In-situ Gel Forming Injectable Depot Liquid Composition of Olanzapine
Field of the Invention
The present invention relates to an in-situ gel forming injectable depot liquid composition of Olanzapine comprising Olanzapine, a biocompatible, biodegradable polymer and a biocompatible organic solvent. The composition forms a gel in-situ after injection and is used for the treatment of psychotic patients.
Background of the Invention
Olanzapine (2-methyl-4- (4-methyl-l-piperazinyl)-10 H-thieno [2,3-b][1,5] benzodiazepine) is a psychotropic agent useful in the treatment of schizophrenia, acute manic episodes in bipolar disorder, acute agitation associated with both these disorders, maintenance treatment in bipolar disorder and for the treatment of depressive episodes associated with bipolar disorder.
Psychotic illness is a chronic and devastating mental illness with significant morbidity and mortality. No treatment is effective for every patient, and non adherence with medication is common, so many treatment options are needed in order to effectively treat patients during the lifecycle of the disease.
Poor compliance with medication regimens is particularly problematic among patients with schizophrenia. This is a major challenge in ensuring continuous antipsychotic therapy. Noncompliance rates range from 12 to 65 percent over a six-month period. Noncompliance accounts for about 40% of all relapse. In addition, relapse from noncompliance is more severe or dangerous than relapse occurring while on neuroleptic medication. Persistent noncompliance worsens the overall course of the schizophrenic illness, and eventually makes the person less likely to respond to medication.
Thus, improving compliance is an unmet need for patients with schizophrenia.
Olanzapine, is commercially available as conventional tablets, orally disintegrating tablets and immediate release intramuscular injection formulations, under the tradename ZYPREXA® tablets and ZYPREXA® ZYDIS® orally disintegrating tablets and ZYPREXA® IM injection respectively.
Patient compliance with such a daily dosing regimen is however, difficult to ensure, especially where the course of therapy is long or of intermediate or lifetime duration. Thus, there is a need for a depot composition of Olanzapine to improve patient compliance/convenience and give patients optimum therapeutic benefit.
A depot composition is specially formulated to provide slow absorption of the drug from the site of administration, often keeping therapeutic levels of the drug in the patient's system for days or weeks at a time. By delivering drug without exposure to the Gl tract, the potential issue of drug degradation is avoided.
Several formulation approaches may be applied to the development of injectable depot composition. Typically a person skilled in the art in order to obtain depot effect would modify the drug by forming salts, complexes and esters. Usually esterification approach has been utilized to render longer duration of neuroleptics. These modified drugs have low solubility in physiological fluid, following intramuscular injection form drug reservoir in muscular tissues and gradually release the drug moiety for absorption into the systemic circulation. However, this technique involves complex chemical reactions so as to obtain the modified drug.
Other method for obtaining depot effect is by means of implants. Both biodegradeable and non-biodegradeable implant versions have been marketed since the 1980s. Examples of these are ZoladexTM, a polylactide-co-glycolide formulation of goserelin for the treatment of breast cancer and NorplantTM, a non-biodegradeable silicone device for contraception.
Small, injectable microparticle formulations are also well known for providing depot effect, an example being Lupron DepotTM, a formulation of leuprolide for the treatment of prostate cancer. A drawback of such preformed delivery systems is administration.
Cylindrical rods such as ZoladexTM require relatively large bore needles for implantation. Microparticle formulations allow smaller bore needles to be used; however, they require dispersion in an aqueous vehicle prior to injection and their manufacturing processes are typically complex and difficult to control, often involving the use of harsh solvents that require removal. Thus, an expensive and complex manufacturing process, and the inability to retrieve the microparticles in case of drug adverse reaction are perceived limitations with these systems.
More recently, formulations have been developed which are injected as a liquid, but undergo a change to a solid formulation in vivo, so-called in-situ gelling systems. They are relatively simple to manufacture, particularly when compared to microparticle formulations.
When the polymer solution is injected into the body, the biocompatible organic solvent dissipates into the surrounding tissue as the water permeates into the implant. This process leads to phase separation and subsequent coagulation of the polymer to form an implant in-situ. Active drugs are added to the polymer solution to produce a ready-to-use homogeneous solution or dispersion depending upon the solubility of the drug. A sterile product can be made by aseptic manufacturing, filtration, autoclaving or exposure to Y-irradiation. Once the drug-containing implant is formed in vivo, drug release is controlled primarily by the properties of the polymer, solvent, and drug employed. This delivery system has still unique challenges associated with its development that are related to drug stability, sterilization and solvent compatibility with body tissues.
PCT application No. 00/18408 assigned to Eli Lilly discloses injectable sustained release oleaginous or cholesterol formulation of olanzapine or olanzapine pamoate or solvate thereof.
U.S. Patent No. 4,938,763 and its divisional U.S. Patent No. 5,278,201 relate to a biodegradable polymer for use in providing syringeable, in-situ forming, solid biodegradable implants for animals. In one embodiment, a thermoplastic system is used wherein a non-reactive polymer is dissolved in a biocompatible solvent to form a liquid which is placed in the animal wherein the solvent dissipates to produce the solid implant. Alternatively, a thermosetting system is used wherein effective amounts of a liquid acrylic ester terminated, biodegradable prepolymer and a curing agent are formed and the liquid mixture is placed within the animal wherein the prepolymer cures to form the solid implant. It is stated that the systems provide a syringeable, solid biodegradable delivery system by the addition of an effective level of a biologically active agent to the liquid before the injection into the animal.
U.S. Publication No. 20020034532 discloses injectable depot gel composition comprising a biocompatible, biodegradable polymer; a solvent that dissolves the biocompatible, biodegradable polymer and forms a viscous gel; a beneficial agent; and an emulsifying agent in the form of a dispersed droplet phase in the viscous gel.
US publication No. 20060154918 discloses an injectable nanoparticulate olanzapine composition comprising olanzapine nanoparticles having an effective average particle size that results in a therapeutic efficacy of about one week or greater; at least one surface stabilizer; and a pharmaceutically acceptable carrier.
US Publication No. 20040146562 pertains to a pharmaceutical kit for preparing an injectable depot formulation comprising a solubilized or unsolubilized aryl-heterocyclic compound; and a liquid vehicle comprising a viscosity agent, with the proviso that when said aryl-heterocyclic compound is unsolubilized, said liquid vehicle further contains a solubilizer.
PCT Application No. 2009/060473 assigned to Panacea discloses injectable depot gel compositions comprising antipsychotics, at least one biocompatible, biodegradable polymer(s); at least one biocompatible organic solvent. The composition comprising olanzapine has polymer to solvent ratio of 1: 0.004.
Lilly has recently launched a depot parenteral formulation for Olanzapine using Olanzapine pamoate, under the tradename Zypadhera, in Europe. This salt dissociates slowly into olanzapine and pamoic acid and thus leads to a sustained effect.
The present invention provides an alternate injectable depot liquid composition of olanzapine. The compositions with olanzapine must be carefully designed as olanzapine is poorly soluble in water and has tendency to be metastable which leads to undesired discoloration of the composition. Olanzapine is subject to hydrolysis, particularly in solution or moist environment, at room temperature or even under refrigeration. Further, Olanzapine is a highly potent compound and requires care to assure homogeneity and stability of the finished formulation.
As Olanzapine is poorly water soluble i.e., solubility at pH 6.8= 0.02mg/ml, undissolved product is particularly problematic when dealing with potent compound like Olanzapine. Potential dosing variations can occur if the active is not completely dissolved.
In view of the above constraints it would be a challenge to formulate ready to use liquid depot composition of Olanzapine, which is economical, safer, effective, having
good syringibility and provides drug delivery over a sustained period of time at concentrations efficacious for treatment of schizophrenia.
Besides having formulation difficulties with Olanzapine as an active compound, there are additional efforts involved when designing an in-situ gel forming injectable depot liquid composition for Olanzapine.
One of the biggest challenges is to optimize the ratio of polymer to solvent in order to achieve desired release profile from the depot without exhibiting burst effect. Further, the viscosity of the composition has to be maintained so as to have good syringability. It was also observed that release rate of olanzapine from the composition further varied by varying the polymer properties, such as type of polymer, viscosity of polymer, Comonomer ratio of the monomers forming the polymer and the end group of the polymer.
We have worked to develop an in-situ gel forming Injectable liquid depot composition of Olanzapine and have surprisingly found that it is possible to produce in-situ gelling composition for the delivery of Olanzapine when the biocompatible, biodegradable polymer and the biocompatible organic solvent are present in a ratio of 1:2 to 1:6.
Summary of the Invention
According to one embodiment there is provided an in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine; b) a biocompatible, biodegradable polymer; and c) a biocompatible organic solvent, wherein the polymer and the solvent are present in a ratio of 1.2 to 1:6.
According to another embodiment there is provided an in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine,
b) a biocompatible, biodegradable polymer having an acid terminated end group, and
c) a biocompatible organic solvent, wherein the polymer and the solvent are present in a ratio of 1:2 to 1:6.
According to another embodiment there is provided an in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine, b) a biocompatible, biodegradable polylactide-co-glycolide polymer having lactide to glycolide ratio of 50:50, and c) a biocompatible organic solvent, wherein the polymer and the solvent are present in a ratio of 1:2 to 1:6.
According to another embodiment there is provided an in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine; b) a biocompatible, biodegradable polymer; and c) a biocompatible organic solvent, wherein the polymer and the solvent are present in a ratio of 1:4.
According to still another embodiment there is provided an in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine; b) a biocompatible, biodegradable polymer; and c) a biocompatible organic solvent, wherein olanzapine, polymer and the solvent are present in a ratio of 1:0.5:2.
According to another embodiment there is provided a process for the preparation of the in-situ gel forming injectable depot liquid composition of Olanzapine disclosed in the various embodiments of the specification.
Detailed Description of the Invention
The term "Olanzapine" as used herein refers to olanzapine free base, its acid addition salts and solvates thereof.
The acid addition salts are preferably the pharmaceutically acceptable, non-toxic addition salts with suitable acids, such as those of inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or of organic acids, such as organic carboxylic acids, for example pamoic, benzoic, glycollic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric or lactic acid, or organic sulphonic acids for example methane sulphonic, ethane sulphonic, 2-hydroxyethane sulphonic, toluene-p-sulphonic or naphthalene-2-sulphonic acid.. For example Olanzapine or Olanzapine pamoate may be used.
The term "depot" refers to a substance containing the active that is retained in close proximity to the site of injection so that release of the active agent occurs over a prolonged period of time. In an embodiment, the depot erodes/dissolves in the in vivo environment of a subject over time and in doing so releases the active agent into the subject.
"Burst effect" often results in a substantial portion of the active agent, if not all, being released in a very short time, e.g., within few hours.
The term "liquid" means having a viscosity that will flow easily through a 20-24 gauge needle. It can be either in the form of a clear solution or dispersion.
The in-situ gel forming Injectable liquid depot composition of olanzapine, typically exhibit viscosity from about 1cps to about 500 cps, preferably from about 1 to about 300 cps. More preferably, the viscosity of the in-situ gel forming Injectable liquid depot composition is from 1-100 cps.
The term "biocompatible" means that the substance, material, polymer, solvent, or the system, does not cause substantial tissue irritation or necrosis at the depot gel site.
The term "biodegradable" refers to a polymer that erodes or degrades at its surfaces over time due, at least in part, to contact with substances found in the surrounding tissue fluids, or by cellular action.
Suitable biocompatible / biodegradable polymers may be selected from one or more of polylactides, polyglycolides, caprolactone-based polymers, polycaprolactones, polyanhydrides, polyamides, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, hydroxymethylcellulose polyphosphoesters, polyesters, polybutylene terephthalate, polysaccharides, chitin, chitosan, hyaluronic acid and copolymers, terpolymers and mixtures thereof.
A polylactide polymer is a polymer based on lactic acid or a copolymer based on lactic acid and glycolic acid. The polylactide polymer can include small amounts of other comonomers that do not substantially affect the advantageous results that can be achieved in accordance with the invention. The term "lactic acid" includes the isomers L-lactic acid, D-lactic acid, DL- lactic acid, and lactide. The term "glycolic acid" includes glycolide
Preferably the biodegradable polymer is a lactic acid-based polymer, more preferably polylactide, or poly (D, L-lactide-co-glycolide) i.e. PLGA. The lactic acid-based polymer has a monomer ratio of lactic acid to glycolic acid in the range of 100:0 to about 0:100. Preferably, ratio of lactide to glycolide is 50: 50.
Examples of polymers include, but are not limited to, lactic acid-based polymers such
as polylactides e.g. poly (D,L- lactide) i.e. PLA; glycolic acid-based polymers such as
polyglycolides (PGA) e.g. Lactel® from Durect; poly (D,L-lactide-co-glycolide) i.e.
PLGA, (Resomer® RG-504, Resomer® RG-503, Resomer® RG-502, Resomer®
RG-504H, Resomer® RG-503H, Resomer® RG-502H, Resomer® RG-504S,
Resomer® RG-502S, from Boehringer, Lactel® from Durect); polycaprolactones such
as Poly(e-caprolactone) i.e. PCL (Lactel® from Durect); polyanhydrides;
poly(Sebacic acid) SA; poly(Ricenolic acid) RA; poly(Fumaric acid), FA; poly(Fatty
acid dimmer), FAD; poly(terephthalic acid), TA; poly(isophthalic acid), IPA; poly(p-
{carboxyphenoxy} methane), CPM; poly(p- {carboxyphenoxy}propane), CPP; poly(p-
{carboxyphenoxy}hexane), CPH; polyamines, polyurethanes, polyesteramides,
polyorthoesters {CHDM: Cis/trans-cyclohexyl dimethanol, HD:l,6-hexanediol.
DETOU: (3,9-diethylidene-2,4,8,10-tetraoxaspiro undecane)}; polydioxanones;
polyhydroxybutyrates; polyalkyene oxalates; polyamides; polyesteramides;
polyurethanes; polyacetals; polyketals; polycarbonates; polyorthocarbonates;
polysiloxanes; polyphosphazenes; succinates; hyaluronic acid; poly(malic acid);
poly(amino acids); polyhydroxyvalerates; polyalkylene succinates;
polyvinylpyrrolidone; polystyrene; synthetic celluloses; polyacrylic acids; polybutyric acid; polyvaleric acid; polyethylene glycol; polyhydroxycellulose; chitin; chitosan; polyorthoesters and copolymers, terpolymers; dimethyl isosorbide; lipids such as cholesterol, lecithin; poly(glutamic acid-co-ethyl glutamate) and mixtures thereof.
It was surprisingly found that the rate of release of Olanzapine from the in-situ gel forming injectable depot liquid composition is controlled by the choice of biocompatible, biodegradable polymer:
- Polymers with different end groups: in-situ gel forming injectable depot liquid compositions of Olanzapine composed of biocompatible, biodegradable polymer having an acid terminated end group e.g. PLGA RG 502H provides low burst effect and uniform dissolution rate in comparison to liquid depot composition composed of ester terminated
- . PLGA RG 502. This is because a polymer with acid terminated end group solidifies faster as compared to the polymer with ester terminated end group in an acidic media.
Polymers with different comonomer ratio of polymer: Varying the comonomer ratio of various components forming the polymer e.g., ratio of lactide to
glycolide for a given polymer, would result in a depot having low burst effect and a regulated duration of delivery. For example, in-situ gel forming injectable depot liquid compositions of Olanzapine having a polymer with lactide to glycolide ratio of 50:50 provide uniform release of the active over an extended period of time.
Suitable biocompatible organic solvents may be selected from one or more of ethanol, benzyl alcohol, 1-butanol, 2- butanol, chloroform, acetic acid, isopropyl alcohol, acetonitrile, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, miglyol, glycerol, methyl acetate, methyl isobutyl ketone, benzyl benzoate, propylene glycol, dimethyl isosorbide, propylene carbonate, ethyl acetate, ethyl lactate, dimethyl sulfone, N,N-diethyl-m-toluamide, methyl ethyl ketone, dimethylformamide, dichloromethane, benzonitrile, dimethyl isosorbide, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, caprolactam, decymethylsulfoxide, oleic acid, and I-dodecylazacyclo-heptan-2-one, and the like or mixtures thereof. For example N-methyl-2-pyrrolidone (NMP) may be used.
It was observed that by varying the ratio of biocompatible, biodegradable polymer to solvent the duration and rate of release of the active substance can be controlled. In general, the higher the polymer to solvent ratio, the lower the burst effect and slower is the release. Compositions with different polymer to solvent ratio were prepared to evaluate its effect on the drug release. Increased polymeric concentration provided the matrix with poor porosity for diffusion of drug. Moreover, higher polymer concentration would have resulted in viscous microenvironment of the system, inhibiting the movement of water into the surrounding.
It was noted that the optimum release profile with minimum burst effect for the present invention is observed when the biocompatible, biodegradable polymer to solvent ratio is 1:2 to 1:6. For example, the ratio may be 1:4.
Further, it was noted that the ratio of Olanzapine to solvent and more preferably the ratio of Olanzapine, polymer and solvent are also important and have an effect on the release of Olanzapine. For example, the ratio of olanzapine to polymer to solvent may be 1:0.4:2, 1: 0.5:2, 1:0.75:2 or 1:1:3. Further, when the ratio of olanzapine to polymer to solvent is 1:0.5:2 optimum release profile with minimum burst effect was observed.
Therefore, according to one embodiment there is provided an in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine; b) a biocompatible, biodegradable polymer; and c) a biocompatible organic solvent, wherein olanzapine, polymer and the solvent are present in a ratio of 1:0.5:2.
The composition of the invention additionally may contain one or more pharmaceutically acceptable excipients. The "pharmaceutically acceptable excipients" may be selected from one or more of anitioxidants, release modifiers, buffering agents, surfactants, preservatives, osmotic agents, isotonicity producing agents and gelling agents.
According to one embodiment there is provided a process for the preparation of in-situ gel forming injectable depot liquid composition of Olanzapine, wherein the process comprises the steps of: a) dissolving olanzapine in a biocompatible organic solvent to obtain a solution; b) adding one or more biocompatible, biodegradable polymers to the solution of step (a) to obtain a final solution; c) sterilizing the solution of step (b) followed by filling into vials or syringes.
According to another embodiment there is provided a process for the preparation of in-situ gel forming injectable depot liquid composition of Olanzapine, wherein the process comprises the steps of: a) dissolving one or more biocompatible, biodegradable polymers in a biocompatible organic solvent to obtain a solution; b) adding olanzapine to the solution of step (a) to obtain a final solution; c) sterilizing the solution of step (b) followed by filling into vials or syringes.
The composition can be a single-component or a multi- component injectable depot composition. The composition may be in the form of a ready-to-use liquid, or a reconstitutable composition. A single-component composition comprises olanzapine, the polymer and the solvent in a single vial. The multi-component composition comprises of at least two components, component-1 and component-2 such that said composition is in the form of a reconstitutable composition. For example, component-1 may comprise olanzapine and component-2 may comprise the polymer and the solvent. Alternatively, component-1 may comprise olanzapine and a part of the solvent; and component-2 may comprise the polymer and the remaining solvent.
The composition of the invention when administered intramuscularly forms gel in-situ and provides depot effect. Optionally, a local anesthetic can be administered prior to the administration of the composition of the invention.
The compositions of the present invention in vivo are capable of producing a prolonged release of the active agents for at least 3 days, preferably for a period of at least 1-4 weeks.
The following non-limiting examples illustrate the injectable liquid depot composition of Olanzapine disclosed in various embodiments of the specification.
Dissolution profile for all the examples was measured in USP Type II dissolution apparatus at 75 rpm in 500ml 0.02N hydrochloric acid for up to 12hr and then in 500ml of 0.1 N Hydrochloric acid for next 36 hours. The data of dissolution is provided in Table 1 & 2.
Example 1:
(Table Removed)
Process for the preparation:
1. Olanzapine was dissolved in N-methyl-2-pyrrolidone to obtain a solution.
2. To the solution obtained in step 1, PLGA 502H was added and it was then
sterilized.
3. The sterilized solution of step 2 was filled in a suitable vial or syringe and
flushed with nitrogen and sealed.
The dissolution Profile of Example 1 is provided in Table 1 below:
Comparative Example 1:
Ratio of Polymer: Solvent is 1:4
(Table Removed)
Process: The composition was prepared using the process of Example 1.
The dissolution Profile of Example 1 & Comparative Example 1 is provided in Table 1 below:
(Table Removed)
The above results show the effect of different polymer types on the release profile of Olanzapine. The results indicate that depot composition composed of polymer having acid terminated end group RG502H (Example 1) has low burst effect and uniform release in comparison to composition composed of polymer having ester terminated end group like RG 502 (Comparative Example 1).
Example 2:
Polymer to solvent ratio is 1: 5
(Table Removed)
Process: The composition was prepared using the process of Example 1.
Example 3:
Polymer to solvent ratio is 1:2.7
(Table Removed)
Process: The composition was prepared using the process of Example 1.
Example 4:
Polymer to solvent ratio is 1: 3
(Table Removed)
Process: The composition was prepared using the process of Example 1. Dissolution profile for Examples 2-4 is provided below in Table 2:
(Table Removed)
Process for Preparation:
1. PLGA 50:50 RG502H was dissolved in N-methyl-2-pyrrolidone to obtain a
solution.
2. To the solution obtained in step 1, Olanzapine was added and it was then
sterilized.
3. The sterilized solution of step 2 was filled in a suitable vial or syringe and
flushed with nitrogen and sealed.
Example 6:
(Table Removed)
Process for the preparation:
1. Dissolve olanzapine in N-methyl-2-pyrrolidone to obtain a solution.
2. To the solution obtained in step 1, add PLGA 50:50 (RG502H) and dissolve it.
3. Dissolve Butylated hydroxyanisole and Butylated hydroxytoluene into the
solution of step 2 and sterilize.
4. Fill the vial or syringe with the sterilized solution obtained in step 3, flush with nitrogen and seal.
Example 7:
(Table Removed)
Process for the preparation: Component-1
1. Dissolve Tartaric acid in distilled water to obtain a solution.
2. Dissolve olanzapine in the solution obtained in step 1.
3. To the solution of step 2 add Poloxamer and sterilize.
4. Fill the vial or syringe with the sterilized solution obtained in step 3, flush with
nitrogen and lyophilise.
Component-2
1. Dissolve PLGA in N-methyl-2-pyrrolidone.
2. Add Tween 80 to the solution obtained in step 1 and sterilize.
3. Fill the vial or syringe with the sterilized solution obtained in step 2, flush with
nitrogen and seal.
Example 8:
(Table Removed)
Process for the preparation: Component-1
1. Dissolve Olanzapine in N- methyl-2-pyrrollidone to obtain a solution.
2. Dissolve BHA & BHT in the solution obtained in step 1 and sterilize.
3. Fill the vial or syringe with the sterilized solution obtained in step 2, flush with nitrogen and seal.
Component-2
1. Dissolve PLGA (RG502H) in N-methyl-2-pyrrolidone and sterilize.
2. Fill the vial or syringe with the sterilized solution obtained in step 1, flush with
nitrogen and seal.

WE CLAIM:
1. An in-situ gel forming injectable depot liquid composition of Olanzapine, the composition comprising: a) Olanzapine; b) a biocompatible, biodegradable polymer; and c) a biocompatible organic solvent, wherein the polymer and the solvent are present in a ratio of 1:2 to 1:6.
2. The in-situ gel forming injectable depot liquid composition according to claim 1, wherein the biocompatible, biodegradable polymer is selected from one or more of polylactides, polyglycolides, caprolactone-based polymers, polycaprolactones, polyanhydrides, polyamides, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, hydroxymethylcellulose polyphosphoesters, polyesters, polybutylene terephthalate, polysaccharides, chitin, chitosan, hyaluronic acid and copolymers and terpolymers.
3. The in-situ gel forming injectable depot liquid composition according to claim
1, wherein the solvent is selected from one or more of ethanol, benzyl
alcohol, 1-butanol, 2- butanol, chloroform, acetic acid, isopropyl alcohol,
acetonitrile, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, miglyol, glycerol,
methyl acetate, methyl isobutyl ketone, benzyl benzoate, propylene glycol,
dimethyl isosorbide, propylene carbonate, ethyl acetate, ethyl lactate,
dimethyl sulfone, N,N-diethyl-m-toluamide, methyl ethyl ketone,
dimethylformamide, dichloromethane, benzonitrile, dimethyl isosorbide,
dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, caprolactam,
decymethylsulfoxide, oleic acid, and 1-dodecylazacyclo-heptan-2-one.
4. The in-situ gel forming injectable depot liquid composition according to claim
2, wherein the biocompatible, biodegradable polymer is a polylactide polymer
having an acid terminated end group.
5. The in-situ gel forming injectable depot liquid composition according to claim
2, wherein a biocompatible, biodegradable polymer is a polylactide-co-
glycolide polymer having lactide to glycolide ratio of 50:50.
6. The in-situ gel forming injectable depot liquid composition according to claim 1, wherein the polymer and the solvent are present in a ratio of 1:4.
7. The in-situ gel forming injectable depot liquid composition according to claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients.
8. The process for the preparation of in-situ gel forming injectable depot liquid composition of Olanzapine according to claim 1, wherein the process comprises the steps of: a) dissolving olanzapine in a biocompatible organic solvent to obtain a solution; b) adding one or more biocompatible, biodegradable polymers to the solution of step (a) to obtain a final solution; and c) sterilizing the solution of step (b) followed by filling into vials or syringes.
9. The process for the preparation of in-situ gel forming injectable depot liquid composition of Olanzapine according to claim 1, wherein the process comprises the steps of: a) dissolving one or more biocompatible, biodegradable polymers in a biocompatible organic solvent to obtain a solution; b) adding olanzapine to the solution of step (a) to obtain a final solution; and c) sterilizing the solution of step (b) followed by filling into vials or syringes.
10. An in-situ gel forming injectable depot liquid composition of Olanzapine and process of preparation thereof substantially described and exemplified herein.