. A composition according to claim 4 wherein the mucosa adhesive cellulose comprises hydroxypropyl cellulose.
6. A composition according to claim 1 wherein the mucosa adhesive cellulose coating comprises between 2% and 15%
(w/w), of the total dosage form weight.
(w/w), of the total dosage form weight.
7. A composition according to claim 6 wherein the mucosa adhesive cellulose coating comprises between 4% and 10%
(w/w) of the total dosage form weight.
(w/w) of the total dosage form weight.
8. A composition according to any one of claims 1, 2 or 3 wherein the higher aliphatic alcohol comprises cetyl alcohol or cetostearyl alcohol.
9. A composition according to claim 1 wherein the higher aliphatic alcohol comprises between 5% and 35% (w/w), of the total dosage form weight.
10. A composition according to claim 9 wherein the higher aliphatic alcohol comprises between 10% and 30% (w/w) of the total dosage form weight.
11. A composition according to claim 1 wherein the water soluble hydroxyalkyl cellulose comprises hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropylmethyl cellulose.
12. A composition according to claim 11 wherein the water soluble hydroxyalkyl cellulose comprises hydroxyethyl cellulose.
13. A composition according to any of claims 1, 2 or 3 wherein the water soluble hydroxyalkyl cellulose comprises between 2% and 15% (w/w) of the total dosage form weight.
14. A composition according to claim 1 wherein the drug comprises morphine, nifedipine, phenazocine, verapamil and salbutamol.
15. A composition according to claim 14 wherein the drug comprises morphine.
16. A composition according to claim 1 wherein the granules further comprise between 2% and 15% (w/w) of a binder comprising a carboxyalkyl cellulose or a hydroxyalkyl cellulose.
17. A composition according to claim 16 wherein the binder comprises sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose and hydroxypropyl cellulose.
18. A composition according to claim 17 wherein the binder comprises hydroxypropyl cellulose.
19. A kidney shaped oral vehicle comprising a sustained release, oral pharmaceutical composition according to any one of claims 1, 2 or 3.
20. A buccal tablet comprising a sustained release, oral pharmaceutical composition according to any one of claims 1, 2 or 3.
21. A process for the preparation of a sustained release, oral pharmaceutical composition in solid unit dosage form, the composition being adapted for application to the mucosa of the oral or nasal cavity, comprising forming granules comprising a drug, a higher aliphatic alcohol and a hydrated water soluble hydroxyalkyl cellulose coating the granules with a mucosa adhesive cellulose, and compressing the mucosa adhesive cellulose coated granules to give a solid unit dosage form.
22. A process according to claim 21 wherein the granules are formed by a process comprising mixing the drug, the water soluble hydroxyalkyl cellulose and, optionally, a binder comprising a carboxyalkyl cellulose or a hydroxyalkyl cellulose to form a drug containing mixture, hydrating the drug containing mixture to form a wet granular mass, drying the wet granular mass to form a dry granular mass, and mixing the dry granular mass with a higher aliphatic alcohol.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB858514665A GB8514665D0 (en) | 1985-06-11 | 1985-06-11 | Oral pharmaceutical composition |
GB8514665 | 1985-06-11 |
Publications (1)
Publication Number | Publication Date |
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CA1277913C true CA1277913C (en) | 1990-12-18 |
Family
ID=10580497
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA000511153A Expired - Fee Related CA1277913C (en) | 1985-06-11 | 1986-06-09 | Oral pharmaceutical composition |
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US (1) | US4940587A (en) |
EP (1) | EP0205282B1 (en) |
JP (1) | JP2513999B2 (en) |
KR (1) | KR890002949B1 (en) |
AT (1) | ATE127687T1 (en) |
AU (1) | AU595801B2 (en) |
CA (1) | CA1277913C (en) |
DE (1) | DE3650390T2 (en) |
DK (1) | DK273086A (en) |
ES (1) | ES8707110A1 (en) |
FI (1) | FI88108C (en) |
GB (1) | GB8514665D0 (en) |
IL (1) | IL78991A (en) |
NO (1) | NO172027C (en) |
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Families Citing this family (135)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8608818D0 (en) * | 1986-04-11 | 1986-05-14 | Reckitt & Colmann Prod Ltd | Pharmaceutical compositions |
GB8613688D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
FR2618073B1 (en) * | 1987-07-16 | 1990-09-07 | Pf Medicament | HYDROPHILIC MATRIX-TYPE TABLETS BASED ON SALBUTAMOL AND THEIR PREPARATION METHOD |
NO883326L (en) * | 1987-08-11 | 1989-02-13 | Bayer Ag | DHP-retard-COOK. |
FR2619718B1 (en) * | 1987-09-02 | 1991-07-12 | Medibrevex | NOVEL GALENIC FORMS OF BETA-2-MIMETICS FOR PER- AND SUBLINGUAL ADMINISTRATION |
FR2621483B1 (en) * | 1987-10-08 | 1991-09-20 | Medibrevex | NOVEL GALENIC FORMS OF CORTICOIDS FOR PER- AND SUBLINGUAL ADMINISTRATION AND THEIR PREPARATION PROCESS |
US5446070A (en) * | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5234957A (en) * | 1991-02-27 | 1993-08-10 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
AU618096B2 (en) * | 1988-04-19 | 1991-12-12 | Southwest Research Institute | Controlled release of active ingredients from capsules having a salt sensitive shell material |
US5064650A (en) * | 1988-04-19 | 1991-11-12 | Southwest Research Institute | Controlled-release salt sensitive capsule for oral use and adhesive system |
CA2007181C (en) * | 1989-01-06 | 1998-11-24 | Angelo Mario Morella | Sustained release pharmaceutical composition |
US5202128A (en) * | 1989-01-06 | 1993-04-13 | F. H. Faulding & Co. Limited | Sustained release pharmaceutical composition |
US5525351A (en) * | 1989-11-07 | 1996-06-11 | Dam; Anders | Nicotine containing stimulant unit |
GB9010039D0 (en) * | 1990-05-03 | 1990-06-27 | Reckitt & Colmann Prod Ltd | Medicament preparation |
US5147654A (en) * | 1990-07-23 | 1992-09-15 | Alza Corporation | Oral osmotic device for delivering nicotine |
US5332576A (en) * | 1991-02-27 | 1994-07-26 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
TW209174B (en) * | 1991-04-19 | 1993-07-11 | Takeda Pharm Industry Co Ltd | |
IT1250421B (en) * | 1991-05-30 | 1995-04-07 | Recordati Chem Pharm | CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION WITH BIO-ADHESIVE PROPERTIES. |
US5364634A (en) * | 1991-11-08 | 1994-11-15 | Southwest Research Institute | Controlled-release PH sensitive capsule and adhesive system and method |
US5478577A (en) * | 1993-11-23 | 1995-12-26 | Euroceltique, S.A. | Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level |
GB9202464D0 (en) * | 1992-02-05 | 1992-03-18 | Danbiosyst Uk | Composition for nasal administration |
US5571533A (en) * | 1992-02-07 | 1996-11-05 | Recordati, S.A., Chemical And Pharmaceutical Company | Controlled-release mucoadhesive pharmaceutical composition for the oral administration of furosemide |
SE9202250D0 (en) * | 1992-07-29 | 1992-07-29 | Gacell Lab Ab | CONTROLLED RELEASE MORPHINE PREPARATION |
WO1994005262A1 (en) * | 1992-09-10 | 1994-03-17 | F.H. Faulding & Co. Limited | Sustained release matrix composition |
EP0865789B1 (en) * | 1993-03-26 | 2005-03-16 | Franciscus Wilhelmus Henricus Maria Merkus | Pharmaceutical compositions for intranasal administration of dihydroergotamine |
IL119660A (en) | 1993-05-10 | 2002-09-12 | Euro Celtique Sa | Controlled release formulation comprising tramadol |
US5773025A (en) * | 1993-09-09 | 1998-06-30 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems--amorphous drugs |
US5662933A (en) * | 1993-09-09 | 1997-09-02 | Edward Mendell Co., Inc. | Controlled release formulation (albuterol) |
ATE192932T1 (en) * | 1993-09-09 | 2000-06-15 | Takeda Chemical Industries Ltd | FORMULATION CONTAINING AN ANTIBACTERIAL AND AN ANTIULCUS ACTIVE |
US5455046A (en) * | 1993-09-09 | 1995-10-03 | Edward Mendell Co., Inc. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
US6726930B1 (en) * | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
KR100354702B1 (en) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | Manufacturing method and sustained release composition of pharmaceutical composition |
US5891471A (en) | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
US5843480A (en) | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
GB9422154D0 (en) | 1994-11-03 | 1994-12-21 | Euro Celtique Sa | Pharmaceutical compositions and method of producing the same |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
WO1998000143A1 (en) * | 1996-06-28 | 1998-01-08 | Knoll Pharmaceutical Company | Slow release pharmaceutical compositions and methods of making same |
WO1998001117A1 (en) * | 1996-07-08 | 1998-01-15 | Edward Mendell Co., Inc. | Sustained release matrix for high-dose insoluble drugs |
FR2766708B1 (en) | 1997-07-30 | 2000-05-05 | Galenix Dev | COMPOSITION CONTAINING HYDROXYPROPYLCELLULOSE, HYDROXYPROPYLMETHYLCELLULOSE AND / OR ETHYLCELLULLOSE AS DISINTEGRANTS, AND PROCESS FOR OBTAINING SAME |
FR2766707A1 (en) * | 1997-07-30 | 1999-02-05 | Galenix Dev | Medicaments containing cellulose based disintegration agents |
US6056977A (en) | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
CN100379407C (en) * | 1997-12-19 | 2008-04-09 | 史密丝克莱恩比彻姆公司 | Process for manufacturing bite-dispersion tablets |
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
PT1685839E (en) | 1997-12-22 | 2013-07-08 | Euro Celtique Sa | Pharmaceutical oral dosage form comprising a combination of an opioid agonist and opioid antagonist |
CA2314896C (en) * | 1997-12-22 | 2005-09-13 | Euro-Celtique, S.A. | A method of preventing abuse of opioid dosage forms |
US6432442B1 (en) * | 1998-02-23 | 2002-08-13 | Mcneil-Ppc, Inc. | Chewable product |
US6573292B1 (en) | 1998-07-09 | 2003-06-03 | Salmedix, Inc. | Methods and compositions for the treatment of chronic lymphocytic leukemia |
DE19842753A1 (en) | 1998-09-18 | 2000-03-23 | Bayer Ag | Multiple-unit retard oral dosage formulation having controlled release independent of agitation and food effect, containing particles of combination of drug and hydroxypropyl cellulose |
US7906143B1 (en) * | 1998-10-05 | 2011-03-15 | Intellipharmaceutics Corp | Controlled release pharmaceutical delivery device and process for preparation thereof |
DE19918325A1 (en) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
FR2794646B1 (en) | 1999-06-09 | 2001-09-21 | Ethypharm Lab Prod Ethiques | MORPHINE SULFATE MICROGRANULES, METHOD OF PREPARATION AND COMPOSITION CONTAINING THEM |
TR200103613T2 (en) * | 1999-06-16 | 2004-08-23 | Nastech Pharmaceutical Co., Inc. | Pharmaceutical formulations and methods containing morphine administered intranasally. |
US7105560B1 (en) | 1999-07-23 | 2006-09-12 | The Regents Of The University Of California | Use of etodolac in the treatment of multiple myeloma |
US7151100B1 (en) | 1999-07-23 | 2006-12-19 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US7361680B2 (en) * | 1999-07-23 | 2008-04-22 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
US6545034B1 (en) * | 1999-07-23 | 2003-04-08 | The Regents Of The University Of California | Use of etodolac for the treatment of chronic lymphocytic leukemia |
US7129262B2 (en) * | 1999-07-23 | 2006-10-31 | The Regents Of The University Of California | Indole compounds useful for the treatment of cancer |
KR100463496B1 (en) | 1999-09-30 | 2005-01-06 | 펜웨스트 파머슈티칼즈 컴파니 | Sustained release matrix systems for highly soluble drugs |
US6555125B2 (en) * | 1999-11-30 | 2003-04-29 | Phillip Campbell | Lesion and ulcer medication |
HUP0204163A2 (en) | 2000-02-08 | 2003-04-28 | Euro-Celtique S.A. | Controlled-release composition containing opioid agonist and antagonist and process for its preparation |
US6716449B2 (en) | 2000-02-08 | 2004-04-06 | Euro-Celtique S.A. | Controlled-release compositions containing opioid agonist and antagonist |
EP1935421A1 (en) | 2000-02-08 | 2008-06-25 | Euro-Celtique S.A. | Controlled-release compositions containing opioid agonist and antagonist |
US6812205B2 (en) | 2000-03-15 | 2004-11-02 | The Brigham & Women's Hospital, Inc. | Suppression of vascular disorders by mucosal administration of heat shock protein peptides |
US8652446B2 (en) * | 2000-03-17 | 2014-02-18 | Lg Household & Healthcare Ltd. | Apparatus and method for whitening teeth |
ES2320321T3 (en) * | 2000-03-17 | 2009-05-21 | LG HOUSEHOLD & HEALTH CARE LTD. | PATCHES FOR WHITENING TEETH. |
US7130822B1 (en) * | 2000-07-31 | 2006-10-31 | Cognos Incorporated | Budget planning |
US20030065002A1 (en) | 2001-05-11 | 2003-04-03 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
CA2452874A1 (en) * | 2001-07-06 | 2003-01-16 | Endo Pharmaceuticals, Inc. | Oral administration of 6-hydroxy-oxymorphone for use as an analgesic |
PT1416842E (en) | 2001-07-18 | 2009-03-31 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
US20030157168A1 (en) | 2001-08-06 | 2003-08-21 | Christopher Breder | Sequestered antagonist formulations |
PL367427A1 (en) | 2001-08-06 | 2005-02-21 | Euro-Celtique S.A. | Opioid agonist formulations with releasable and sequestered antagonist |
US20030044458A1 (en) | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US7666337B2 (en) * | 2002-04-11 | 2010-02-23 | Monosol Rx, Llc | Polyethylene oxide-based films and drug delivery systems made therefrom |
US7357891B2 (en) | 2001-10-12 | 2008-04-15 | Monosol Rx, Llc | Process for making an ingestible film |
US7425292B2 (en) * | 2001-10-12 | 2008-09-16 | Monosol Rx, Llc | Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom |
US8603514B2 (en) | 2002-04-11 | 2013-12-10 | Monosol Rx, Llc | Uniform films for rapid dissolve dosage form incorporating taste-masking compositions |
US20070281003A1 (en) | 2001-10-12 | 2007-12-06 | Fuisz Richard C | Polymer-Based Films and Drug Delivery Systems Made Therefrom |
US7910641B2 (en) * | 2001-10-12 | 2011-03-22 | Monosol Rx, Llc | PH modulated films for delivery of actives |
US8900497B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for making a film having a substantially uniform distribution of components |
US11207805B2 (en) | 2001-10-12 | 2021-12-28 | Aquestive Therapeutics, Inc. | Process for manufacturing a resulting pharmaceutical film |
US20190328679A1 (en) | 2001-10-12 | 2019-10-31 | Aquestive Therapeutics, Inc. | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
US20070154527A1 (en) * | 2001-10-12 | 2007-07-05 | Monosoirx, Llc | Topical film compositions for delivery of actives |
US8765167B2 (en) | 2001-10-12 | 2014-07-01 | Monosol Rx, Llc | Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions |
US8900498B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for manufacturing a resulting multi-layer pharmaceutical film |
US10285910B2 (en) | 2001-10-12 | 2019-05-14 | Aquestive Therapeutics, Inc. | Sublingual and buccal film compositions |
US20060039958A1 (en) * | 2003-05-28 | 2006-02-23 | Monosolrx, Llc. | Multi-layer films having uniform content |
US20110033542A1 (en) | 2009-08-07 | 2011-02-10 | Monosol Rx, Llc | Sublingual and buccal film compositions |
US8663687B2 (en) | 2001-10-12 | 2014-03-04 | Monosol Rx, Llc | Film compositions for delivery of actives |
US20100021526A1 (en) * | 2001-10-12 | 2010-01-28 | Monosol Rx, Llc | Ph modulated films for delivery of actives |
SI2425824T1 (en) | 2002-04-05 | 2017-06-30 | Mundipharma Medical Cee Gmbh | Pharmaceutical preparation containing oxycodone and naloxone |
US8017150B2 (en) * | 2002-04-11 | 2011-09-13 | Monosol Rx, Llc | Polyethylene oxide-based films and drug delivery systems made therefrom |
AU2003268015A1 (en) * | 2002-07-22 | 2004-02-09 | Kosmos Pharma | Packaging and dispensing of rapid dissolve dosage form |
WO2004026116A2 (en) * | 2002-09-19 | 2004-04-01 | The Regents Of The University Of California | Use of etodoclac to treat hyperplasia |
HUE038446T2 (en) | 2002-09-20 | 2018-10-29 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and methods |
US20040202717A1 (en) | 2003-04-08 | 2004-10-14 | Mehta Atul M. | Abuse-resistant oral dosage forms and method of use thereof |
TWI347201B (en) | 2003-04-21 | 2011-08-21 | Euro Celtique Sa | Pharmaceutical products,uses thereof and methods for preparing the same |
US7834147B2 (en) | 2003-04-28 | 2010-11-16 | Childrens Hospital Medical Center | Saposin C-DOPS: a novel anti-tumor agent |
CA2529984C (en) | 2003-06-26 | 2012-09-25 | Isa Odidi | Oral multi-functional pharmaceutical capsule preparations of proton pump inhibitors |
DE602005015838D1 (en) * | 2004-03-19 | 2009-09-17 | Tapemark Co | THERMOPLASTIC FILMS AND MANUFACTURING METHOD THEREFOR |
US20050208108A1 (en) * | 2004-03-19 | 2005-09-22 | Jannusch Leonard C | Thermoplastic films and methods for making |
JP2005335448A (en) | 2004-05-25 | 2005-12-08 | Yamaha Marine Co Ltd | Steering rod for outboard motor |
EP1604666A1 (en) | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
US8394409B2 (en) | 2004-07-01 | 2013-03-12 | Intellipharmaceutics Corp. | Controlled extended drug release technology |
US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
CA2591761A1 (en) * | 2004-12-27 | 2006-07-06 | Astellas Pharma Inc. | Stable particulate pharmaceutical composition of solifenacin or salt thereof |
US8691772B2 (en) | 2005-01-04 | 2014-04-08 | Yeda Research And Development Co. Ltd. | HSP60, HSP60 peptides and T cell vaccines for immunomodulation |
EP1702558A1 (en) | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
US20090068207A1 (en) * | 2005-04-15 | 2009-03-12 | Vascular Biogenics Ltd. | Compositions Containing Beta 2-Glycoprotein I-Derived Peptides for the Prevention and/or Treatment of Vascular Disease |
US20070048369A1 (en) * | 2005-08-26 | 2007-03-01 | National Starch And Chemical Investment Holding Corporation | Mucosal delivery tablet |
US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
EP1810669A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Application form for burprenorphine |
WO2007084587A2 (en) * | 2006-01-20 | 2007-07-26 | Monosol Rx, Llc | Film lined pouch and method of manufacturing this pouch |
EP1986602A2 (en) * | 2006-01-20 | 2008-11-05 | MonoSol Rx LLC | Film bandage for mucosal administration of actives |
US9561188B2 (en) | 2006-04-03 | 2017-02-07 | Intellipharmaceutics Corporation | Controlled release delivery device comprising an organosol coat |
US9271932B2 (en) | 2006-04-28 | 2016-03-01 | Children's Hospital Medical Center | Fusogenic properties of saposin C and related proteins and peptides for application to transmembrane drug delivery systems |
US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
EP2484346B1 (en) | 2006-06-19 | 2017-02-22 | Alpharma Pharmaceuticals LLC | Pharmaceutical compositions |
US7915247B1 (en) | 2006-08-21 | 2011-03-29 | Mutual Pharmaceutical Company, Inc. | Methods of use of fenofibric acid |
EP1897543A1 (en) | 2006-08-30 | 2008-03-12 | Euro-Celtique S.A. | Buprenorphine- wafer for drug substitution therapy |
JP4739452B2 (en) * | 2006-09-20 | 2011-08-03 | モノソル アールエックス リミテッド ライアビリティ カンパニー | Eatable water-soluble film containing flavor enhancer to reduce foaming |
CN101534799A (en) * | 2006-09-29 | 2009-09-16 | 莫诺索尔克斯有限公司 | Film embedded packaging and method of making same |
US20090061008A1 (en) * | 2007-08-30 | 2009-03-05 | Levy Mark M | Fiber/granule complex for treatment of the gi tract |
AU2008296971B2 (en) * | 2007-09-03 | 2014-10-02 | Nanoshift, Llc | Particulate compositions for delivery of poorly soluble drugs |
US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
PL2405915T3 (en) | 2009-03-10 | 2019-05-31 | Euro Celtique Sa | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
US8475832B2 (en) * | 2009-08-07 | 2013-07-02 | Rb Pharmaceuticals Limited | Sublingual and buccal film compositions |
US9224995B2 (en) | 2010-03-06 | 2015-12-29 | Husqvarna Ab | Battery powered tool and battery pack for a battery powered tool |
CN103209681B (en) | 2010-06-10 | 2017-05-24 | Mida科技有限公司 | Nanoparticle film delivery systems |
US9149959B2 (en) | 2010-10-22 | 2015-10-06 | Monosol Rx, Llc | Manufacturing of small film strips |
MX357655B (en) | 2011-11-15 | 2018-07-18 | Walter & Eliza Hall Inst Medical Res | Soluble mediator. |
US9757432B2 (en) | 2012-11-14 | 2017-09-12 | Ohio State Innovation Foundation | Materials and methods useful for treating glioblastorna |
KR20180037074A (en) | 2013-07-23 | 2018-04-10 | 유로-셀티큐 에스.에이. | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
CA3022840A1 (en) | 2016-05-05 | 2017-11-09 | Aquestive Therapeutics, Inc. | Enhanced delivery epinephrine compositions |
US11273131B2 (en) | 2016-05-05 | 2022-03-15 | Aquestive Therapeutics, Inc. | Pharmaceutical compositions with enhanced permeation |
WO2018208241A1 (en) * | 2017-05-10 | 2018-11-15 | İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi | Formulation and optimization of controlled release tablets of morphine sulphate |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1171691A (en) * | 1967-02-24 | 1969-11-26 | Forest Laboratories | Lond-Acting Oral Carrier |
NL159577B (en) * | 1968-02-15 | 1979-03-15 | Organon Nv | PROCESS FOR PREPARING FAST DISINTEGRATING SOLID PARTS. |
GB1405088A (en) * | 1971-06-03 | 1975-09-03 | Mundipharma Ag | Slow release formulation |
US3916899A (en) * | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US4039653A (en) * | 1974-01-23 | 1977-08-02 | Defoney, Brenman, Mayes & Baron | Long-acting articles for oral delivery and process |
JPS5438167B2 (en) * | 1974-04-27 | 1979-11-19 | ||
JPS5562012A (en) * | 1978-11-06 | 1980-05-10 | Teijin Ltd | Slow-releasing preparation |
GB2042888B (en) * | 1979-03-05 | 1983-09-28 | Teijin Ltd | Preparation for administration to the mucosa of the oral or nasal cavity |
US4259314A (en) * | 1979-12-10 | 1981-03-31 | Hans Lowey | Method and composition for the preparation of controlled long-acting pharmaceuticals |
IE49324B1 (en) * | 1979-12-19 | 1985-09-18 | Euro Celtique Sa | Controlled release compositions |
JPS5758615A (en) * | 1980-09-26 | 1982-04-08 | Nippon Soda Co Ltd | Film agnent and its preparation |
US4443428A (en) * | 1982-06-21 | 1984-04-17 | Euroceltique, S.A. | Extended action controlled release compositions |
CA1208558A (en) * | 1982-10-07 | 1986-07-29 | Kazuo Kigasawa | Soft buccal |
US4695591A (en) * | 1985-03-29 | 1987-09-22 | Schering Corporation | Controlled release dosage forms comprising hydroxypropylmethylcellulose |
-
1985
- 1985-06-11 GB GB858514665A patent/GB8514665D0/en active Pending
-
1986
- 1986-05-28 AT AT86304044T patent/ATE127687T1/en not_active IP Right Cessation
- 1986-05-28 DE DE3650390T patent/DE3650390T2/en not_active Expired - Fee Related
- 1986-05-28 EP EP86304044A patent/EP0205282B1/en not_active Expired - Lifetime
- 1986-06-02 IL IL78991A patent/IL78991A/en not_active IP Right Cessation
- 1986-06-02 ZA ZA864105A patent/ZA864105B/en unknown
- 1986-06-03 AU AU58284/86A patent/AU595801B2/en not_active Ceased
- 1986-06-03 US US06/870,027 patent/US4940587A/en not_active Expired - Lifetime
- 1986-06-09 CA CA000511153A patent/CA1277913C/en not_active Expired - Fee Related
- 1986-06-09 NO NO862287A patent/NO172027C/en not_active IP Right Cessation
- 1986-06-10 ES ES555899A patent/ES8707110A1/en not_active Expired
- 1986-06-10 FI FI862479A patent/FI88108C/en not_active IP Right Cessation
- 1986-06-10 JP JP61134739A patent/JP2513999B2/en not_active Expired - Lifetime
- 1986-06-10 DK DK273086A patent/DK273086A/en not_active Application Discontinuation
- 1986-06-10 KR KR1019860004594A patent/KR890002949B1/en not_active IP Right Cessation
- 1986-06-11 PT PT82746A patent/PT82746B/en unknown
Also Published As
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DE3650390D1 (en) | 1995-10-19 |
FI88108B (en) | 1992-12-31 |
EP0205282A3 (en) | 1987-08-26 |
AU595801B2 (en) | 1990-04-12 |
PT82746B (en) | 1988-04-21 |
US4940587A (en) | 1990-07-10 |
AU5828486A (en) | 1986-12-18 |
FI88108C (en) | 1993-04-13 |
ES8707110A1 (en) | 1987-07-16 |
ES555899A0 (en) | 1987-07-16 |
NO172027B (en) | 1993-02-22 |
KR890002949B1 (en) | 1989-08-14 |
KR870000068A (en) | 1987-02-16 |
ZA864105B (en) | 1987-01-28 |
NO172027C (en) | 1993-06-02 |
FI862479A (en) | 1986-12-12 |
JPS61286321A (en) | 1986-12-16 |
IL78991A0 (en) | 1986-09-30 |
NO862287L (en) | 1986-12-12 |
EP0205282A2 (en) | 1986-12-17 |
FI862479A0 (en) | 1986-06-10 |
GB8514665D0 (en) | 1985-07-10 |
DE3650390T2 (en) | 1996-04-04 |
IL78991A (en) | 1990-07-26 |
DK273086A (en) | 1986-12-12 |
PT82746A (en) | 1986-07-01 |
DK273086D0 (en) | 1986-06-10 |
NO862287D0 (en) | 1986-06-09 |
EP0205282B1 (en) | 1995-09-13 |
ATE127687T1 (en) | 1995-09-15 |
JP2513999B2 (en) | 1996-07-10 |
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