PHARMACEUTICAL COMPOSITION CONTAINING GOSERELIN FOR
IN-SITU IMPLANT
FIELD OF THE INVENTION
This invention relates to pharmaceutical composition capable of forming in-situ implant,
which comprises goserelin or its pharmaceutically acceptable salts, biodegradable polymer
and a biocompatible organic solvent. Such implant formed in-situ, releases the drug in the
body for prolonged period of time. Present invention also relates to a process for preparing
said composition.
BACKGROUND
Goserelin is a synthetic decapeptide analogue of luteinizing hormone-releasing hormone
(LHRH), also known as gonadotropin releasing hormone (GnRH) agonist analogue. On
chronic administration Goserelin results in inhibition of pituitary luteinizing hormone
secretion leading to a fall in serum testosterone concentrations in males and serum estradiol
concentrations in females.
Goserelin is indicated in the palliative treatment of advanced carcinoma of the prostate as
well as endometriosis. Goserelin has been approved in USA since 1989 as ZOLADEX®
implant for subcutaneous implantation and is marketed by AstraZeneca in the USA. It is
available as ZOLADEX ® 10.8 mg implant containing goserelin acetate equivalent to 10.8 mg
of goserelin, designed for subcutaneous implantation with continuous release over a 12-week
period and as ZOLADEX ® 3.6 mg implant containing goserelin acetate equivalent to 3.6 mg
of goserelin, designed for subcutaneous implantation with continuous release over a 28-day
period.
ZOLADEX® is a 1 to 1.5 mm diameter cylinder, preloaded in a special single-use syringe
with a 14-gauge to 16-gauge hypodermic needle. The main disadvantage related with
ZOLADEX® is that it causes severe pain and haematomas when implanted into the patient.
Hence, patient friendly mode of administration is not only desirable attribute but would also
improve compliance to therapy.
US5366734 discloses the solid implant formulation of peptide and US5004602 discloses
process for the preparation of such solid implant using melt extrusion in which freeze dried
drug (peptide) and polymer has been extruded together under pressure at 70° C to form a rod,
from which implants of the required weight has been obtained. WO9324150 discloses
composition in the form of microparticles or an implant containing salt of peptide with the
polymer having carboxyl terminal group. US6620422 discloses dispersion of drug dispersed
into polymer and use of such particles for the preparation of implant. During implant
preparation, peptides and proteins are exposed to various unfavorable conditions. The
exposure to high temperatures, shear forces, or high pressures may cause protein unfolding
and irreversible aggregation. Further, complex manufacturing process for the solid implant
by melt extrusion or injection moulding is difficult and requires tight process controls.
Various options have been explored to deliver controlled release goserelin such as
microspheres, microparticles, nanoparticles etc, but production of microspheres is complex
multiple step process involving optimization and control on many critical process parameters
and high process loss add to the overall cost of the product.
Alternative approaches have been developed to overcome the shortcomings of solid implant,
particularly pain at site of injection. US4938763 discloses method of forming in-situ implant
containing biodegradable water insoluble polymer and biocompatible water soluble solvent.
US5077049 discloses in-situ implant preparation containing biodegradable water insoluble
polymer and biocompatible water soluble solvent for the periodontal pocket. US6565874 and
US6773714 disclose in-situ implant composition of leuprolide acetate. US200400 10224
discloses kits for the preparation of an in-situ implant composition containing biodegradable
polymer and biocompatible solvents.
However, it has been found that the formed in-situ implants by above technologies, gives
initial burst release and hence it is difficult to maintain constant plasma drug concentration
throughout treatment regimen. Further, if the active agent is particularly toxic, this initial
burst release of the active agent is likely to lead to increased incidences and magnitude of
adverse drug reactions. To reduce this initial burst release various approaches have been
developed by the scientists. For example, US5702716 discloses use of the rate-retarding
agents such as ester of a mono, di or tricarboxylic acid, a polyhydroxy alcohol, a fatty acid, a
fatty acid ester, an epoxidized oil, a sterol to retards the rate of release of the biologically
active agent from the matrix. US5744153 discloses incorporation of drug into
microstructures, such as lipospheres, liposomes, microcapsules, microparticles, and
nanoparticles followed by suspending such drug containing microstructure into liquid
implant forming composition. US6630155 discloses use of poly (lactide-co-glycolide) /
polyethylene glycol (PLG/PEG) block copolymer to reduce the initial burst of biologically
active agent released from the polymeric composition as it solidifies to form the solid implant
upon administration. WO2005067889 discloses controlled release device comprising
biodegradable polymer system of copolymers and polymeric blends comprising a
hydrophobic component and a hydrophilic component to reduce burst effect or lag period.
WO2008008363 discloses method of conjugating peptide with lipophilic moiety to reduce
the initial burst release.
Applicant is unaware about any prior arts, which discloses pharmaceutical composition for
the preparation of in-situ implant of goserelin which overcomes the above cited problems
such as initial burst release. Moreover prior art uses complex & costly process, particularly
the sterilization procedure is carried out using gamma-irradiation which has implications on
polymer stability. Inventors of the present invention have surprisingly found the
pharmaceutical composition of goserelin for the preparation of in-situ implant, which
overcomes the above cited problems. Additionally, inventors have also discovered simpler
and more efficient process for the preparation of the goserelin in-situ implant.
SUMMARY OF THE INVENTION
The first embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin or its pharmaceutically acceptable
salts thereof, biodegradable polymer and a biocompatible organic solvent which is miscible
to dispersible in aqueous medium or body fluid.
The first embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin or its pharmaceutically acceptable
salts thereof, biodegradable polymer and a biocompatible organic solvent which is miscible
to dispersible in aqueous medium or body fluid, characterized in that the biodegradable
polymer is aseptically dried either by lyophilization or spray drying prior to the mixing it
with biocompatible organic solvent.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, biodegradable polymer and
a biocompatible organic solvent which is miscible to dispersible in aqueous medium or body
fluid.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin pamoate, biodegradable polymer and
a biocompatible organic solvent which is miscible to dispersible in aqueous medium or body
fluid.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, biodegradable polymer
which is PLGA (lactic acid and glycolic acid copolymer) and a biocompatible organic
solvent which is miscible to dispersible in aqueous medium or body fluid.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, biodegradable polymer
which is PLGA (lactic acid and glycolic acid copolymer) and a biocompatible organic
solvent which is miscible to dispersible in aqueous medium or body fluid; wherein the
composition exhibits minimal burst.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) which is carboxyl terminated or ester terminated and a
biocompatible organic solvent which is miscible to dispersible in aqueous medium or body
fluid.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) which is carboxyl terminated and a biocompatible organic solvent
which is miscible to dispersible in aqueous medium or body fluid.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) and N-methyl-2-pyrrolidone (NMP).
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) which is carboxyl terminated and N-methyl-2-pyrrolidone (NMP).
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) which is caboxyl terminated and a mixture of solvent comprises Nmethyl-
2-pyrrolidone (NMP) and at least one another solvent.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) which is carboxyl terminated and a mixture of solvent comprises Nmethyl-
2-pyrrolidone (NMP) and benzyl benzoate.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, mixture of PLGA and at
least one another biodegradable polymer, and a biocompatible organic solvent which is
miscible to dispersible in aqueous medium or body fluid, preferably N-methyl-2-pyrrolidone
(NMP).
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, mixture of biodegradable
polymer comprising PLGA, and N-methyl-2-pyrrolidone (NMP).
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, mixture of biodegradable
polymer comprising PLGA, and a biocompatible organic solvent comprising mixture Nmethyl-
2-pyrrolidone (NMP) and at least one another solvent.
An another embodiment of the present invention is to provide pharmaceutical composition
capable of forming in-situ implant comprising goserelin acetate, PLGA (lactic acid and
glycolic acid copolymer) and a biocompatible organic solvent comprising mixture N-methyl-
2-pyrrolidone (NMP) and at least one another solvent.
In another embodiment, present invention provides pharmaceutical composition capable of
forming in-situ implant comprising goserelin acetate which is in the range of about 0.5 % to
about 5 % by weight of the composition, biodegradable polymer which is in the range of
about 20% to about 80%, preferably in the range of about 30% to about 50% by weight of the
composition and biocompatible organic solvent in the range of about 20% to about 80% by
weight of the composition, preferably in the range of about 50% to about 70% by weight of
the composition.
In another embodiment, present invention provides pharmaceutical composition capable of
forming in-situ implant comprising goserelin acetate, PLGA comprising different ratio of
lactic acid to glycolic acid, such as 85:15 PLGA, 75:25 PLGA, 70:30 PLGA, 65:35 PLGA
and 50:50 PLGA and the mixture thereof and biocompatible organic solvent.
In another embodiment, present invention provides a method to suppress the serum
testosterone level with a pharmaceutical composition capable of forming in-situ implant
comprising goserelin acetate.
In another embodiment, present invention provides a pharmaceutical composition capable of
forming in-situ implant comprising goserelin acetate to suppress the serum testosterone level.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin solution in a suitable solvent, sterilizing the solution by suitable
technique and subsequent lyophilizing in a suitable container closure system;
2. Mixing biodegradable polymer and biocompatible organic solvent and sterilized into a
suitable container closure system by suitable technique or aseptically mixed after sterilizing
separately and filled into a suitable container closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin solution in a suitable solvent, sterilizing the solution by membrane
filtration and subsequent lyophilizing in a suitable container closure system;
2. Mixing biodegradable polymer and biocompatible organic solvent and sterilized into a
suitable container closure system by suitable technique or aseptically mixed after sterilizing
separately and filled into a suitable container closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin acetate solution in a suitable solvent followed by sterilizing it by
membrane filtration and subsequent lyophilizing in a suitable container closure system;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by suitable
technique and lyophilizing in bulk;
3. Sterilizing biocompatible organic solvent separately by suitable technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin acetate solution in a suitable solvent followed by sterilizing it by
membrane filtration and subsequent lyophilizing in a suitable container closure system;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by suitable
technique and drying aseptically by spray drying;
3. Sterilizing biocompatible organic solvent separately by suitable technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin acetate solution in a suitable solvent followed by sterilizing it by
membrane filtration and subsequent lyophilizing in a suitable container closure system;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by membrane
filtration technique and lyophilized in bulk;
3. Sterilizing biocompatible organic solvent separately by membrane filtration technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing solution of goserelin acetate and biodegradable polymer in a suitable solvent
followed by sterilizing it by membrane filtration and subsequent lyophilizing in a suitable
container closure system;
2. Dissolving remaining biodegradable polymer in a suitable solvent and sterilizing by
suitable technique and lyophilized;
3. Sterilizing biocompatible organic solvent separately by suitable technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin acetate solution in a suitable solvent followed by sterilizing it by
membrane filtration and subsequent lyophilizing in a suitable container closure system in
which primary drying is performed above glass transition temperature of the goserelin acetate
solution;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by membrane
filtration technique and lyophilized in bulk;
3. Sterilizing biocompatible organic solvent separately by membrane filtration technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin acetate solution in a suitable solvent followed by sterilizing it by
membrane filtration and subsequent lyophilizing in a suitable container closure system in
which primary drying is performed above glass transition temperature of the goserelin acetate
solution;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by membrane
filtration technique and lyophilizing in bulk;
3. Biocompatible organic solvent containing strong acid is sterilized separately by membrane
filtration technique;
4. Aseptically mixing polymer and solvent obtained in step 2 & 3 and filling in a suitable
container closure system.
In another embodiment, present invention provides method for administration of the
composition into the mammal for treatment of the prostate cancer, endometriosis, as an
endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding,
and in the palliative treatment of advanced breast cancer in pre- and perimenopausal women.
Definitions:
As used herein, the phrase "in-situ implant" is used to indicate that gel or semisolid or solid
implant structure is formed when a pharmaceutical composition is placed into a mammalian
body and is intended to remain at the site of administration and release the drug for a period
of several weeks or more in the mammalian body.
As used herein, the phrase "a prolonged period of time" shall have different meanings with
respect to the various drug delivery systems and its application. Normally, it includes one
hour or higher, up to one year or more. In accordance with the present invention, the meaning
of the phrase "a prolonged period of time" is defined as release of active agent for the time up
to one week or up to six months.
The phrase "pharmaceutically acceptable salt" is defined as the salts of goserelin suitable for
use in the treatment of mammals without undue toxicity, irritation, allergic response and the
like except that is exerted by the goserelin. Preferable pharmaceutical salts for present
invention are acetate, pamoate or mesylate salt of goserelin.
In the present invention, the term "biodegradable" refers to a material that gradually
decomposes, dissolves, hydrolyzes and/or erodes in vivo. Generally, the "biodegradable
polymers" herein are polymers that are hydrolysable, and/or bioerodable in-situ primarily
through hydrolysis and/or enzymolysis. The term "biodegradable polymer" as used herein is
meant to include any biocompatible and/or biodegradable synthetic and natural polymers that
can be used in vivo.
The phrase "biocompatible organic solvent" is defined here as the organic solvent generally
does not react or cause any untoward interaction with the biological tissues.
The phrase "Pharmaceutical composition capable of forming in-situ implant" is defined here
for the pharmaceutical composition which forms gel or semisolid or solid implant upon
administration in-vivo upon contact with body fluids.
"Polydispersity Index (PDI)" is defined here as a measure of the distribution of molecular
mass in a given polymer sample. The PDI calculated is the weight average molecular weight
divided by the number average molecular weight. It indicates the distribution of individual
molecular masses in a batch of polymers. Weight average molecular weight of a polymer
material or fraction of a polymer material describes an average property derived from the
individual molecular weights of all the individual polymer molecules making up the material
or fraction. For any given weight average molecular weight that a polymer material or
fraction may have there are many possible distributions of individual molecular weights of
the molecules making up the material or fraction.
PDI = Mw / Mn
Mn is more sensitive to molecules of low molecular mass, while Mw is more sensitive to
molecules of high molecular mass. Gamma rays are known to induce structural changes
through scission and crosslinking. PDI after gamma irradiation of polymer solution is
increased which indicates broad molecular weight distribution.
The use of the terms "a" and "an" and "the" and similar referents in the context of describing
the invention are to be construed to cover both the singular and the plural, unless otherwise
indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words
"comprise" and "include" and variations such as "comprises", "comprising", "includes",
"including" are to be interpreted inclusively, unless the context requires otherwise. That is,
the use of these words may imply the inclusion of an element or elements not specifically
recited.
The term "Burst" as used herein denotes undesirable increase in the release of goserelin in
first 24-48 hours after administration of pharmaceutical composition of present invention
The phrase "Suitable container" as used herein refers to container for holding unit or multiple
dose of sterile liquid or carrying out lyophilization and holding lyophilized product. The
"suitable container" as referred herein is compatible with the drug product as characterized
by physical and chemical stability and low leach ability. The suitable container can be vial or
syringe and material of construction range from glass to elastomeric material. The inner
surface of container can be uncoated or coated with silicon or any other hydrophobic material.
The phrase "Suitable container closure system" as referred herein comprises of " suitable
container" as defined above and closure to seal the container. It can be a elastomeric cap for
vials or plunger for vial. The closure can be uncoated or coated with inert material like
Teflon (PTFE).
The term "Burst Index" as used herein is a measure to determine the reduction in burst effect
and is calculated here as a ratio of maximal plasma concentration observed in-vivo in the first
24 hour after implant administration between different formulations.
The term "Mammal" as used herein means warm blooded animals, that can be human or non
human (mice, rat, guinea pig, rabbit, dog), preferably human.
DESCRIPTION OF THE DRAWINGS
Fig. 1 - Dissolution profile of Example 8
Fig. 2 - In vitro release profile of Example 11
DETAIL DESCRIPTION OF THE INVENTION
The present invention provides a pharmaceutical composition capable of forming in-situ
implant, which releases the drug in a body for a prolonged period of time. The composition
includes goserelin or its pharmaceutically acceptable salts, biodegradable polymer and a
biocompatible organic solvent wherein the biocompatible organic solvent is miscible to
dispersible in aqueous medium or body fluid. The present invention also provides method of
preparation of such pharmaceutical composition capable of forming in-situ implant.
In the present invention, goserelin can be used in any suitable salts, which can be
incorporated in the present composition to provide the drug release for a prolonged period of
time. The preferred salt of the present invention is goserelin acetate. However the invention
is not limited to acetate salt, other pharmaceutically acceptable salts of goserelin such as
pamoate and mesylate can also be employed.
The composition is formulated as a subcutaneous/intra muscular/intra peritoneal injection for
administration about once per month, about once per two months, about once per three
months, or about once per four months to about once per six months. Preferably, the
composition is a liquid or a gel composition, suitable for injection into a patient.
Further, in the invention, suitable biodegradable polymer and biocompatible organic solvent
can be selected based on the results of the experiments, along with further optimization of the
formulation by evaluating effect on drug release from the formulation in-vitro and in-vivo
and an effect on the storage stability.
Any biodegradable polymer, which is suitable for present invention can be used. Some nonlimiting
examples of the polymers are polylactides, polyglycolides, polycaprolactones,
polydioxannones, polycarbonates, polyhydroxybutyrates, polyalkyene oxalates,
polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetals, polyketals,
polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates,
poly(malic acid), poly(amino acids), chitin, chitosan, polyorthoesters, and copolymers,
polyethylene-polypropylene glycol, block polymer of polylactides-glycolides with
polyethyleneglycol, terpolymers, block copolymers, branched copolymers, and mixtures
thereof. In the present invention, preferred biodegradable polymers are polylactides,
polyglycolides, copolymer of lactic acid and glycolic acid, polycaprolactones, or their
mixtures thereof. More preferred biodegradable polymer is copolymer of lactic acid and
glycolic acid (PLGA). Commercially available PLGAs are RESOMER® (Resomer polymers
are available in different Lactide to Glycolide molar ratio and inherent viscosity, e.g.,
Resomer RG 502H, Resomer RG 502, Resomer RG 503H, Resomer RG 503, Resomer RG
504H, Resomer RG 504, Resomer RG 653H, Resomer RG 752H, Resomer RG 752, Resomer
RG 753; first two digit in grade indicates molar ratio of lactide in polymer, H indicates acid
terminated polymer, and grades without H indicate ester terminated polymer), PURASORB®
and Lakeshore (These are also providing PLGAs in different molar ratio and viscosity
grades), WAKO (Low to medium viscosity Polymers are available). In one of the preferred
embodiment mixture of PLGA and PLA is used as a biodegradable polymer.
The terminal groups of the poly(DL-lactide-co-glycolide) can either be hydroxyl, carboxyl,
or ester depending upon the method of polymerization. Polycondensation of lactic or glycolic
acid will provide a polymer with terminal hydroxyl and carboxyl groups. Ring-opening
polymerization of the cyclic lactide or glycolide monomers with water, lactic acid, or
glycolic acid will provide polymers with the same terminal groups. However, ring-opening of
the cyclic monomers with a monofunctional alcohol such as methanol, ethanol, or 1-
dodecanol will provide a polymer with one hydroxyl group and one ester terminal groups.
Ring-opening polymerization of the cyclic monomers with a diol such as 1,6-hexanediol or
polyethylene glycol will provide a polymer with only hydroxyl terminal groups. In the
present invention, copolymer of lactic acid and glycolic acid (PLGA) could be either
carboxyl terminated, hydroxyl terminated or ester terminated, preferably carboxyl terminated.
In the present invention copolymer of lactic acid and glycolic acid having a monomer ratio of
lactic acid to glycolic acid in the range of about 50:50 to about 100:0 are used, depending
upon the requirement. Preferably 85:15 PLGA, 75:25 PLGA, 70:30 PLGA, 65:35 PLGA,
50:50 PLGA and more preferably 50:50 PLGA is used.
Polymers such as PLGA are available in different molecular weight ranges e.g. starting from
about average molecular weight of 1,000 to 200,000 Dalton or even more than that. In one of
the embodiment PLGA is used having average molecular weight ranging from 4,000 to
60,000 Dalton, more preferably PLGA having average molecular weight ranging from
10,000 to 30,000 Dalton are used as a biodegradable polymer. Alternatively in one of the
embodiment mixture of PLGA having average molecular weight from 10,000 to 30,000
Dalton and PLGA having average molecular weight from 4,000 to 6,000 Dalton is used.
The molecular weight of the polymer used can affect the rate of drug release. Under these
conditions, as the molecular weight of the polymer increases, the rate of drug release from
the system decreases. For relatively quick release of drug, low molecular weight polymers
can be chosen to provide the desired release rate. However, in the present invention inventors
have found that while using high molecular weight polymers, initial burst release was
observed. Inventors have surprisingly found that initial burst release could be controlled by
addition of low molecular weight biodegradable polymer.
The selection of type, molecular weight, and amount of biodegradable polymer for the
composition generally depend upon the desired properties of the prolonged release implant.
For example, the type, molecular weight, and amount of biodegradable polymer can
influence the length of time up to which the goserelin acetate is released from the in-situ
prolonged release implant. It has also been observed that the selection of mixture of different
PLGAs , having different molecular weight in different ratios are critical in controlling the
burst. Preferably PLGA having average molecular weight ranging from 4000 to 20000
Dalton is considered as low molecular weight polymer, 20000 to 40000 dalton is considered
as medium molecular weight polymer and more than 40000 dalton is considered as high
molecular weight polymer. Polymer concentration in the polymer solution is critical for the
release of goserelin from in-situ implant as it is generally seen that more dilute the
concentration, more readily the drug would releases and as the concentration get increase,
release of drug get slow. The inventor of present invention have found that optimization of
polymer concentration in polymer solution can produce the desired release of goserelin from
in-situ implant.
The biodegradable polymer can be present in any suitable amount. The suitable
biodegradable polymer is preferably present in an about 20 wt. % to about 80 wt. % of the
composition, more preferably present in about 30 wt. % to about 50 wt. % of the composition.
Biocompatible organic solvent can be employed, provided that such solvent is miscible to
dispersible in aqueous medium or body fluid. Such biocompatible organic solvent should be
able to diffuse into body fluid so that the in-situ implant composition coagulates or solidifies
to form solid implant. Further, such selected solvent should be compatible with the used
biodegradable polymer. Examples of suitable organic solvents include organic solvents
having an amide group, an ester group, a carbonate group, a ketone, an ether, a sulfonyl
group, or a combination thereof.
Specifically, the biocompatible organic solvent can be used in the present invention are Nmethyl-
2-pyrrolidone (NMP), 2-pyrrolidone, propylene carbonate, ethylene carbonate,
dimethyl carbonate, 2-ethyoxylyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl
butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin,
isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate,
triethyl citrate, acetyl tributyl citrate, glyceryl triacetate, acetone, methyl ethyl ketone,
solketal, ' glycerol formal, glycofurol, dimethylformamide, dimethylacetamide,
dimethylsulfoxide (DMSO), dimethylsulfone; tetrahydrofuran; epsilon-caprolactone,
butyrolactone, caprolactam, N,N-dimethyl-m-toluamide, l-dodecylazacycloheptan-2-one,
benzyl alcohol, benzyl benzoate, triaetin or mixtures thereof. Preferred biocompatible
organic solvent is N-methyl-2-pyrrolidone. In the present invention concentration of
biocompatible organic solvent can be taken in the range of about 20% to about 80% by
weight of the composition, more preferably in the range of about 50% to about 70% by
weight of the composition. Surprisingly, in the present invention the inventors have found
that combination of biocompatible organic solvents also helps in reducing the burst release,
preferably combination of NMP with benzyl benzoate. The preferred range of benzyl
benzoate is of about 10 to about 25% by weight of the composition.
The type and amount of biocompatible organic solvent present in the composition will
typically depend upon the desired properties of the controlled release implant. For example,
the type and amount of biocompatible organic solvent can influence the length of time in
which the goserelin acetate is released from the controlled release implant.
In one of the embodiment, rate retarding agents can also be added to reduce the burst effect
in the composition. Such retarding agents can be selected from the group comprising of ester
of a mono, di or tricarboxylic acid, a polyhydroxy alcohol, a fatty acid, a fatty, acid ester,
epoxidized oil, a sterol, a higher alkyl alcohol, and any mixture thereof.
In one of the embodiment of the present invention, goserelin solution can be prepared in a
suitable solvent, which is then sterilized by suitable technique such as membrane filtration
and lyophilized subsequently in a container, preferably in a syringe or vial.
In one of the preferred embodiment, goserelin acetate solution can be prepared in either
acetic acid or in water which is sterilized by membrane filtration and lyophilized
subsequently. Preferably goserelin acetate solution is prepared in water, sterilized by
membrane filtration and lyophilized subsequently in a suitable container.
In one of the embodiment, suitable biodegradable polymer is dissolved in a suitable solvent,
which is then sterilized by suitable technique such as membrane filtration and subsequently
subjected to aseptic drying using suitable technique such as lyophilization or spray drying.
Then the polymer can be mixed with sterilized biocompatible organic solvent & filled in to
suitable container, preferably syringe or vial.
In one of the preferred embodiment, PLGA is dissolved in an acetic acid, which is then
sterilized by membrane filtration technique and subsequently subjected to aseptic drying
using suitable technique such as lyophilization or spray drying. Then the polymer is mixed
with sterilized NMP & filled into suitable container, preferably syringe or vial.
It has been observed from the prior art that the viscosity of the mixture of biodegradable
polymer in biocompatible organic solvent is too high and hence filtration through membrane
filter becomes difficult. Surprisingly, in the present invention the inventors have found that
dissolving biodegradable polymer in suitable solvent helps in filtration and solvent is then
removed by lyophilization or spray drying, prior to mixing with biocompatible organic
solvent and hence makes processing easy. For example, dissolving PLGA into acetone, acetic
acid, chloroform, dichloromethane, ethyl acetate, ethyl formate, methyl ethyl ketone, methyl
isobutyl ketone or suitable solvent, solution having lower viscosity and hence membrane
filtration becomes easy.
In an alternative embodiment of the present invention, part of the biodegradable polymer can
be added with goserelin solution and subsequently lyophilized in a suitable container,
preferably syringe or vial, whereas the remaining part of the biodegradable polymer can be
either mixed with the biocompatible organic solvent and sterilized separately by suitable
technique and filled in the suitable container or remaining part of the biodegradable polymer
can be processed as per above technique i.e. dissolving in solvent followed by sterilization,
lyophilization, mixing with organic solvent and filling.
In an another embodiment of the present invention, goserelin solution is prepared in a
suitable solvent, which is than sterilized by suitable technique such as membrane filtration
and lyophilized subsequently and filled in the suitable container, preferably syringe or vial.
Suitable biodegradable polymer is dissolved in a suitable solvent which is than sterilized by
suitable technique such as membrane filtration and lyophilized subsequently. The strong acid
is dissolved in a biocompatible organic solvent and sterilized by suitable technique & mixed
with lyophilized polymer and filled in to suitable container, preferably syringe or vial.
The strong acids suitable for the present invention may be selected from, but not limited to,
the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, chromic acid,
sulfuric acid, methanesulfonic acid, trifluromethane sulfonic acid, trichloroacetic acid,
dichloroacetic acid, bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-chloropropanoic
acid, 2-oxobutanoic acid, 2-chlorobutanoic acid, 4-cyanobutanoic acid, pamoic acid,
perchloric acid, phosphoric acid, hydrogen iodide, acetic acid, trifluoroacetic acid, propionic
acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid,
ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic
acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic
acid, fumaric acid, toluenesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid
and the like.
Such strong acid when mixed with the drug is capable of forming different pharmaceutically
acceptable salt having different solubility property than the original salt. Preferably in the
present invention pamoic acid or methanesulfonic acid is used.
In the lyophilization of any solution primary drying is generally performed below glass
transition temperature of the solution to obtain elegant porous cake. Surprisingly, in the
present invention it has been found that the lyophilization of the solution of goserelin acetate
or its mixture with biodegradable polymer in acetic acid and also of the aqueous solution of
goserelin acetate, primary drying performed above glass transition temperature have given
elegant porous cake.
In another embodiment, the present invention provides a kit which includes a first container
and a second container. Preferably, the first container is a syringe or vial and the second
container is a syringe or vial. The containers can be connected or separate.
One of the embodiment of present invention is a method of administration of composition of
invention wherein prior to administration the content of the two containers are mixed
together until the polymer/solvent solution and the goserelin are effectively mixed together
and the prepared composition can then be injected through the needle into the body.
The amount of goserelin incorporated into the present composition depends upon the desired
release profile, the concentration of goserelin required for a biological effect, and the length
of time that the goserelin has to be released for treatment.
The goserelin or its pharmaceutically acceptable salts can be used in the present invention in
amounts ranging from equivalent to about 1mg to about 25 mg of goserelin base. Preferably
the goserelin present in amounts ranging from equivalent to about 3.6 mg to about 21.6 mg of
goserelin base.
Specifically, in one embodiment of the present invention, the composition can be used to
formulate a one month delivery system of goserelin. Alternatively, in another embodiment of
the present invention, the composition can be used to formulate a three month delivery
system of goserelin or a six month delivery system of goserelin. In such an embodiment, the
goserelin can preferably be present in about 0.5 wt. % to about 5 wt. % of the composition.
It has been observed that the time required to prepare a polymer solution in a biocompatible
organic solvent is less when using lyophilized polymer as compared to polymer without
processed under lyophillization.
The amount of composition to be administered will typically depend upon the desired
properties of the prolonged release implant. For example, the amount of composition can
influence the length of time in which the goserelin is released from the implant.
In one of the embodiment, the present invention also provides process for the preparation
pharmaceutical composition capable of forming in-situ implant. The process includes mixing,
in any order, a biodegradable polymer, a biocompatible organic solvent, and goserelin. These
ingredients, their properties, and preferred amounts are as disclosed above.
There are various techniques available for the sterilization such as membrane filtration,
gamma-irradiation, chemical sterilization etc. Effect of gamma irradiation on polymer
molecular weight was also observed. When the polymer solution was subjected to gamma
irradiation for sterilization, the polymer molecular weight decreases and eventually PDI
increases. When the polymer solution was subjected to membrane filtration for sterilization,
the polymer molecular weight almost remains constant and eventually PDI remain constant.
In the present invention the biodegradable polymers and biocompatible organic solvents are
preferably sterilized by membrane filtration or gamma-irradiation and more preferably by
membrane filtration.
In one of the embodiment, present invention provides a general process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin solution in a suitable solvent, sterilizing the solution by membrane
filtration and subsequent lyophilizing in a suitable container closure system;
2. Mixing biodegradable polymer and biocompatible organic solvent and sterilized into a
suitable container closure system by suitable technique or aseptically mixed after sterilizing
separately and filled into a suitable container closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin solution in suitable solvent, sterilizing the solution by membrane
filtration and subsequent lyophilizing in a suitable container closure system;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by membrane
filtration technique and lyophilized in bulk;
3. Sterilizing biocompatible organic solvent separately by membrane filtration technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In another embodiment, present invention provides a process for the preparation of
composition capable of forming in-situ implant comprising:
1. Preparing goserelin solution in suitable solvent, sterilizing the solution by membrane
filtration and subsequent lyophilizing in a suitable container closure system;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by membrane
filtration technique and drying aseptically by spray drying;
3. Sterilizing biocompatible organic solvent separately by membrane filtration technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In one of the preferred embodiment, present invention provides a process for the preparation
of composition capable of forming in-situ implant comprising:
1. Preparing goserelin acetate solution in water, sterilizing the solution by membrane
filtration and subsequent lyophilizing in a suitable container in which primary drying is
performed above glass transition temperature of the goserelin acetate solution;
2. Dissolving PLGA in an acetic acid and sterilizing the solution by membrane filtration
technique and lyophilized;
3. Sterilizing NMP by membrane filtration technique;
4. Mixing polymer and solvent of step 2 & 3 aseptically and filling in a suitable container
closure system.
In one of the embodiment, the present invention provides a method of treating cancer in a
patient. The method includes administering to the patient in need of such treatment an
effective amount of a composition of the present invention. Specifically, the cancer can be
prostate cancer, endometriosis, as an endometrial-thinning agent prior to endometrial ablation
for dysfunctional uterine bleeding, and in the palliative treatment of advanced breast cancer
in pre- and perimenopausal women.
In another embodiment, present invention includes kit containing composition for in-situ
implant comprising: (a) a first vial comprising a composition comprising a biodegradable
polymer and a biocompatible organic solvent; wherein the biocompatible organic solvent is
miscible to dispersible in aqueous medium or body fluid; and (b) a second vial comprising
goserelin, preferably goserelin acetate in a lyophilized form.
In another embodiment, present invention includes kit containing composition for in-situ
implant comprising: (a) a first vial comprising a composition comprising a biodegradable
polymer and a biocompatible organic solvent characterized in that the biodegradable polymer
is aseptically dried either by lyophilization or spray drying prior to mixing with
biocompatible organic solvent; and (b) a second vial comprising goserelin, preferably
goserelin acetate in a lyophilized form.
In another embodiment, present invention includes kit containing composition for in-situ
implant comprising: (a) a first vial comprising a composition comprising a biodegradable
polymer and goserelin; preferably goserelin acetate in a lyophilized form and (b) a second
vial comprises a biocompatible organic solvent; wherein the biocompatible organic solvent is
miscible to dispersible in aqueous medium or body fluid. ,
Pharmacodynamic study
The composition as mentioned hereinafter in example 8 was subjected to pharmacodynamic
study conducted in healthy male wistar rat to compare the effect with Zoladex®.
An evaluation of pharmacodynamic profile of goserelin in-situ implant of present invention
in comparison with Zoladex® depot was carried out in wistar rats. Implants, containing 3.6
mg of goserelin, were administered by subcutaneous route. Each group (N=15) was
administered three doses of goserelin implants at an interval of 28 days. Blood samples were
withdrawn at predefined time intervals for the measurement of testosterone levels.
Serum Testosterone Castration Incidences (N=15)
Goserelin in-situ Zoladex 3.6 g Goserelin in-situ Zoladex 3.6 mg
implant implant
(Example 8) (Example 8)
Day 1 8.30 10.68 0 0
Day 4 1.38 1.01 3 4
Day 8 0.46 0.33 13 12
Day 16 0.47 0.24 11 14
Day 20 0.43 0.28 10 14
Day 24 0.66 0.48 8 10
Day 29 0.78 0.60 5 10
Day 36 0.87 0.65 4 8
Day 43 0.76 0.57 4 10
Day 50 0.20 0.15 15 15
Day 57 0.15 0.12 15 15
Day 60 0.24 0.19 14 15
Day 64 0.31 0.32 15 13
Day 68 0.39 0.31 14 14
Day 72 0.43 0.34 13 14
Note: Castration level:Testosterone Level below 0.5 ng/ml.
The invention will be further illustrated by the following Examples, however, without
restricting its scope to these embodiments.
EXAMPLES
Example-1
Tg' (Glass transition temperature) of aqueous goserelin solution (100 mg/ml) was determined
by DSC (Mettler). About 60 Dl of sample was taken and cooled rapidly to -65°C at 20°C/min.
The sample was then heated slowly at 5°C/min to 15°C.
Observation: Onset of glass transition was observed at -56.4°C and mid point was observed
at -55.16°C (Tg').
Example-2
Tg' of goserelin solution in acetic acid (100 mg/ml) was determined by DSC (Mettler).
About 50 of sample was taken and cooled rapidly to -65°C at 20°C/min. The sample was
then heated slowly at 5°C/min to 15°C.
Observation: Onset of glass transition was observed at -56.4°C and mid point was observed
at -55.14°C (Tg').
ExampIe-3
Ingredients Example 3A Example 3B
Goserelin 12 mg/ml 12 mg/ml
Solvent Purified water Acetic acid
Fill volume 0.5 ml 0.5 ml
Vial 2 ml clear 2 ml clear
Vials: 2 ml clear tubular glass vial (USP Type I).
Stopper: 13 mm double slotted grey bromo butyl rubber stopper.
For the example-3A & example-3B lyophilization was performed as per the lyophilization
cycle mentioned below.
Lyophilization cycle
No Stages Temperature Pressure Duration
(°C) (mtorr) (Hr:min)
Freezing
1(Freezing) -40 6:00
Product Freeze Temp -35
Vacuum set temp -50
(Condenser temp)
Vacuum required 300
Vacuum stabilization time 0:01
Primary Drying Shelf Temp. Pressure Duration
(°C) (mtorr) (Hnmin)
Step-1 -30 262 8:00
Step-2 -20 262 7:00
Step-3 -10 262 6:00
Step-4 0 150 7:00
Step-5 10 150 6:00
Step-6 20 112 6:00
Secondary Drying 30 50 10:00
Total cycle 56:00:00
time
Observations: Good intact cake was obtained for both compositions.
Ingredients Content
PLGA (50:50, 0.2 dl/g) 40%
N - methyl-2-pyrrolidone 55 %
(NMP)
PLGA was dissolved in NMP to get polymer solution and the solution was sterilized by
gamma-irradiation. The sterilized polymer solution was added to lyophilized goserelin and
gently stirred to get uniform dispersion. Dispersion when injected subcutaneously into rats,
solid implant was formed after some time in-situ.
Example 5 & 6
Ingredients Example 5 Example 6
Goserelin 0.5 - 2 % 0.5 - 2 %
PLGA (50:50, 0.2 dl/g) 25 - 55% 20 - 50%
PLGA (50:50, 0.09 dl/g) - 5 - 30 %
N - methyl-2-pyrrolidone 45 - 70 % 40 - 70 %
(NMP)
Dissolve PLGA into acetic acid and filter through 0.22 membrane filter. Lyophilize the
filtered solution to get dried powder. Dissolve lyophilized PLGA in sterilized NMP with
continuous stirring to get polymer solution. Fill the polymer solution in suitable container
and closure.
Separately, dissolve goserelin in water for injection and filter through 0.22 membrane filter.
Fill the solution in suitable vials and lyophilize to get dried product.
Before use, add polymer solution into lyophilized goserelin and mix gently to get
homogeneous dispersion.
Ingredients Content
Goserelin 0.5 - 2 %
PLGA (50:50, 0.2 dl/g) 25 - 55%
Benzyl benzoate 5 - 30 %
N - methyl-2-pyrrolidone 20 - 70 %
(NMP)
Dissolve PLGA into acetic acid and filter through 0.22 membrane filter. Lyophilize the
filtered solution to get dried powder. Dissolve lyophilized PLGA in sterilized mixture of
NMP and Benzyl benzoate with continuous stirring to get polymer solution. Fill the polymer
solution in suitable container and closure.
Separately, dissolve goserelin in water for injection and filter through 0.22 membrane filter.
Fill the solution in suitable vials and lyophilize to get dried product.
Before use, add polymer solution into lyophilized Goserelin and mix gently to get
homogeneous dispersion.
Example-8: Preparation of in-situ implant of goserelin acetate
1. Preparation of Goserelin Acetate Vial Lyophilized
Aqueous solution of Goserelin was prepared by dissolving 1.2 g Goserelin in 100 ml WFI.
Solution was filtered through 0.2 PVDF membrane filter and 0.5 ml solution filled in 2 ml
vials each. Vials were loaded into lyophilizer after closing partially with rubber closure and
lyophilized.
2. Preparation of Lyophilized PLGA and Polymer solution
2.5 g of PLGA 5050 (I.V. 0.18 dl/g) and 7.5 g of PLGA 5050 (I.V. 0.28 dl/g) were dissolved
in acetic acid (volume 100 ml) and filtered through 0.2 PVDF membrane filter. Solution
was filled in 20 ml clear vial and lyophilized with primary drying at -30 to 20 °C for 47 hrs
and secondary drying at 30 °C for 12 hrs. In each lyophilized vial 1.2 ml NMP (aseptically
filtered) was added to yield polymer solution
3. Preparation of reconstituted formulation
0.5 ml polymer solution was withdrawn in syringe and injected in a vial of lyophilized
Goserelin and allowed to mix. 0.3 ml of Reconstituted formulation was withdrawn in syringe
to deliver 3.6 mg Goserelin.
Goserelin 3.6 mg
Polymer solution 0.3 ml
5050DLG2A 10 % w/w
5050DLG3A.... 30 % w/w
NMP 60 % w/w
4. Dissolution method
0.3 ml reconstituted formulation was injected in 0.3 ml PBS buffer pH 7.4 at temperature
39 °C and allowed implant to form. After 2 hrs, 50 ml media was added in the same flask and
incubated at 39°C for 28 days with complete media replacement at every 7 days. Samples
were withdrawn at regular interval and analyzed for goserelin content using reversed phase
HPLC method
In vitro release profile:
Time Mean %release
(Days) (N=3)
0.08 5.4
1 20.1
3 34.6
7 37.3
9 40.8
12 48.9
14 56.4
17 61.8
2 1 64.0
24 71.2
28 73.1
Example-9
Preparation of in-situ implant of goserelin acetate
Goserelin acetate equivalent to 3.6 g Goserelin
Polymer solution
Purasorb 5002A..... 40%
Wako 5005 5%
NMP 55%
Procedure:
1. PLGA was dissolved in N-methyl pyrrolidone to achieve desired concentration.
2. PLGA solution was filled in vials and sterilized by gamma radiation at 25 KGy.
(Time for solution preparation - 60 to 150 min)
3. Polymer solution was added in lyophilized Goserelin for reconstitution.
Example-10
Preparation of in-situ implant of goserelin acetate
Procedure:
1. Dissolved PLGA in glacial acetic acid at concentration 10 % w/v.
2. Filtered the prepared solution through PVDF filter membrane with 0.22 pore size.
3. Filtered solution was filled in container (vials) and lyophilize.
4. Lyophilized PLGA was dissolved in N-methyl pyrrolidone to achieve desired
concentration. (Time for Solution preparation - 15 to 20 min)
5. Polymer solution was added in a vial containing lyophilized Goserelin for
reconstitution.
Goserelin acetate equivalent to 3.6 mg Goserelin
Polymer solution 0.3ml
Purasorb 5002A 40%
Wako 5005 5%
NMP 55%
Example-11
Preparation of in-situ implant of goserelin acetate (For Three months profile)
Goserelin acetate equivalent to 10.8 g Goserelin
Polymer solution 0.4ml
Purasorb 7507 (30% w/w)
Triacetin (5% w/w)
NMP (65% w/w)
Injection wt/ vol 400 mg
*Each 400 mg contains Goserelin acetate equivalent to 10.8 mg Goserelin
Procedure:
1. PLGA was dissolved in N-methyl pyrrolidone to achieve desired concentration .
(Time for solution preparation - 60 to 150 min)
2. PLGA solution was filled in vials and sterilized by gamma radiation at 25 KGy.
3. Polymer solution was added in lyophilized Goserelin for reconstitution.
In vitro release profile: (Mean calculated on the basis of average of three diffeent in-situ
implants of the same formulation)
Time Mean %Release
(days) (N=3)
0 0
0.08 5.8
1 22.5
7 41.5
14 49.2
2 1 52.2
28 54.0
35 55.2
44 56.3
56 72.7
68 77.4
70 79.0
82 79.5
Example-12
Evaluation of burst release in rats
Goserelin dose: 3.6 g /Rat
Route of administration: Subcutaneous
Injection volume: 0.3 ml
Number of animals: 3
Sampling Points: 2, 6 and 24 hrs
Formulation Composition ma Burst Index
(ng/ml)
PLGA 5050 (I. V. 0.21 dl/g) 40% 1310.4 1.0
NMP (Pharmasolve) 60%
PLGA 5050 (I. V. 0.21 dl/g) 40% 841.1 0.6418536
PLGA 5050 (I. V. 0.09 dl/g) 5 %
NMP (Pharmasolve) 55%
PLGA 5050 (I. V. 0.21 dl/g) 40 % 248.8 0.1898657
PLGA 5050 (I. V. 0.09 dl/g) 5 %
Benzyl benzoate 15 %
NMP (Pharmasolve) 40 %
Addition of low molecular weight polymer reduces Cmax by 40% as compared to high
molecular weight polymer alone.
2. Combination of polymers & addition of non-polar solvent like benzyl benzoate in
formulation caused 80% reduction in Cmax as compared to single polymer and single
solvent system.
Example-13
3g of PLGA 5050(1.V. 0.3dl/g) dissolved in 30 ml of Acetone and filtered through 0.22 □
membrane filter. The filtered solution was subsequently spray dried in mini-spray dryer with
inert loop. Nitrogen was used as inert gas and other process conditions were
Inlet air temperature: 75°C
Outlet air temperature: 40-45°C
Air flow: 35 - 37 m3/hr
Spray rate: 3 ml / in
The inherent viscosity of dried polymer was determined. There was no change observed in
the inherent viscosity indicating polymer remains intact during the process.
Example-14
Solution of PLGA 5050 (I.V. 0.3dl/g) was prepared in the solvent mentioned in table below
and stability of PLGA was studied at room temperature by determining the viscosity of
polymer solution. Viscosity of solution was determined using Brookfield CAP2000+
viscometer.
Time points Viscosity (cps) of polymer solution
Solvent Acetic Acetone DCM Ethyl MEK
acid acetate
Polymer 20% w/w 25% 25% 25% w/w 25% w/w
Concentration w/w w/w
Initial 62.5 49.65 40.95 76.9 84.9
1 hr 62.6 46.1 43.05 79.6 74.45
2 hr 61.85 47.25 46.25 75.4 69.55
3 hr 61.9 47.85 39.75 78.3 72.4
4 hr 62.4 47.8 38 75.45 81.7
5 hr 63.7 52.05 39.95 81.6 81.1
There was no significant change in the viscosities of polymer solution indicating
degradation of polymer during this time interval.

CLAIMS
1. A pharmaceutical composition capable of forming in-situ implant comprising: goserelin or
its pharmaceutically acceptable salts thereof, biodegradable polymer and a biocompatible
organic solvent wherein the biocompatible organic solvent is miscible to dispersible in
aqueous medium or body fluid.
2 The pharmaceutical composition as claimed in claim 1 wherein the biodegradable polymer
is aseptically dried either by lyophilization or spray drying prior to mixing with
biocompatible organic solvent.
3. The pharmaceutical composition as claimed in claim 1 wherein the biodegradable polymer
is selected from the group comprising of polylactides, polyglycolides, polycaprolactones,
polydioxannones, polycarbonates, polyhydroxybutyrates, polyalkyene oxalates,
polyanhydrides, polyamides, polyesteramides, polyurethanes, polyacetals, polyketals,
polyorthocarbonates, polyphosphazenes, polyhydroxyvalerates, polyalkylene succinates,
poly(malic acid), poly(amino acids), chitin, chitosan, polyorthoesters, and copolymers,
terpolymers, block copolymers, branched copolymers, and mixtures thereof.
4. The pharmaceutical composition as claimed in claim 3 wherein the biodegradable polymer
is selected from the group comprising of polylactides, polyglycolides, copolymer of lactic
acid and glycolic acid, polycaprolactones, or their mixtures thereof.
5. The pharmaceutical composition as claimed in claim 4 wherein the biodegradable polymer
is copolymer of lactic acid and glycolic acid .
6. The pharmaceutical composition as claimed in claim 5 wherein the copolymer of lactic
acid and glycolic acid is having a carboxyl terminal group or ester terminal group.
7. The pharmaceutical composition as claimed in claim 5 wherein copolymer of lactic acid
and glycolic acid is having a carboxyl terminal group.
8. The pharmaceutical composition as claimed in claim 1 wherein the amount of
biodegradable polymer is between about 20% to about 80% by weight of the composition.
9. The pharmaceutical composition as claimed in claim 1 wherein the amount of
biodegradable polymer is between about 30% to about 50% by weight of the composition.
10. The pharmaceutical composition as claimed in claim 1 wherein biocompatible organic
solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), 2-
pyrrolidone, propylene carbonate, ethylene carbonate, dimethyl carbonate, 2-ethyoxylyl
acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl
glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate; dimethyl adipate,
dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate,
glyceryl triacetate, acetone, methyl ethyl ketone, solketal, glycerol formal, glycofurol,
dimethylformamide, dimethylacetamide, dimethylsulfoxide (DMSO), dimethylsulfone;
tetrahydrofuran; epsilon-caprolactone, butyrolactone, caprolactam, N,N-dimethyl-mtoluamide,
l-dodecylazacycloheptan-2-one, benzyl alcohol, benzyl benzoate, triacetin or
mixtures thereof.
11. The pharmaceutical composition as claimed in claim 1 wherein the biocompatible
organic solvent is N-methyl-2-pyrrolidone (NMP).
12. The pharmaceutical composition as claimed in claim 1 wherein the biocompatible
organic solvent is a mixture N-methyl-2-pyrrolidone (NMP) and benzyl benzoate.
13. The pharmaceutical composition as claimed in claim 1 wherein the biocompatible
organic solvent is present in about 20 % to about 80 % by weight of the composition.
14. The pharmaceutical composition as claimed in claim 1 wherein the biocompatible
organic solvent is present in about 50 % to about 70 % by weight of the composition.
15. A process for the preparation of pharmaceutical composition capable of forming in-situ
implant comprising following steps:
1. Preparing goserelin solution in suitable solvent, sterilizing the solution by suitable
technique and subsequent lyophilizing in a suitable container;
2. Separately sterilizing biodegradable polymer and biocompatible organic solvent by
suitable technique, and filling the mixture into a suitable container.
16. A process for the preparation of pharmaceutical composition capable of forming in-situ
implant comprising following steps:
1. Preparing goserelin solution in suitable solvent, sterilizing the solution by
membrane filtration and subsequent lyophilizing in a suitable container;
2. Dissolving biodegradable polymer in a suitable solvent and sterilizing by
membrane filtration technique and lyophilized;
3. Biocompatible organic solvent is sterilizing separately by membrane filtration
technique;
4. Mixing polymer and solvent of step 2 & 3 and filling in a suitable container.
17. A kit containing composition for in-situ implant comprising (a) a first vial comprising a
composition comprising a biodegradable polymer and a biocompatible organic solvent;
wherein the biocompatible organic solvent is miscible to dispersible in aqueous medium or
body fluid; and (b) a second vial comprising goserelin acetate.
18. The kit as claimed in claim 17 wherein the goserelin acetate is in lyophilized form.
19. The pharmaceutical composition as claimed in claim 1 is for once a month administration.
20. The pharmaceutical composition as claimed in claim 1 is for once in three months
administration.
21. The pharmaceutical composition as claimed in claim 1 is for once in two months
administration.