WO1984000304A1

WO1984000304A1 - Injectible sustained release dosage cylinders

Info

Publication number: WO1984000304A1
Application number: PCT/US1982/000927
Authority: WO
Inventors: Mitchell Harman
Original assignee: Mitchell Harman
Priority date: 1982-07-08
Filing date: 1982-07-08
Publication date: 1984-02-02
Also published as: EP0113713A1

Abstract

A device (10) for administering elongate medicinal pellets (13) in subcutaneous applications. The device includes a hand-held guide element (11) including a hollow barrel (16) enclosing a sliding member (30) having a needle locking means at one end thereof. A disposable cartridge element (12) includes a hollow needle (40) containing a pellet to be implanted and an obturator (44) of length somewhat greater than that of the needle. In use, the cartridge element is engaged at an end thereof with the guide element. The free end of the needle is inserted into the subcutaneous fat of the patient, and the sliding member is moved in an opposite direction to withdraw the needle into the hollow barrel. During this movement, the obturator is maintained relatively stationary by engaging an abutment on the guide element, at one end thereof, the opposite end of the obturator engaging an end of the pellet, so that as the needle is withdrawn, the pellet remains in implanted position. A composite pellet having a core formed of a first ingredient, and a surrounding sleeve formed of a second ingredient is also disclosed.

Description

INJECTIBLE SUSTAINED RELEASE DOSAGE CYLINDERS Background of the Invention This invention relates generally to the field of surgical instrumentation, and more particularly to an improved means and method for administering certain solid form medicaments in subcutaneous applications.

While most subcutaneous applications involve the use of a liquid medicament injected through a syringe, some treatments require the introduction of small a- mounts of medicament into the blood stream on a sub¬ stantially continuous basis over an extended period of time. This requirement is best fulfilled by the use of a medicament in solid .pellet form, the exposed surfaces of which continuously dissolve into the blood stream.

A typical example of this procedure is the treat¬ ment of menopausal estrogen deficiency in women using 17 beta-estradiol pellet implants. Such replacement has a number of important salutory effects. In the known method, the implanted does is in the form of compressed, cylindrical pellets containing 25 mg. of 17 beta- estradiol without excipient. The pellets measure appro¬ ximately 3.2 mm. in diameter and are 3.5 mm. long. Implantation is effected using a cannula with the same inside diameter as that of the pellet (3.2 mm.) and provided with two trocars. A first trocar 'is pointed for introducing the cannula, and a second trocar is blunt for inserting the pellet thereafter. After a small quantity of local anesthesia has been injected intra and subcutaneously, a small incision is made through the skin with a pointed scalpel blade. Through this incision the cannula with the pointed trocar is inserted several cm. into the subcutaneous fat, and nearly parallel to the skin, after which the implant pellet is inserted into the cannula and pushed there through using the blunt trocar, following which the cannula is withdrawn. One or two sutures may be re¬ quired to close the incision. While a skilled physician can often complete the procedure in a few minutes, the cannula and the trocars must be sterilized for each use, and the procedure can hardly be considered convenient. Furthermore the known pellet is of such a size that the continued administration of estrogen lasts approximately three months.

There is considerable medical authority to the effect that optimum treatment for women who require estrogen replacement therapy is by administering small daily doses of estradiol for three to four weeks fol¬ lowed by five or seven days off, with the addition of a small dose of an "opposing" progestin during the last week of the estrogen treatment, at present, following the use of oral medication. It is increasingly apparent from well-conducted medical research that the oral route exposes the liver to unphysiologically high blood high doses of estrogen, resulting in altered liver protein synthesis and increased risks of various untoward ef¬ fects including: high blood pressure, increased clot¬ ting of blood (phlebitis, lung clots, and cerebral clots) , altered blood lipids (possible increased risk of coronary artery disease) , and benign vascular tumors of the liver itself (which may rupture and bleed) .

As detailed above, the alternative parenteral method for supplying estrogen directly to the systemic circulation results in prolonged exposure to unopposed and continuous exposure to unopposed and continuous estrogen. Such unopposed and continuous exposure to estrogens, by either the oral or parenteral route, has been shown to result in an increased risk of uterine cancer. Therefore the ideal method would use a small pellet, lasting only three-four weeks, provide for progestin administration to mature the uterine lining, and be convenient and painless enough that monthly repetition would be feasible for most patients. The other parenteral alternative, utilizing intramuscular injection of estradiol in oil, results in transient very high estrogen levels, slowly decreasing in an unpre¬ dictable fashion, and is painful. The invention des¬ cribed herein is designed to overcome the objections and side effects of such replacement therapy.

Summary of- he Invention An elongated cylindrical pellet is provided con¬ taining a drug suitable for subcutaneous release into the tissue of a patient for systemic effect, said cylin¬ drical pellet containing a sufficient quantity of said drug for sustained systemic effect to a patient, the diameter of said cylindrical pellet being less than about one millimeter, said cylindrical pellet addition¬ ally being adapted to fit inside a hollow sleeve of a hypodermic needle.

A device for affecting the subcutaneous implacement of a solid pellet medicament is provided which com¬ prises: an elongated rigid guide element having, a first relatively fixed member having manually engageable operating means and abutment means thereon, and a second member slideably engaged with said first member, having a first and a second end, said first end having manually engageable operating means at said first end and a cartridge engaging means on said second end; and an elongated cartridge including, a hollow needle member having a first free end adapted for piercing the skin of a patient and with a diameter sufficient for receiving the solid pellet medicament therewithin, and a second end having a hub engageable with said cartridge engaging means on said second member and engaged therewith, and an elongated obturator of a length greater than that of said needle member, said obturator having a first end slideably positioned within said second end of said needle member, and a second end abutting said abutment on said first member.

Brief Description of the Drawings

In the drawings, to which reference will be made in the specification, similar reference characters have been employed to designate corresponding parts through¬ out the several views.

Figure 1 is a perspective side view, partly broken away to show detail of an embodiment of the invention, with a disposable needle cartridge removed.

Figure 2 is a central longitudinal sectional view thereof with the needle cartridge attached, wherein the apparatus is in the "ready" or pre-injection config¬ uration.

Figure 3 is a central sectional view of a needle cartridge element in detached condition.

Figure 4 is a central longitudinal sectional view of a pellet element.

Figure 5 is an end elevational view of the pellet element shown in Figure 4.

Figure 6 is a central longitudinal sectional view thereof, with needle cartridge attached, and showing the device in "discharged" or post-injection configuration. Detailed Description of the Disclosed Embodiment

The invention contemplates the provision of an improved device for the subcutaneous implantation of a solid elongated composite pellet in a manner somewhat resembling the administration of of a liquid drug using a conventional hypodermic syringe. The device includes a hollow cylinder slidably mounting a pair of arms having a cartridge engaging terminal at a distal end thereof. A disposable sealed, pre-sterilized cartridge element includes a hollow needle with means at the base or hub thereof for engaging said terminal. A pellet of cylindrical configuration is positioned in the needle, and a blunt obturator extends through the base of the needle. After subcutaneous insertion, the guide arms

_0MPI are moved outwardly within the cylinder to result in the withdrawal of the needle. Following implantation of the pellet, the cartridge element is discarded. The pellet may be of either of two types. For example, a single composition pellet such as a pure estradiol pellet delivers estrogen only which may be supplemented at the end of a cycle by orally administering progestin. A second type of pellet with a core of a different drug might contains a 0.2 mm core of progesterone estradiol mixture to release progestin during the last one third of the cycle. The exact size and proportional mix of the core may be varied to suit specific requirements.

In accordance with the invention, the device, generally indicated by reference character 10, comprises broadly: guide element 11, and disposable needle car¬ tridge element 12 including a pellet element 13.

Guide element 11 is reusable, and is preferably formed of metallic construction. It includes hollow elongated barrel 16, first end 17 which is provided with finger grips 18 on outer surface 19. Removable (thread¬ ed) end wall or cap 20 includes a centrally disposed internally facing projection 21 forming an abutment, and first and second through openings 22 and 23. Second end 24 is partially closed by wall 25 having centrally dis¬ posed opening 26. Disposed within barrel 16 is slide member 30, first end 31 having manually engageable grip 32 supported on the end of first and second elongated arms 33 and 34 which pass through openings 22 and 23, respectively. The opposite end of arms 33 and 34 sup¬ port cylinder 37 having centrally disposed recess 38 and cartridge engaging means 39 which may be of luer or bayonet type for quick attachment. An alternate means (not shown) comprises a simple threaded interconnection. Cartridge element 12 includes hollow needle member 40 having pointed tip 41, second end 42 including hub 43 having engagement means corresponding to means 39. Obturator 44 includes first end 45 which engages

O PI abut ent 21 and second end 46 which extends into the base of needle member 40 at 47.

Pellet element 15 contains 8 mg of estradiol and is of diameter 0.6 corresponding to the bore of the needle, and is 20 mm. in length. It may include a core of diameter approximating 0.2 mm of progesterone/estradiol mixture to release progestin during the latter one third of the cycle, which core is then surrounded by a pure estradiol sleeve of outer diameter 0.4 mm. This size pellet element is calculated to provide normal physio¬ logic levels of estradiol for three to four weeks before being completely absorbed. Adjustment of exact size and progesterone content may be necessary following appro¬ priate experimentation.

Administration of the pellet will be apparent from a consideration of the drawings. To conveniently as¬ semble the device, threaded end wall 20 or cap may first be removed from the barrel 16 with its sliding arms 33-34 and cylinder-lock 37. Disposable cartridge 12 is then attached to cylinder-lock 37 so that obturator 44 passes through the cylinder and comes to rest with its free end 15, in abutment 21 of cap 20. The cartridge is then passed down barrel 16 to emerge through the central opening 26 and the cap rethreaded into place on barrel 16. Figure 2 shows assembled device 10 with the needle inserted into the subcutaneous fat of a patient. At this point, the pellet is positioned in the desired implant location, and the device is then removed by leaving guide element 11 in the location shown, and while holding barrel grips 18, slide grip 32 is moved outwardly to result in withdrawing needle member 40 while maintaining obturator 44 in place. This results in uncovering the pellet, in situ in a progressive fashion until slide member 30 has reached its outermost position, at which point end 46 of the obturator has passed the free end of the needle. The pellet, at this

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-fy Sλ . WIPO _, point is completely disengaged, and the device may be removed without difficulty.

For a completely disposable device as required, it is possible to eliminate the guide element, and place manually engageable means on a somewhat enlarged hub of the cartridge element which may be engaged between the index and third fingers of the hand, and the outer end of the obturator may be provided with thumb engaging means. In such case, index means is provided on the outer surface of the obturator to indicate when the needle member has been completely withdrawn.

A hypodermic syringe contemplated for use with the above pellet must have a relatively narrow needle in order to be relatively painless for a patient and pro¬ vide so minimal a wound as to not require suturing. Perhaps the largest interior bore diameter that could be remotely contemplated for injection into a patient would be 17 gauge (1.06) mm, and even that gauge would not be considered sufficiently small for most patients. Such a large gauge bore would cause the patient much pain, no matter how skillful the physician or nurse that would make the injection, so that a maximum interior bore for a needle of the present invention when defined in terms of the bore of a hypodermic syringe would not be greater than about 1 mm (i.e., an 17 gauge maximum bore would be 1.06 mm) .

Opioid antagonist delivery over a period of 24 hours is contemplated in accordance with the present invention which would typically indicate the use of from about 0.1 to about 10 mg total dose of Naloxone, and preferably about 2.5 mg. Alternatively, about 0.1 to about 10 mg total dose of Naltrexone may be substituted for the Naloxone, and preferably about 0.5 mg. A third opioid antagonist that may be used is Nalmetrene which is present in a total dosage of from about 0.1 to about 10 mg, and preferably about 0.5 mg.

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. AV.^W°.., Opioid analgesic delivery over a period of 24 hours is also contemplated in accordance with the present invention which would typically include the use of from about 1 mg to about 15 mg total dose of Oxymorphone, and preferably about 6 mg. Also, about 1 to about 15 mg total dose of Hydromorphone may be substituted for Oxymorphone, preferably about 6 mg. Another opioid analgesic that may be used is Etorphine which would have a total dose from about 0.01 mg to about 0.1 mg, pre¬ ferably about 0.05 mg.

Anti-hypertensive delivery over a period of 30 days is also contemplated in accordance with this invention, which would typically include from about 1 mg to about 15 mg of Clonidine, and preferably about 3 mg.

Q.'. I

Claims

I claim:

1. An elongated cylindrical pellet containing a drug suitable for subcutaneous release into the tissue of a patient for systemic effect, said cylindrical pellet containing a sufficient quantity of said drug for sustained systemic effect to said patient, the diameter of said cylindrical pellet being less than about one mm, said cylindrical pellet additionally being adapted to fit inside a hollow sleeve of a hypodermic needle.

2. A cylindrical pellet of claim 1, wherein said drug is for the treatment of women who have reached the stage of menopause.

3. A cylindrical pellet of claim 2, wherein said drug is estradiol.

4. A cylindrical pellet of claim 1, wherein said diameter is about 0.6mm.

5. A cylindrical pellet of claim 1 or 4, wherein said pellet contains an inner cylindrical core of progesterone.

6. A device for affecting the subcutaneous implacement of a solid pellet medicament, comprising: an elongated rigid guide element having, a first relatively fixed member having manually engageable operating means and abutment means thereon, and a second member slideably engaged with said first member, having a first and a second end, said first end having manually engageable operating means at said first end and a cartridge engaging means on said second end; and an elongated cartridge including, a hollow needle member having a first free end adapted for piercing the skin of a patient and with a diameter sufficient for receiving the solid pellet medicament therewithin, and a second end having a hub engageable with said cartridge engaging means on said second member and engaged therewith, and

OMPI an elongated obturator of a length greater than that of said needle member, said obturator having a first end slideably positioned within said second end of said needle member, and a second end abutting said abutment on said first member.

7. A device in accordance with claim 6, further characterized in said first member having a hollow barrel for receiving said second member, and said second member having a pair of arms connecting said first end thereof to said second end, said manually engageable operating means of said first end being an annular grip, and said second end terminating in a cylinder having said cartridge engaging means.

8. A needle element for the subcutaneous implanting of a medicamentcontaining pellet, comprising: a hollow needle element having a pointed first free end of sufficient sharpness for piercing the skin of a patient and a second end terminating in a hub, said needle element having the general diameter of the needle of a hypodermic syringe, with an inside diameter and configuration sufficient to accept the medicament¬ containing pellet; an obturator of length greater than said needle element and at least partially disposed within said needle element such that the relative movement between said needle element and said obturator in a given dir¬ ection will eject said medicament containing pellet from with said needle element; and said hub having instrument engaging means thereon for maintaining said obturator in an immobile position while said needle element is withdrawn around it.