GB2103927A - Sub-dermal sustained-release pharmaceutical implants - Google Patents

Abstract

Sub-dermal sustained-release pharmaceutical implants for the administration release of a drug over an extended period in a human or animal system are prepared by microencapsulating a predetermined portion of the drug into micro- capsules of non-toxic bio-degradeable material (e.g. ethyl cellulose, cellulose acetate phthalate), dispersing said microcapsules into a supporting matrix formed from a blend of the remaining portion of the drug with a biocompatible/bioabsorbable biodegradable material (e.g. cholesterol, sitosterol), and compressing the mixture so obtained into pellets for use as sub-dermal implants. The drug may be acedapsone or primaquine phosphate.

Description

SPECIFICATION Sub-dermal drug implants and their production The present invention relates to sub-dermal drug implants for the controlled release of a drug over an extended period in a human or animal system.

For the administration of medicaments or drugs fro the treatment or diseases recourse is generally had to the oral or parenteral modes of administration. The medicaments or drugs usually employed are in the form of tablets, capsules, injectibles or suppositories. Unfortunately, the administration of medicines in this manner suffers a very acute disadvantage in that tablets, capsules, injectibles and so on do not ensure a substantially constant, therapeutically effective level of the drug in the bloodstream over a prolonged period of time. The reason for this lies in the short biological half-life of the drug.As a result, administration of medicine often has to be repeated several times a day in order to obtain the desired therapeutic effect and this frequently implies that in order to maintain the desired therapeutically effective level of the drug in the blood, a much larger quantity of the drug than is actually required has to be administered.

The shortcomings of the oral and parenteral modes of administration of drugs will be fairly obvious. In the first instance, the administration of a larger quantity of the drug than is actually required often causes adverse side-reactions in the subject being treated. Then, particularly in the case of administration by the oral route, failure to take the drug on time or at all becomes reasonably common due either to the patient forgetting to take the dose regularly at the appropriate time or through inaccessibility or unavailability of the drug. Such irregular administration of medicine can lead to complications such as drug resistance which may be difficult to control.

One of the alternatives to the standard mode of administration of drugs has been the sub-dermal drug implant which provides for the controlled release of a drug over an extended period of time.

A sub-dermal implant is usually in the form of a medicinal pellet containing a predetermined quantity of the appropriate drug located within a biocompatible/bioabsorbabie/biodegradable matrix. These pellets are adapted to be inserted, e.g. by means of a trocar, under the skin of a human or animal subject. Once inserted, the implants gradually degrade. The matrix dissolves and is absorbed by the body fluids and/or tissue while the drug contained within the implant is released at a controlled rate. Normally, in the case of humans, the implant is located under the skin of the arms or the thighs while in animals it is inserted beneath the skin of the neck. As can be appreciated, sub-dermal drug implants have found particular use in the treatment of diseases where long-term continuous drug therapy is required, e.g.

in the treatment of tuberculosis, leprosy, filaria, malaria, arthritis and in the control of fertility.

The manufacture of sub-dermal implants composed of a matrix made from polyglycolates, polylactates, polypeptides or similar polymers of hydroxyaliphatic fatty acids and containing as the drug substance one or more contraceptive steroids has been known for some time and such implants have been employed for contraceptive purposes in humans and in animals.

Unfortunately, as a result of the difference over a wide range in the molecular weights of the polymers employed for the matrices, the rate of release of the drug from implants made of such polymers has been found to be irregular. This irregularity makes it impossible for implants composed of matrices made from the abovementioned polymers to provide the desired controlled rate of release of the drug.

The applicants are aware of an attempt made to provide improved medicinal pellets for use as sub-dermal drug implants for the controlled release of a drug in humans or animals. According to this prior art process, the appropriate drug is fused with cholesterol by heating a mixture thereof at approximately 1 500 C. The fused product of such heating is cooled to room temperature, compressed into a pellet and sterilised by exposure to gamma radiation.

Unfortunately, it was found that when the subdermal drug implants prepared by such prior art process were inserted beneath the skin of a subjet, the initial rate of release of the drug was extremely high. As a result, the level of the drug in the blood during the first five to seven days after insertion was sometimes from fifteen to twenty times higher than the required therapeutically effective level. Obviously, such an initially high rate of release of the drug is undesirable because of the adverse side effects or allergic reactions produced thereby and the increased level of toxicity in the human or animal system.

It is, therefore, the primary object of the present invention to provide an improved sub-dermal drug implant which on a single administration is capable of controlled release of the drug over an extended period of time in a human or animal system, thereby ensuring a constant therapeutically effective level of the drug in the bloodstream. The new sub-dermal drug implant produces no tissue reaction or adverse sideeffects such as allergic reactions in the subject and is composed of a carrier or matrix which is entirely biocompatible and bioabsorbable within the body of the subject treated.

The essential novelty of the present invention resides in the applicants' discovery that by microencapsulating the drug sought to be administered, incorporating the microcapsules within a carrier or matrix composed of a blend of a biocompatible/bioabsorbable/biodegradable material with a portion of the drug itself and compressing the mass so obtained into pellets, there are obtained sub-dermal drug implants which when inserted beneath the skin of human or animals achieve an evenly controlled release of the drug over an extended period without adverse side-effects or tissue reaction. For convenience of reference, the biocompatible/bioabsorbable/ biogegradable material employed for the carrier or matrix will hereinafter be referred to simply as 'bio-material'.

Accordingly, the present invention provides a sub-dermal implant for the controlled release of a drug in the form of a pellet comprising a supporting matrix formed of a blend of a predetermined part of the drug with a biocompatible/bioabsorbable/biodegradable material, the said matrix having a plurality of microcapsules embedded therein, the said microcapsules containing the remainder of the drug within shells of biologically compatible material.

According to a feature of the invention, the new implants are made by forming a plurality of microcapsules each containing a predetermined portion of the said drug within a protective shell of a biologically compatible material, forming a matrix for support of said microcapsules by blending the remaining portion of the said drug within a bio-material as herein described, locating said microcapsules within said matrix by intimately mixing together said drug-containing microcapsules and the blend of remaining drug and bio-material, and compressing the mixture so produced into pellets adapted to be employed as the improved sub-dermal drug implants.

It is the microencapsulation of the drug within the degradable matrix that is essentially responsible for the controlled release of the drug over a prolonged period of time. In fact, experiments with implants of the present invention have established that such controlled release of the drug at a slow but constant rate extends to well over 100 days thus overcoming the disadvantages normally associated with the short half-life of drugs. A high initial release rate of the drug immediately after insertion of the implant is controlled and the quantum of drug released by the implant and distributed through the body fluids was found to result in a drug level only a little higher, i.e. three or four times higher, than the therapeutically effective level of the drug in the bloodstream.Over and above this, the duration of the drug release into the body fluids was found to increase considerably.

The biologically compatible material employed for forming microcapsules is preferably cellulose ether or other cellulose derivative such as ethyl cellulose or cellulose acetate phthalate.

The bio-materiai forming the matrix for support of the microcapsules is a biocompatible, bioabsorbable, biodegradable naturally occurring sterol. The most important of such naturally occurring sterols are cholesterol and /3-sitosterol but other similar biologically compatible sterols can also be employed.

According to a preferred feature of the invention the blending for formation of the matrix of the implants is effected by heating together said remaining portion of the drug and said biomaterial at a temperature in the range of from 1 400C to 1 600C to form a molten mass, cooling the molten mass so produced, and finely powdering the cooled mass to a micro-particle size of from 60 to 120 mesh.

However, care must be exercised in the blending and heating of the drug and the biomaterial. The blended ingredients are required to be heated gradually to a temperature where they just melt and once this molten stage is reached, the source of heat should be immediately removed and the molten mass quickly cooled.

In the case of drugs which are sensitive to heat and could therefore deteriorate when heated, the invention provides an alternative procedure of blending for formation of the matrix of the improved drug implants. According to this alternative feature, the blending is effected by dissolving the said remaining portion of the drug and bio-material in an organic solvent, removing said solvent from the solution to obtain a solid mass, and finely powdering the mass so obtained to a microparticle size of from 60 to 120 mesh.

Preferably, the solvent is removed under reduced pressure or in vacuo at a temperature below 450C., preferably below 400 C.

The formation of the microcapsules of the drug dispersed within the implant of the present invention is preferably effected by means of organic phase separation. Such organic phase separation comprises dissolving in an organic solvent the biologically compatible material adapted to form the shell of the capsules, adding to the solution thus formed a predetermined portion of said drug and stirring said solution until a suspension of the drug is obtained, adding slowly to the suspension while still stirring an amount of petroleum ether until coacervation takes place, further stirring the suspension, discontinuing the stirring to enable the coacervated microcapsules containing the drug to settle, and separating the formed microcapsules from the solvent, e.g. by decantation of the solvent.The stirring of the drug into the solution for formation of the suspension can be continued for the period of up to four hours while the suspension itself may be further stirred for about one hour to enable the coacervated microcapsules to settle.

The organic solvent employed for dissolving the drug and bio-material for the formation of the matrix or that employed in the organic phase separation for formation of the microcapsules can be e.g., alcohol, chloroform, acetone, ethyl acetate and the like.

For the formation of the pellets from the mixture of the microcapsules and matrix/blend, the mixture is treated with a binding agent in an amount of from 1% to 5% of the weight of the mixture prior to compressing the latter into tablets. The binding agent is preferably glyceryl monostearate, glyceryl distearate or glyceryl tristearate. The compressed pellets are then sterilised, for instance by subjecting them to gamma radiation or exposing them to ethylene oxide vapour.

For each improved sub-dermal drug implant produced by the process of the present invention the drug blended with the bio-material of the matrix, the bio-material itself and the drug within the microcapsules are found to exist in a ratio of from 1:1:1 to 1:2:4. More preferred ratios are 1:2:1, 1:2:2 and 1:2:3.

In general, an implant produced by the process of the present invention contains from about 25 to 300 milligrams of drug, about 30 to 200 milligrams of bio-material, and about 20 to 400 milligrams of the biologically compatible material forming the microcapsules.

The invention is illustrated in the following Examples.

EXAMPLE I A. 25 milligrams of finely powdered acedapsone were intimately mixed with 25 milligrams of cholesterol and mixture was gently heated to between 1 400C and 1 600C with constant stirring to bring about a completely molten blend of the two substances but taking care to ensure that no decomposition of either took place. As soon as a completely molten blend was achieved, the source of heat was immediately removed and the blend cooled quickly to give a solid mass which was then finely powdered to a microparticle size of from 60 to 120 mesh.

B. In a separate procedure, 20 milligrams of ethyl cellulose and 10 milligrams of cellulose acetate phthalate were dissolved in 10 ml of acetone. 100 milligrams of finely powdered acedapsone were added to the solution which was stirred vigorously. Stirring was continued until the acetone was completely evaporated leaving microencapsulated acedapsone as the resulting product. The latter was then micronised.

The end products of operations A and B were then combined and intimately mixed with 5 milligrams of glyceryl tristearate. The mixture was then compressed into a cylindrically shaped pellet about 8 mm in length and 2.5 mm in diameter.

The pellet thus prepared was placed within a sealed glass or polythene tube and sterilised by means of gamma radiation at 2.5 megarads.

EXAMPLE II A. 35 milligrams of finely powdered rifampicin and 50 milligrams of cholesterol were dissolved in 25 ml of chloroform. The solvent was then evaporated and the resulting amorphous powder was micronised to a size of from 100 to 120 mesh.

B. Separately, 40 milligrams of ethyl cellulose were dissolved in 20 ml of acetone. 100 milligrams of finely powdered rifampicin were added to the solution which was stirred for four hours. Petroleum either at a temperature of 400C to 600C was added slowly to the suspension at a rate of about 1 ml per minute until coacervation of the suspension took place. After stirring for another hour, microcapsules of rifampicin settled down and the supernatant solvent was decanted off. The microcapsules so formed were washed three times with additional petroleum ether and the washings also decanted off. The residual microcapsules were then dried.

The end products of operations A and B were intimately mixed together and the mixture compressed into a tiny pellet about 10 mm in length and 2 mm in diameter. The pellet was then sterilised by means of gamma radiation.

EXAMPLE Ill A. 25 milligrams of primaquine phosphate were intimately mixed with 50 milligrams of p-sitosteroi and the mixture was gently heated until it just became molten. The molten mass was then immediately removed from the source of heat and cooled quickly to give a solid mass which was then finely powdered to a microparticle size of from 80 to 120 mesh.

B. In a separate procedure, 100 milligrams of ethyl cellulose were dissolved in 20 ml methyl ethyl ketone under stirring at 600C. 100 milligrams primaquine phosphate were added to the solution which was vigorously stirred for another one hour. 75 ml of hexane were then added in five equal portions of 1 5 ml each under stirring for a further two hours. After stirring was stopped, the coacervated microcapsules settled down and the supernatant solvent was decanted off. The residual microcapsules were then dried.

The end products of operations A and B were intimately mixed together along with 5 milligrams of glyceryl tristearate. The mixture so prepared was compressed into a small pellet of a size about 8 mm in length and 2 mm in diameter. The pellet was then sterilised by exposure to ethylene oxide vapour.

The sub-dermal drug implants prepared by the process of the present invention show clear advantages over anything known in this field in the past. By microencapsulating the drug within the matrix of bio-material, the initial high rate of release of the drug which was a feature of prior art implants has been done away with. At the same time, the implants of the present invention maintain the drug in the blood at a level sufficiently in excess of the requisite therapeutic level. Experiments have shown that the release ensures a level three to four times in excess of the therapeutically effective level.

As a result of the avoidance of a high initial release of the drug, it has proved possible to achieve a longer overall duration of release of the drug with the implants of the present invention. In the case of prior art implants, this duration extended for about 60 to 100 days. On the other hand, the implant of the present invention is capable of a controlled release of drug into the bloodstream for considerably longer periods of from 100 to 1 50 days while maintaining the level of the drug in the blood above the therapeutically effective level.For instance, in the case of acedapsone, the requisitive therapeutically effective level of the drug in the blood is approximately 0.02 zlg/ml It was-found that when an implant prepared according to the present invention was inserted below the skin of a subject, the amount of acedapsone released initially was from approximately 0.05 to 0.1 Hg/ml which level reduced to about 0.03 to 0.05 ,ug/ml after 10 days and remained at the latter level for approximately 1 50 days. Such a well controlled release has not been achieved by any other drug delivery system of which the applicants are so far aware of this fact removes any risks of toxicity in the subject's system as a result of excessive release of the drug.

Such controlled release of the drug from the implants of the present invention has been made possible by the use of naturally occurring sterols for the formation of the matrix. These sterols with their definite molecular weights represent a vast improvement on earlier matrices prepared from polymers of hydroxy aliphatic fatty acids the molecular weights of which vary over wide ranges.

Cholesterol has been suggested as the material for forming the matrix. However, according to the present invention, it has been established that naturally occurring sterols other than cholesterol can be employed. Research to determine this was particularly effected in view of the fact that the use of cholesterol, even in small amounts, is not generally favoured by the medical profession.

The choice of a biocompatible/bioabsorbable/ biodegradable material for the matrix and the slow release of the drug from the implant of the present invention ensure an entirely harmless manner of absorption of both matrix and drug within the body fluids and the blood.

Claims (21)

1. A sub-dermal implant for the controlled release of a drug in the form of a pellet comprising a supporting matrix formed of a blend of a predetermined part of the drug with a biocompatible/bioabsorbable/biodegradable material, the said matrix having a plurality of microcapsules embedded therein, the said microcapsules containing the remainer of the drug within shells of biologically compatible material.

2. An implant as claimed in claim 1, wherein the biologically compatible material forming the shell of the microcapsules is a cellulose ether or other cellulose derivative.

3. An implant as claimed in claim 2, wherein the said cellulose derivative is ethyl cellulose or cellulose acetate phthalate.

4. An implant as claimed in any of claims 1 to 3, wherein the said biocompatible, bioabsorbable, biodegradable material is a naturally occurring sterol.

5. An implant as claimed in claim 4, wherein the said sterol comprises cholesterol, p-sitosterol or a similar naturally occurring sterol.

6. An implant as claimed in any of claims 1 to 5, wherein the amount of drug blended with the biomaterial, the biomaterial and the amount of drug within the microcapsules are in a ratio of from 1:1:1 to 1:2:4.

7. An implant as claimed in claim 6, wherein the said ratio is 1:2:1, 1:2:2, or 1:2:3.

8. An implant as claimed in any of claims 1 to 7, wherein the matrix contains a binding agent in an amount of from 1% to 5% of the weight of the mixture.

9. An implant as claimed in claim 8, wherein the binding agent is glyceryl monostearate, glyceryl distearate or glyceryl tristearate.

1 0. Process for producing a sub-dermal implant as claimed in any of claims 1 to 9 which comprises forming a plurality of microcapsules each containing a predetermined portion of the said drug within a protective shell of a biologically compatible material, forming a matrix for support of the said microcapsules by blending the remainder of said drug with the biomaterial, locating sa,d microcapsules within the said matrix by intimately mixing together said drug-containing microcapsules and the blend of remaining drug and biomaterial, and compressing the mixture so produced into pellets adapted to be employed as sub-dermal drug implants.

11. Process as claimed in claim 10, wherein the blending for formation of the said matrix is effected by heating together the said remainder of the drug and said biomaterial at a temperature in the range of from about 1400 to 1600C to form a molten mass, cooling the molten mass so produced, and finely powdering the cooled mass to a microparticle size of from 60 to 120 mesh.

12. Process as claimed in claim 10, wherein the blending for formation of said matrix is effected by dissolving the said remaining portion of the drug and the said bio-material in an organic solvent, removing said solvent from the solution to obtain a solid mass, and finely powdering the mass so obtained to a microparticle size of from 60 to 120 mesh.

1 3. Process as claimed in claim 12, wherein the solvent is removed under reduced pressure at a temperature below 450C.

14. Process as claimed in any of claims 10 to 13, wherein the formation of the microcapsules is effected by organic phase separation.

1 5. Process as claimed in claim 14, wherein said organic phase separation comprises dissolving in an organic solvent the biologically compatible material adapted to form the shell of the capsules, adding to the solution thus formed a predetermined portion of said drug and stirring said solution until a suspension of the drug is obtained, adding slowly to the suspension while still stirring an amount of petroleum ether until coacervation takes place, further stirring the suspension, discontinuing the stirring to enable the coacervated microcapsules containing the drug to settle, and separating the formed microcapsules from the solvent.

1 6. Process as claimed in any of claims 12 to 15, wherein said organic solvent is alcohol, chloroform, acetone, ethyl acetate, or methyl ethyl ketone.

17. Process as claimed in any of claims 10 to 16, wherein the compressed pellets are sterilised.

18. Process as claimed in claim 17, wherein the said sterilisation is effected by exposing the pellets to gamma radiation.

19. Process as claimed in claim 17, wherein the said sterilisation is effected by exposing the pellets to ethylene oxide vapour.

20. Process for producing sub-dermal drug implants for the controlled release of a drug over an extended period in a human or animal system.

substantially as herein described in any of the foregoing Examples.

21. Sub-dermal drug implants for the controlled release of a drug over an extended period in a human or animal system, whenever produced by the process claimed in any of claims 10 to 20.