DESC:Field of the invention
The present invention relates to a new form of pharmaceutical preparation and more particularly to a biodegradable implant adapted to be located within a specified region of the body for releasing the drug buprenorphine at a sustained rate for systemic utilization.

Background of the invention
Buprenorphine also known as (2S)-2-[(-)-(5R,6R,7R,14S)-9a-cyclo-propyl-methyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-di-methyl-butan-2-ol and the structure of buprenorphine is shown in Formula 1

Formula 1

Buprenorphine is a semi-synthetic opiate classified as a “partial agonist” behaves very much like classical µ agonists such as morphine, exerting an analgesic effect through high affinity binding to µ subclass opiate receptors in the central nervous system.Buprenorphine is most often used to treat symptoms arisingfrom opioid addiction and for the long term relief of pain.Currently, the commercial products are Subutex™ andSuboxone™ marketed by RB Pharma Inc. These productsare in a tablet formulation and are intended to deliver therapeuticlevels ofbuprenorphine for short periods of time of upto several hours and are typically taken either buccally or sub-lingually. However, the patient is required to supplementthis dose at regular intervals, and there are often issues withdiversion in patients with an opioid dependence problem.
In the treatment of opioid addiction, buprenorphine is gaining favour due to its efficacy and superior safety profile compared with methadone and other drugs.(e.g. L-alpha-acetyl-methadol) (Strain et al. 1994; Johnson et al. 2000). Due to its mixed agonist-antagonist effects on the opioid receptor, high doses of buprenorphine usually do not cause significant complications (Lewis, 1985; Walsh et al. 1994). Where the supervision of dosing is required, frequent visits to the clinic or pharmacy reduce patients independence and incur significant staff time and cost (Kakko et al. 2007; Byrne and Wodak, 2007). These limitations of standard buprenorphine treatment have raised in the development of alternative formulations (Sobel et al. 2007; Lanier et al. 2007). An implantable, long-term delivery formulation of buprenorphine could improve treatment by ensuring compliance, maintaining stable blood plasma concentrations of the drug and reducing the likelihood of abuse and diversion.

An implantable device of buprenorphine is marketed by Titan Pharmaceuticals with the brand name Probuphine®byusingabiocompactible, non-erodablecopolymer,ethylene vinyl acetate (EVA) which is disclosed in patents US7736665, US10111830 and US10123971.This implantable device consists ofa polymeric matrix of ethylene vinyl acetatecopolymer blended withbuprenorphine, wherein buprenorphine iscontinuously released in vivo over a sustained period of timethrough pores that open to the surface of the matrix at a ratethat results in a steady state plasma buprenorphine level of about 0.1 ng/ml to 1 ng/mlfor 6 months of treatment foropioid addiction, wherein the implantabledevice has the dimensions of about 1.5 mm to 5 mm in diameter and about 0.5 cm to 7 cm in length.The ethylene vinyl acetate copolymer (EVA) is a non-erodable polymer and does not degrades within the body, sothe implant has to be removed from the body at the end of 6 months treatment.

Probuphine® implants has the drawbacks like during removal of implants, there is a greater risk of injury to neural and vascular structures located deeper than the subdermal space. Also Probuphine®implants should not be used for patients who are new entrants to buprenorphine treatment and it can be used only in patients who meet the criteria like the patients who has achieved sustained and prolonged clinical stability on transmucosal buprenorphine or the patients are currently on a maintenance dose of 8 mg per day or less of a Subutex or Suboxone sublingual tablet or its transmucosal buprenorphine product equivalent or the patients with stable transmusosal buprenorphine dose of 8 mg per day or less of a sublingual subutex or suboxone sublingual tablet or its transmucosal buprenorphine product equivalent for three months or longer without any need for supplemental dosing or adjustments.Probuphine® serves as a suitable alternative to daily or alternate day sublingual buprenorphine compositions which can thereby eliminate the need for daily supervision, minimizing fluctuations in plasma concentrations and allowing these patients to reduce frequent clinic or pharmacy visits.

Another patent application CN111714442 A discloses a method of preparing poly(lactic-co-glycolic acid) copolymer implant of buprenorphine by hot-melt extrusion method which comprises a) mixing an active pharmaceutical ingredient with poly(lactic-co-glycolic acid) (PLGA) to obtain a first mixture; b) mixing the first mixture with a first solvent to obtain a second mixture, wherein the first solvent can dissolve in the water-ethanol mixture and can dissolve the polylacticacid-glycolic acid copolymer; c) extruding the second mixture to obtain a first extrudate; and d) immersing the first extrudate in a water-ethanol mixture to obtain the implant.

Indivior UK Ltd has filed patents US8921387, US8975270, US9272044, US9498432, US9782402, US9827241 and US10198218 which disclosesan injectable flowable composition of buprenorphine along with poly(DL-lactide-co-glycolide) polymer and organic solvents such as N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, PEG, or any combination thereof, wherein the composition is a liquid or a gel form and when injected into the body whereupon the composition is transformed in situ into a solid implant by contact with water, body fluid or other aqueous medium. Thecomposition is administered once per month by subcutaneous injection. The blood levels of buprenorphine obtained with the sustained release delivery system are from about 0.5 ng/mL to 20 ng/mL after a 60 mg buprenorphine dose injection. In situ forming implant has the disadvantages like initial rapid drug release prior to solidification of the polymer, the use of organic solventleads to toxicity and high viscosity of the polymeric solution cause problems during administration.(Nirmala Musmade, Anil Jadhav, PriyankaMoin et al; An overview of in situ gel forming implants; published 07 Feb, 2019).

The biocompatible, non-erodable implant of buprenorphine marketed as Probuphine® is indicated for the maintenance treatment of opioid dependence in patients who have achieved sustained and prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (i.e., doses of not more than 8 mg per day of Subutex® or Suboxone® sublingual tablet or generic equivalent). These implants should be used as part of a complete treatment program to include counselling and psychosocial support. These Probuphine® implants are not appropriate for new entrants for treatment and patients who have not achieved sustainedandprolonged clinical stability, while being maintained on buprenorphine 8 mg per day orless of a Subutex® or Suboxone® sublingual tablet equivalent or generic equivalent. These subdermal implants are intended to be in place for 6 months of treatment andthese implants needs to be removed by the end of the sixth month, as the polymer used in these implants are not biodegradable. If new implants are not inserted on the same day as the removal, patients should be maintained on their previous dose of transmucosal buprenorphine.

After Probuphine® insertion, an initial buprenorphine peak was observed and the median Tmax occurred at 12 hours after insertion. After the initial buprenorphine peak, the plasma buprenorphineconcentrations decreased slowly and steady-state plasma buprenorphine concentrations werereached by approximately 4 weeks. Mean steady-state plasma buprenorphine concentrations were approximately 0.5 to 1 ng/mL and were maintained for approximately 20 weeks (4 week through24 week) in a 24-week treatment period. At steady state, the buprenorphine concentrations werestable and comparable to the trough buprenorphine concentration of 8 mg per day sublingualbuprenorphine at steady state.In some patients after Probuphine®insertion; patients may require occasional supplemental dosing with buprenorphine,even though such patients should not be provided with prescriptions for transmucosal buprenorphine-containing products for as-needed use and the patients should undergo clinical supervision once every months for continued counselling and psychosocial support.

The information from Suboxone® sublingual film available in public domain suggests that blood plasma concentration after administration of 2/0.5mg to 16/4mg of buprenorphine/naloxone yields to plasma concentration of buprenorphine between 0.95 ng/ml to 6.05ng/ml. Similarly information from Probuphine available in public domain suggests one implant yields plasma concentration of buprenorphine between approx. 0.7 to 1ng/ml. This suggests that therapeutic effective dose of buprenorphine in opioid deaddiction lies between approx. 0.7ng/ml to 6ng/ml.

Thus there is a need in the art for a biodegradable implant which degrades within the body itself, which is suitable for long-term use for about 6 months or more for continuous administration of buprenorphine that will improve patient compliance for both pain relief and drug dependency treatment regimens. There is also a need for a buprenorphine formulation that will reduce abuse potential, and in which the addition of an antagonist such as naloxone will not be necessary.

Summary of the invention
Accordingly, provided herein is a biodegradable polymeric implant of buprenorphine, which permits a sustained release of buprenorphine in the blood over a period of 6 months or more. The biodegradable implant of present invention improves patient compliance with drug dosing regimens due to continuous release of a therapeutic concentration of the burprenorphine from the polymeric matrix and reduce abuse potential since such biodegradable implant is not subject to diversion as oral dosage forms or other formulations.

In one embodiment, the biodegradable polymer used in the present invention includes polyesters, poly(ether-esters), poly(ortho-esters), poly(amino acids), polyanhydrides, polyamides, polyphophazenes, polyphosphoesters, and copolymers therein known to ones skilled in the art. In certain embodiments disclosed herein are biodegradable polymers possessing degradation rates significantly slower than the release rate of therapeutic agent including but not limited to Polycaprolactone, Poly(L-lactide), Poly(DL-lactide), Poly(L-lactide-co-glycolide),Poly(lactic-co-glycolicacid),Poly(L-lactide-co-caprolactone), Poly(dioxanone) and Poly(glycolide-co-trimethylene carbonate). In preferred embodiments, the biodegradable polymer is Poly(lactic-co-glycolic acid) or PLGA.
In another embodiment, the biodegradable implant comprises buprenorphine embedded in biodegradable polymer comprises poly(lactic-co-glycolic acid) and at least one biodegradable lubricant to provide a controlled release of buprenorphine over a period of about 6 months or more. The in vivo release of buprenorphine from the biodegradable implant is controlled by the rate of the polymer degradation and subsequent release of drug from the drug polymer matrix by diffusion, swelling or erosion that results in a consistent therapeutic level of buprenorphine in the blood plasma in the range of 1.0 ng/ml to 6.0 ng/ml for about 6 months to 1 year or longer for the treatment of opioid dependence and pain, wherein the biodegradable buprenorphine implant is prepared by compression moulding process or hot melt extrusion process.

In another embodiments, the polymeric matrix comprises poly(lactic-co-glycolic acid) selected from the grades of 0/100, 50/50, 75/25, 85/15, 55/45, 60/40, 65/35, 70/30, 80/20, 90/10 or 95/5. In another embodiment, the implantable devices generally comprise about 4%w/w to about 90%w/w of the polymer. In yet another embodiment, the biodegradable polymers in buprenorphine implant is to control the release rate of the drug in the blood for an extended period of time.
In another embodiments, the biodegradable implant also consists of a biodegradable lubricant in the range of 1% w/w to 15% w/w of total composition by weight to improve the flow properties of the drug. In certain embodiments, the lubricant is selected from the group of stearic acid or glycerylmonostearate or combination thereof..

In another embodiment, the biodegradable implant comprises buprenorphine in a concentration of about 9% w/w to 95% w/w of total composition which is suitable to release buprenorphine with the consistent therapeutic level of about 3 ng/ml to 6 ng/ml in blood for about 6 months or more.

In another embodiment, the biodegradable implant comprises the dimensions of about 1.5 to 5 mm in diameter and about 5 to 60 mm in length which is inserted subcutaneously at a site of the arm or a suitable body part. In certain embodiments, the biodegradable implant is implanted subcutaneously using any procedures known to those skilled in the art.

In another embodiment, one of ordinary person skill in the art will be able to convert animal dose (e.g., rat) in mg/kg to human equivalent dose (HED) in mg/kg:
(See e.g, Guidance for Industry and Reviewers – Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, Example 3)
The HED can be calculated directly from the animal dose (mg/kg) by multiplying by the ratio of the animal/human km factor.(km factor for rat is 6 and km factor for human is 37).‘km factor’ is the factor for converting mg/kg dose to mg/m2 dose.
HED (mg/kg) = Animal dose (mg/kg) x Animal km /Human km
= Animal dose (mg/kg) x 6/37
= 50/0.3 x 6/37
= 27.03 x 60 (average weight of human)
= 1621 mg/kg

The dose of one buprenorphine implant inserted into a rat was 50 mg/kg, resulted into the in vivo plasma concentration of 4.0 ng/ml to 6.0 ng/ml, whereas the targeted plasma concentration was 3.75 ng/ml, which is approximately 1.6 times higher than the required plasma concentration. Therefore, in humans, the targeted drug concentration can be achieved with the insertion of approximately 5 to 6 biodegradable buprenorphine implants.

In another embodiment, the buprenorphine implants of the present invention control the opiate dependency associated with the drugs such as heroin, morphine, codeine, oxycodone and methadone while maintaining the minimum therapeutic levels in the blood.

In another embodiment, the biodegradable implant of the invention will improve patient compliance with dosing regimens for therapeutic indication of pain relief, preferably for the treatment of moderate to severe pain in postoperative cancer patients.

In another embodiment, the present invention provides a biodegradable implant of buprenorphine wherein the implant biodegrades into the blood of the patient over the course of treatment and thus eliminate the requirement of removal of the implants from the patient.

In another embodiment, a method for sterilizing a biodegradable implant comprising of buprenorphine or its salts or prodrug thereof, a biodegradable polymer and a biodegradable lubricant comprising, providing a biodegradable implant to be sterilized by irradiating the product with gamma irradiation with and intensity ranging between 4 to 20 kGy and for a period of 2 to 20 hours. The irradiation cycle provides biodegradable implant, having a purity of >99.91% to >99.95%, which has a total impurity of 0.09% to 0.05%.

Brief Description of Drawings:
Figure 1 illustrates the in vitro release of buprenorphine overtime from the biodegradable implants (F1, F2 and F3) with respect to targeted drug release expressed as mg/day.

Figure 2 illustrates average cumulative in vivo release of buprenorphine over time in rat group G1 were inserted sub-dermally with Buprenorphine implant F1 with a dose of one implant per animal.

Figure 3 illustrates average cumulative in vivo release of buprenorphine over time in rat group G2 were inserted sub-dermally with buprenorphine implant F2 with a dose of one implant per animal.

Figure 4 illustrates average cumulative in vivo release of buprenorphine over time in rat group G3 were inserted sub-dermally with buprenorphine implant F3 with a dose of one implant per animal.

Figure 5 illustratesthe biodegradable implants F1, F2 and F3 generally exhibits near zero order pharmacokinetics in vivo for release of buprenorphine in rats implanted sub-dermally with a dose of one implant per animal.

Figure 6:(a) illustrates placing the rat wherein the hair was clipped at the dorsal region with a trimmer about 2-3 centimeters area of skin in rat 24 hours before dosing;(b) and (c)illustrate the surgical insertion of biodegradable buprenorphine implant of the present invention in vivounder the skin of Wistar Rat; (d) illustrates the sutures are hold together with the edges of the wound after surgical insertion of biodegradable buprenorphine implant of the present invention.

Figure 7 illustrates a residual biodegradable implant which was observedin 3 rats of G1 group on 180 days after insertion of F1 implant shown in images (a), (b) and (c).
Figure 8 illustrates a residual biodegradable implant which was observed in 3 rats of G2 group on 180 days after insertion of F2 implant shown in images (a), (b) and (c).

Figure 9 illustrates a residual biodegradable implant which was observed in 3 rats of G3 group on 180 days after insertion of F3 implant shown in images (a), (b) and (c).

Description of the invention
The invention will be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be fully understood and appreciated.

As used herein “buprenorphine” refers to the amount of buprenorphine to be delivered, absent the molecular weight of any salt counter-ion, associated solvate, etc.

The term “subject” is generally synonymous with the term “patient” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

The term “Disease” refers to Pain (postoperative pain, cancer pain, arthritic pain, lumbo-sacral pain, musculoskeletal pain, neuropathic pain etc.) and Opoid Agonist dependent patients.

The term “Opioid Agonist” refers to the products containing active ingredients such as codeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium, heroin, and certain narcotic-antagonist analgesics, such as, nalbuphine, pentazocine butorphanol, tapentadol and tramadol or a combination thereof.
The phrase “Therapeutically Effective Dose (TED)” is intended to qualify the therapeutically effective amount of buprenorphine (0.7ng/ml to 6ng/ml) used in the treatment of the Disease.

The term “Therapeutically Acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The present invention provides a gamma sterilized biodegradable implant of buprenorphine which degrades within the body itself during the treatment period of about 6 months to 1 year which is suitable for long-term treatment of the Disease associated with the use of Opioid Agonists in a Subject, wherein the biodegradable implant comprises of Buprenorphine in a concentration of about 9% w/w to 95% w/w of the total composition, in a biodegradable polymer in a concentration of 4% w/w to 90% w/w along with a biodegradable lubricant in a concentration of about 1%w/w to 15%w/w, to provide a sustained release of buprenorphine in blood with the consistent Therapeutic Effective Dose about 6 months or more.

In the case of Suboxone® sublingual tablet formulation available in the market, the maximum concentrations (Cmax) of buprenorphine increases in a linear fashion, from 1.8 ng/ml to 6.0 ng/ml with the sublingual tablet dose ranging from4 mg to 16 mg.

The studies show that with the implantation of 4 implants of Probuphine® to the patient, each implant having 80 mg of buprenorphine initiatedwith the maintenance dose of 8 mg per day or less of a Subutex or Suboxone sublingual tablet, the plasma buprenophine concentration has reached to 3.23 ± 0.48 ng/ml initially followed by a slow decrease to a steady state levels of 0.72 ± 0.11 ng/ml of buprenorphine for 21 days. These steady state levels were maintained through the end of 6 month treatment period. At steady state, the buprenorphine concentrations were stable and comparable to the trough buprenorphine concentration of 8 mg per day sublingual buprenorphine in need of treatment for opiate addiction (Jason white, James bell, John B. Saunders, Paul Williamson, Maria Makowska, Aaron Farquharson, Katherine L. Beede; Open-label dose-finding trial of buprenorphine implants (Probuphine®) for treatment of heroine dependence, ((2009) 37-43).

The present invention, wherein 1-6 rods of the biodegradable implants deliver buprenorhphine at a plasma level of about 0.1 ng/ml to 70 ng/ml, more often about 1ng/ml to 10 ng/ml.

In another aspect, poly(lactic-co-glycolic acid)is used as a biodegradable polymer for manufacture of buprenorphine implant to control the release rate over a period of time. In certain embodiments, the period of time is about 6 months or more. In certain embodiments, the poly(lactic-co-glycolic acid)polymers which are used in different grades with varying lactide:glycolide compositions such as 0/100, 50/50, 75/25, 85/15, 55/45, 60/40, 65/35, 70/30, 80/20, 90/10 or 95/5.

However, in preferred embodiments, the poly(lactic-co-glycolic acid)polymer is used with the grades of 50/50, 75/52 and 85/15.

The lubricant that can be used in the biodegradable implant is selected from the group of stearic acid or glyceryl monostearate or combination thereof. Preferably, the biodegradable lubricant is glycerol monostearate.

In a preferred embodiment, the biodegradable implant comprises dimensions of about 1.5 to 8 mm in diameter and about 5 to 60 mm in length.

The in vitro release of buprenorphine from the biodegradable implant in 900ml water as media at 37°C comprises the release of buprenorphine initially with a rate of not more than 40 mg/day, which is declined to about 2 mg/day over a period of 0 to 100 days, this initial release of buprenorphine is followed by a consistent release of buprenorphine over a period of 100 to 150 days with the concentration of 2 mg/day to 0.2 mg/day, followed by the drug release to below 1 mg/day over a period of 150 days to 360 days from the biodegradable implant.

The buprenorphine from the biodegradable implant is continuously released over a sustained period of time which is controlled by the rate of the polymer degradation and subsequent release of drug from the drug polymer matrix by diffusion, swelling and erosion that results in a consistent release of buprenorphine of at least about 2 mg to 0.2 mg per day.

Each biodegradable implant is having concentration of 80 to 400 mg of buprenorphine by implanting 1 to 6 biodegradable implants of buprenorphine subcutaneously into the body, which results in the release of drug from each biodegradable implant by maintaining in vivo plasma concentration of 4.0 ng/ml to 6.0 ng/ml, whereas the targeted plasma concentration was 3.75 ng/ml, which is approximately 1.6 times higher than the required plasma concentration, which result ininitial release followed by a consistent release of buprenorphine over a period of 30 to 180 days with the concentration of 3.0 ng/ml to 5.0 ng/ml from the biodegradable implant.

A skilled artisan would be able to readily determine an appropriate method of preparing such a biodegradable implant, depending on the shape, size, drug loading, and release kinetics desired for a particular type of patient or clinical indication.

In some embodiments, the biodegradable implant of buprenorphine for treatment of opiate addiction and pain is produced by injection moulding, compression moulding, hot melt extrusion and/or gel processing the polymer. In preferred embodiment, the biodegradable implant of buprenorphine is produced by compression moulding process.
In another embodiment, biodegradable implant for the sustained release of buprenorphine, wherein the implant comprises:

a) buprenorphine, or its salts, or prodrugs thereof; in the concentration of about 9% w/w to 95% w/w of the total composition;
b) a polymeric matrix comprising of biodegradable polymer, in a concentration of about 4%w/w to 90%w/w, having the particle diameter of 10 µm to 150 µm; and
c) a biodegradable lubricant in a concentration of about 1%w/w to 15%w/w,

wherein the buprenorphine in the biodegradable implant is continuously released over an extended period of time which is controlled by the rate of the polymer degradation and subsequent release of drug from the drug polymer matrix by diffusion, swelling or erosion that results in a consistent release of buprenorphine in the blood plasma for at least about one month to about one year.

In another embodiment, the biodegradable buprenorphine implant is produced by compression moulding process which is formed into a rod shaped configuration after the process of mixing buprenorphine with PLGA polymer and glycerol monostearate. Accordingly, the process for preparation of biodegradable implant by using pressure moulding/compression moulding process, comprises:
a) mixing the polymer poly(lactic-co-glycolic acid) with buprenorphine or its pharmaceutically acceptable salts thereof,
b) melting the material around 100°C to 120°C, adding glycerol monostearate and mixing well,
c) Inserting the molten mass into die cavity and
d) Removing the biodegradable implant material from the die and cutting to suitable size of Implants.

In an embodiment, the die cavity can have a diameter of 1 mm to 8mm and the biodegradable implant can be formed into a rod shaped configuration.
In a further embodiment, the invention provides a process for preparation of biodegradable implant by using hot melt extrusion process, which process comprises:
a) homogenously mixing buprenorphine and glycerol monostearate with PLGA powder and heating the powder mixture from 100°C to 120°C and mixed well and formed into a molten mass;
b) inserting the molten mass into a die cavity having a diameter of 1.5 mm to 5 mm and a length ranging from about 5 to 60 mm;
c) extruding the molten mass mixture with the exposure time in the extruder between 1 and 10 minutes with a temperature profile which ranges from 110ºC to 120ºC on entering the extruder followed with a higher temperature in the range of 80ºC to 110ºC, further at a temperature of 20ºC to 30ºC on leaving the extruder;
d) rapidly cooling the extrudate material in air, or by a stream of inert gas and recovering the cooled, hot melt extruded material;
e) cutting the cooled, hot melt extruded material into required dimensions suitable for the subcutaneous biodegradable implants, preferably, diameter of between 1.0 and 8 mm and a length of between 10 and 30 mm.

In yet another embodiment, the invention provides a method for sterilizing a biodegradable implant comprising of buprenorphine or its salts or prodrug thereof, a biodegradable polymer and a biodegradable lubricant which method comprises, providing a biodegradable implant sterilized by irradiating the product with gamma irradiation with and intensity ranging between 4 to 20 kGy and for a period of 2 to 20 hours, more preferably at 8kGy for a duration of about 10 hours. The irradiation cycle provides biodegradable implant, having a purity of >99.91% to >99.95%, which has a total impurity of 0.09% to 0.05%.

In yet another embodiment, the invention provides a method for treating opiate addiction and pain, which method comprises subcutaneously implanting the biodegradable implant comprising buprenorphine, wherein the buprenorphine is released continuously over a period of at least about one month to about one year, by polymer matrix degradation and subsequent release of the drug from the drug polymer matrix by diffusion, swelling and erosion that results in a consistent release of buprenorphine in the blood plasma.

This biodegradable implant is administered by subcutaneous implantation at a site of the arm or suitable body part. After implantation, all the components of implant biodegrade or can be swept away from the implant site by body fluids, thus the biodegradable implant is eliminated from the body and eventually disappears. The biodegradable implant components may complete their biodegradation or disappearance after or at the same time when buprenorphine or its pharmaceutically acceptable salts, a metabolite or a prodrug thereof has been completely released.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Example 1:
Preparation of biodegradable buprenorphine implants (F1, F2 and F3) according to invention:
The biodegradable buprenorphine implants are typically formulated with buprenorphine at a loading dose of about 10% to 85% w/w, glycerol monostearate with the dose of about 1% to 15% w/w and the PLGA polymer with the dose of about 4% to 95% w/w. The pharmacokinetic studies have been conducted by using 3 different versions of biodegradable implants (F1, F2 and F3) based on using 3 different types of polymers, Expansorb DLG 50-5A,Expansorb DL 75-7A and Expansorb DLG 85-12Erespectively.
Composition of Buprenorphine Implant (F1)
Sr No. Ingredient Function Mg/Implant % w/w
1 Buprenorphine hydrochloride Active 200.0 47.5
2 Expansorb DLG 50-5A,
(PLGA 50/50)* Polymer 200.0 47.5
3 GMS (Glycerol monostearate) Lubricant 20.0 5.0
Total 420.0 100.0
Composition of Buprenorphine Implant (F2)
Sr No. Ingredient Function Mg/Implant % w/w
1 Buprenorphine hydrochloride Active 200.0 47.5
2 Expansorb DL 75-7A,
(PLGA 75/25)* Polymer 200.0 47.5
3 GMS (Glycerol monostearate) Lubricant 20.0 5.0
Total 420.0 100.0
Composition of Buprenorphine Implant (F3)
Sr No. Ingredient Function Mg/Implant % w/w
1 Buprenorphine hydrochloride Active 200.0 47.5
2 Expansorb DLG 85-12E
(PLGA 85/15)* Polymer 200.0 47.5
3 GMS (Glycerol monostearate) Lubricant 20.0 5.0
Total 420.0 100.0
*lactide:glycolide ratio
In preferred embodiment, the biodegradable implants F1, F2 and F3 are prepared by compression moulding method.

Procedure for the preparation of biodegradable implants:
The different grades of PLGA polymers used for preparing the biodegradable implants F1, F2 and F3 are PLGA 50/50, PLGA 75/25and PLGA 85/15 respectively.
The biodegradable implants of the present invention are prepared by hot melt extrusion process, which comprises:
a) homogenously mixing buprenorphine and glycerol monostearate with PLGA powder followed by heating the powder mixture to 100°C to 120°C to form a molten mass;
b) Inserting the molten mass into a die cavity having a diameter of about 1.5 to 5 mm and a length ranging from about 5 to 60 mm;
c) extruding the molten mass mixture with the exposure time in the extruder between 1 and 10 minutes with a temperature profile which ranges from 110ºC to 120ºC on entering the extruder followed with a lower temperature in the range of 80ºC to 110ºC, further at 20ºC to 30ºC on leaving the extruder;
d) rapidly cooling the extrudate material in air, or by a stream of inert gas and recovering the cooled, hot melt extruded material;
e) cutting the cooled, hot melt extruded material into required dimensions suitable for the subcutaneous biodegradable implants and
f) cutting the implants are cut into a diameter of between 1.0 and 8 mm and a length of between 10 and 45 mm.
In a process variant, the die is having a diameter of 1 mm to 4 mm. Thus a biodegradable buprenorphine implant was formed into a rod shaped configuration with diameter ranging from about 1.5 to 5 mm and length ranging from about 5 to 45 mm.

Sterilization process:
The implants comprising buprenorphine or its salts or prodrug thereof, a biodegradable polymer and a biodegradable lubricant, thus obtained are sterilized by irradiating the implant with gamma irradiation for a period of 10 hours at a rate sufficient to pass the sterility test. The three versions of Implants were irradiated with different gamma irradiation ranging of 4 to 20 kGy.
Example 2:
In vitro drug release rate of buprenorphine from biodegradable implants (F1, F2 and F3):
The rod shaped buprenorphine biodegradable implants (F1, F2 and F3) were accurately weighed, placed in tightly closed borosilicate glass jars containing 900ml water as media at 37°C and continuously stirred at room temperature. Sample aliquots were removed periodically and the release rate of buprenorphine from a single implant was analysed by HPLC. The release rate of buprenorphine from a single rod of biodegradable implants F1, F2 and F3 in in vitrostudies are expressed as mg/day and illustrated in Figure 1. In vitro drug release was carried out in 900ml water as media at 37°C.
In vitro release of buprenorphine from implants (in milligrams)
Days Targeted release F1 implant F2 implant F3 implant
1 4.44 9.93 18.77 7.08
10 1.5 3.14 4.27 3.59
20 1.5 3.17 1.78 1.88
30 1.5 1.36 0.79 2.82
40 1.5 1.13 1.31 2.28
50 1.5 1.42 1.13 1.26
60 1.5 1.75 1.27 1.42
70 1.5 2.11 0.31 1.1
80 1.5 0.58 0.6 1.8
90 1.5 0.69 0.84 1.15
100 1.5 1.12 1.29 1.17
110 1 1.84 0.85 0.73
120 1 0.94 0.62 0.64
130 1 0.69 0.29 0.24
140 1 0.79 0.23 0.20
150 0.5 0.19 0.46 0.16
160 0.5 0.03 0.37 0.13
170 0.5 0.01 1.66 0.19
180 0.5 0.07 0.59 0.24

At the time period of 0 to 100 days, the plasma buprenorphine concentrations reached at the peak initially with a rate of 10 mg/day to 19.0 mg/day which is declined to 1.0 mg/day to 2.0 mg/day. This initial release was followed by a consistent release of buprenorphine over a period of 100 to 150 days with the concentration of 2.0 mg/day to 0.2 mg/day, followed by the drug release of less than 1 mg/day over a period of 150 to 180 days from the biodegradable implants.

The implant composition of buprenorphine according to the present invention releases a dose of about 0.01 to 19.0 mg/day in vitro to give a targeted effective dose of about 1.0 ng/ml to 10.0 ng/ml per day in vivo over a period of about 6 months or more for the treatment of opioid drug addiction and pain.

Example 3:
In vivo drug release of buprenorphine after implantation of biodegradable buprenorphine implants in Rats.
Rat group Dose (One implant/Animal) No. of male rats
G1 F1 3
G2 F2 3
G3 F3 3

Healthy, young male adult rats (Rattusnorvegicus) of Wistar strain with 7 to 8 weeks old ranging in the weight from 275 g to 300 g (healthy adult) were used for the pharmacokinetic study, the hair was clipped at the dorsal shoulder region with a trimmer about 2 to 3 centimeters area of skin in all rats 24 hours before dosing. Surgery was carried out under anesthesia by giving intramuscular injection using xylazine and ketamine. A small incision of about 0.5 cm was made on dorsalshoulder region of rat group (G1, G2 and G3) of 3 male rats respectively. All rats were inserted sub-dermally with Buprenorphine implants F1, F2 and F3 with a dose of one implant per animal in all rat groups (G1 to G3). The wound was closed by a non-absorbable suture. The blood samples (approximately 500 µL/timepoint) were collected on days 1, 4, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 90, 97, 104, 111, 118, 125, 132, 139, 146, 153, 160, 167, 174 and 180 from the tail vein by micro sampling method i.e. using microvette tubes coated with EDTA. Plasma was separated from blood by centrifugation at 2500 rpm at 8ºC for approximately 10 minutes and the separated plasma was kept for pharmacokinetic analysis.

Example 4:
Pharmacokinetic profile of buprenorphine after subcutaneous implantation of biodegradable buprenorphine implants in Rats
Plasma concentration of Buprenorphine (ng/ml) after insertion of biodegradable implant (one implant/animal) in Rats

Days Sixmo Implant (Probuphine) Targeted release G1 - using Expansorb
50-5A
(F1 implant) G2 - using Expansorb
75-7A
(F2 implant) G3 - using Expansorb DLG 85-12E
(F3 implant)
0 0.00 0.00 0.00 0.00 0.00
1 1.00 3.5 2.41 1.35 2.50
4 1.00 3.5 3.45 1.36 2.86
7 1.00 3.5 2.30 1.54 3.44
14 1.00 3.5 2.98 0.65 4.60
21 1.00 3.5 3.14 4.60 4.49
28 1.00 3.5 3.10 4.79 3.74
35 1.00 3.5 3.20 3.37 2.71
42 1.00 3.5 2.88 3.89 2.10
49 1.00 3.5 2.89 5.22 3.76
56 1.00 3.5 2.90 2.95 4.03
63 1.00 3.5 2.73 3.26 3.86
70 1.00 3.5 3.11 2.07 3.76
77 1.00 3.5 2.96 4.22 4.22
84 1.00 3.5 2.88 4.47 3.42
90 1.00 3.5 2.96 3.87 4.83
97 1.00 3.5 3.41 5.34 3.72
104 1.00 3.5 3.33 4.11 5.48
111 1.00 3.5 2.96 4.92 4.98
118 1.00 3.5 2.73 3.16 4.88
125 1.00 3.5 2.93 3.99 5.18
132 1.00 3.5 2.49 4.79 4.22
138 1.00 3.5 2.87 3.25 2.42
146 1.00 3.5 3.22 3.86 2.84
153 1.00 3.5 2.86 4.35 3.43
160 1.00 3.5 3.34 4.10 3.11
167 1.00 3.5 3.19 3.91 3.49
174 1.00 3.5 2.77 3.98 3.76
180 1.00 3.5 3.13 3.44 3.00

After an initial limited burst release of buprenorphine from biodegradable implant, a slow decrease in the concentration of buprenorphine in the blood plasma was observed in all the rats by maintaining the mean buprenorphine plasma levels to about 1.0 ng/ml to 5.5 ng/ml through 30 days. This initial release was followed by a sustained release of buprenorphine from the biodegradable implant to provide a consistent therapeutic level of buprenorphine in blood plasma to about 3.0 ng/ml to 6.0 ng/ml over a period of about 31 to 180 days, which is required for the long term treatment of opioid dependence and pain in a subject for about 6 months or more. The peak plasma concentration of buprenorphine ranges from about 3.5 ng/ml to 6.0ng/ml in any given time.

As is evident from the above, the biodegradable implant can be implanted to any patient populations including those patients who are new entrants for buprenorphine treatment without the need of any maintenance treatment using other dosage forms of buprenorphine. The biodegradable implant exhibits near zero order pharmacokinetics in vivo for release of buprenorphine for the treatment of opioid dependence and pain.

Moreover, no mortality or morbidity was observed during the experimental period in all treated groups. Normal growth pattern of body weight was observed in all rats. External and internal examination of terminally sacrificed rats did not reveal any pathological lesion. However, there was residual implant observed at site of implant in all the rats. Microscopic examination of injection site (sub-dermal) inserted with buprenorphine implants of treated groups (G1, G2 and G3) revealed infiltration of inflammatory cells and fibrous encapsulation in rats. The nature and extend of the observed injection site findings were consistent with local minimal inflammatory reaction of injection of buprenorphine implants in subcutaneous tissue.
,CLAIMS:
1. A biodegradable implant for the sustained release of buprenorphine, wherein the implant comprises:

a) buprenorphine, or its salts, or prodrug thereof; in the concentration of about 9% w/w to 95% w/w of the total composition;
b) a polymeric matrix comprising of biodegradable polymer, in a concentration of about 4%w/w to 90%w/w, having the particle diameter of between 10 µm to 150 µm; and
c) a biodegradable lubricant in a concentration of about1%w/w to 15%w/w,
wherein the buprenorphine in the biodegradable implant is continuously released over an extended period of time which is controlled by the rate of the polymer degradation and subsequent release of drug from the drug polymer matrix by diffusion, swelling or erosion that results in a consistent release of buprenorphine in the blood plasma for at least about one month to about one year.
2. The biodegradable implant as claimed in claim 1a, comprises of buprenorphine preferably about 47.5% w/w of the total composition.
3. The biodegradable implant as claimed in claim 1b, wherein the biodegradable polymer is poly(lactic-co-glycolic acid) of variable compositions selected from the group consisting of (50/50), (75/25) and (85/15) grades preferably about 47.5% w/w of the total composition.
4. The biodegradable implant as claimed in claim 1c, wherein the biodegradable lubricant is glyceryl monostearate at about 5% w/w of the total composition.
5. The biodegradable implant as claimed in claim 1, wherein the biodegradable implant comprises dimensions of about 1.0 to 8 mm in diameter and about 5 to 45 mm in length.
6. The biodegradable implant as claimed in claim 5, wherein the biodegradable implant comprises dimensions of about 3 mm in diameter and about 45 mm in length.
7. The biodegradable implant as claimed in claim 1, wherein the biodegradable implant provides in vitro release of buprenorphine in 900 ml water as media at 37°C with the release of buprenorphine initially with a rate of not more than 40 mg/day, which is declined to about 2 mg/day over a period of 0 to 100 days, followed by a consistent release of buprenorphine over a period of 100 to 150 days with the concentration of 2 mg/day to 0.2 mg/day, followed by the drug release to below 1 mg/day over a period of 150 days to 360 days from the biodegradable implant.
8. The biodegradable implant as claimed in claim 1, wherein the buprenorphine from the biodegradable implant is continuously released over a sustained period of time which is controlled by the rate of the polymer degradation and subsequent release of buprenorphine from the drug-polymer matrix by diffusion, swelling and erosion that results in a consistent release of buprenorphine of at least about 2 mg to 0.2 mg per day.
9. The biodegradable implant as claimed in claim 1, wherein each of the biodegradable implant comprises 80 to 400 mg of buprenorphine and by implanting at least 1 biodegradable implant of buprenorphine subcutaneously into the body, which results in the release of buprenorphine from each biodegradable implant by maintaining in vivo plasma concentration of buprenorphine between 0.70 ng/ml to 10.0 ng/ml, more preferably 3.75 ng/ml, over a period of 30 to 180 days and more.
10. A process for preparation of biodegradable implant by using pressure moulding process, comprising the steps of:
a) mixing the polymer poly(lactic-co-glycolic acid) with buprenorphine or its pharmaceutically acceptable salts thereof,
b) melting the above mix at around 100°C to 150°C, by adding biodegradable lubricant and mixing well,
c) inserting the molten mass into a die cavity having a diameter of about 1.5 to 5 mm and a length ranging from about 5 to 60 mm.
d) removing the biodegradable implant from the die after cooling and cutting into suitable size.
11. The process for preparation of biodegradable implant as claimed in claim 10, wherein the biodegradable implant is formed into a rod shaped configuration.
12. The process for preparation of biodegradable implant as claimed in claim 10, wherein the die is having the diameter of 1 mm to 8 mm.
13. A process for preparation of biodegradable implant by using hot melt extrusion process, which comprises of:
a) homogenously mixing buprenorphine and glycerol monostearate with PLGA powder, heating the powder mixture to 100°C to 150°C and mixed well to form a molten mass;
b) extruding the molten mass mixture with the exposure time in the extruder between 1 and 10 minutes with a temperature profile which ranges from 110ºC to 150ºC on entering the extruder followed with a lower temperature in the range of 80ºC to 110ºC, further at 20ºC to 30ºC on leaving the extruder;
c) rapidly cooling the extrudate material in air, or by a stream of inert gas and recovering the cooled, hot melt extruded material;
d) cutting the cooled, hot melt extruded material into required dimensions suitable for the subcutaneous biodegradable implants and
e) cutting the implants into a diameter of between 1.0 and 8 mm and a length of between 10 and 45 mm.
14. A method for sterilizing a biodegradable implant comprising of buprenorphine or its salts or prodrug thereof, a biodegradable polymer and a biodegradable lubricant comprising, providing a biodegradable implant to be sterilized by irradiating the product with gamma irradiation with and intensity ranging between 4 to 20 kGy and for a period of 2 to 20 hours, providing a purity of >99.91% to >99.95%, which has a total impurity of 0.09% to 0.05%.
15. A method for treating opiate addiction and pain, comprising subcutaneously implanting at least one gamma irradiated biodegradable implant comprising buprenorphine, a biodegradable polymer and a biodegradable lubricant wherein the buprenorphine is continuously released over a sustained period of time controlled by the rate of the polymer degradation and subsequent release of buprenorphine from the drug-polymer matrix by diffusion, swelling and erosion that results in a consistent release of buprenorphine in the blood plasma delivering a therapeutically effective dose of about 0.7 ng/ml to about 10 ng/ml for at least about one month to about one year or more.