Microsphere formulation by novel coacervation method

Abstract

The present invention relates to a novel coacervation method for preparation of controlled release microsphere formulation comprises pharmaceutically active ingredient or salt thereof; wherein the novel process of preparation of microsphere is free from moisture.

Description

[0001] “MICROSPHERE FORMULATION BY NOVEL COACERVATION METHOD”

[0002] FIELD OF THE INVENTION:

[0003] The present invention relates to a novel coacervation method for preparation of controlled release microsphere formulation comprises pharmaceutically active ingredient or salt thereof; wherein the novel process of preparation of microsphere is free from moisture.

[0004] BACKGROUND OF THE INVENTION:

[0005] Coacervation, emulsion solvent evaporation, and spray drying are the common methods for preparing microspheres, among which coacervation is longstanding and widely used. Introduced by Bungenberge de Jong and Kruyt in 1930, coacervation involves phase separation in a hydrocolloid solution due to thermodynamic changes, leading to a colloid-rich coacervate phase and a colloid-poor phase (Jong and Kruyt, 1930). In microspheres fabrication, coacervation is achieved by adding a non-solvent or another polymer to copolymer solution to induce phase separation. The method primarily involves two steps. The first step is phase separation and drug encapsulation and the second step, solidification, entails pouring the emulsion into a hardening agent (e.g., n-heptane), and the solvent in the coacervate droplets is extracted by the hardening agent, leading to solidification into microspheres. The final product is obtained after subsequent filtration, washing, and drying. [Yuelei Wei et al, Investigating key factors in the phase separation step of microspheres fabrication via coacervation, International Journal of Pharmaceutics, Volume 666, 2024]

[0006] The microsphere formulation by the coacervation method, up to yet approved products are Decapeptyl® SR [triptorelin pamoate], Sandostatin® LAR [Octreotide acetate], Relstar® [Triptorelin pamoate], Arestin® [Minocycline Hydrochloride] and Bydureon Bcise® [Exenatide]. These long-acting formulations significantly prolong the dosing interval.

[0007] US20100086596A1 the disclosure is directed to polymer delivery of active agents, in particular, delivery of octreotide from polymer microspheres without an initial time lag.

[0008] W02004045633A2 the disclosure is directed to pharmaceutical composition comprises octreotide acetate microparticles of linear poly(lactide-co-glycolide) polymer wherein the polymer contains less than 1% silicone oil or heptane.W02007071395A1 the disclosure is directed to sustained release formulations comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and two or more different polylactide-co-glycolide polymers (PLGAs).

[0009] WO2019155396A1 the disclosure is directed to provides sustained release microspheres of the Octreotide or pharmaceutically acceptable salts thereof with low initial burst comprises poly (D, L-lactide-co-glycolide) polymer and process of preparation thereof.

[0010] WO2011087496A1 the disclosure is directed to microspheres for releasing an octreotide compound without an initial time lag include a poly(D, L-lactide-co-glycolide) polymer (PLGA polymer) matrix having a ratio of lactide to glycolide ranging from 80:20 to 90: 10 mol%. The polymer has a molecular weight ranging from about 6000 to 16000. The octreotide compound is dispersed in the polymer matrix. The microspheres can be made by forming a dispersed phase by combining the above polymer, dichloromethane, the octreotide compound, methanol and acetic acid. A target loading of the octreotide compound in the dispersed phase ranges from 7 to 12% by weight. Polyvinyl alcohol is dissolved in water to form a continuous phase. The dispersed phase is mixed in the continuous phase to form a microsphere suspension. The dichloromethane, acetic acid, methanol and polyvinyl alcohol are removed from the microsphere suspension. Residual dichloromethane and methanol are removed from the microspheres by washing.

[0011] WO2022013233A1 the disclosure is directed to water-free process for preparing a pharmaceutical composition for a more sustained and controlled release of triptorelin or a salt thereof and further discloses a process and apparatus for preparing a pharmaceutical composition for sustained and controlled release of triptorelin or a salt thereof, said process comprising the steps of: - mixing, in a plurality of reactors, triptorelin or a salt thereof with one or more organic solvents; - adding encapsulation polymer to the resulting suspension; - adding a coacervation agent to the resulting dispersion to form soft microcapsules comprising encapsulation polymer and triptorelin or a salt thereof; - transferring the mixture comprising the soft microcapsules from the plurality of reactors to at least one hardening vessel; - mixing, in the at least one hardening vessel, the mixture comprising the soft microcapsules with a hardening liquid; - filtering and drying, in at least one filtering device, the resulting hardmicrocapsules; and - adding, to a container, the dried microcapsules as well as one or more dried pharmaceutical excipients.

[0012] WO2023172021 Al the disclosure is directed to method for manufacturing microspheres with improved suspension using a coacervation method, and specifically relates to a manufacturing method that can significantly improve the suspension and injectability of microspheres through a washing process using a surfactant.

[0013] US5538739 the disclosure is directed to microparticles comprising a polypeptide, preferably somatostatin or an analog or derivative thereof, more preferably octreotide, in a polymeric matrix, preferably poly(lactide-co-glycolide) glucose. Also discloses sustained release formulations containing said microparticles and the use of said formulations in treating acromegaly and breast cancer.

[0014] There are many problems in the development of long-acting microspheres, among which the uneven particle size of the microspheres, low encapsulation rate, and severe burst release are the main problems.

[0015] Due to the significant technical challenges associated with controlled release microsphere formulations, present inventor developed the novel Coacervation method wherein process of preparation for microsphere is free from moisture.

[0016] OBJECT OF THE INVENTION:

[0017] An object of the present invention relates to a novel coacervation method for preparation of microsphere formulation.

[0018] An object of the present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein the process of preparation of microsphere is free from moisture.

[0019] An object of the present invention relates to a novel coacervation method for preparation of controlled release microsphere formulation, wherein the process of preparation of microsphere is free from moisture.SUMMARY OF THE INVENTION:

[0020] The present invention relates to a novel coacervation method for preparation of microsphere formulation.

[0021] The present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein the process of preparation of microsphere is free from moisture.

[0022] The present invention relates to a novel coacervation method for preparation of controlled release microsphere formulation, wherein the process of preparation of microsphere is free from moisture.

[0023] The present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein before start of manufacturing process one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection(s) thereof.

[0024] The present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein before start of manufacturing process one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection(s) thereof.

[0025] The present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein before transfer of phase(s) into vessel(s), one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection line thereof.

[0026] DETAILED DESCRIPTION:

[0027] The present invention relates to a novel coacervation method for preparation of controlled release microsphere formulation comprises pharmaceutically active ingredient or salt thereof wherein the process of preparation of microsphere is free from moisture.

[0028] Before the present process and methods are described, it is to be understood that this invention is not limited to particular compound(s), composition (s), embodiment(s), process described, that as such may, of course, vary.

[0029] Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materialsare now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0030] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise.

[0031] As used herein, the words or terms set forth below have the following definitions:

[0032] The “active pharmaceutical ingredient” is selected from group comprising triptorelin, octreotide, minocycline and exenatide or pharmaceutically acceptable salts, or derivative(s) thereof.

[0033] In one embodiment the term “treatment” or “treating” as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. In one embodiment the term “treatment of triptorelin or octreotide or minocycline or exenatide sensitive diseases or disorders” is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound triptorelin or octreotide or minocycline or exenatide to alleviate the symptoms or complications; to delay the progression of the disease, disorder, or condition; to alleviate or relieve the symptoms and complications; and / or, to cure or eliminate the disease, disorder, or condition as well as to prevent the condition. In one embodiment prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compound triptorelin or octreotide or minocycline or exenatide to prevent the onset of the symptoms or complications.

[0034] By "pharmaceutically acceptable excipient(s)", it is meant any of the components of a pharmaceutical composition other than the active ingredients and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

[0035] The term "pharmaceutically acceptable salts" or “salts thereof’ refers to derivative(s) of the disclosed compounds wherein the parent compound is modified by making acid or base salts, solvate, hydrate, esters and the like thereof. Pharmaceutically-acceptable salt forms ofcompounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

[0036] The term "pharmaceutically acceptable form” refers to any pharmaceutically acceptable form, including, solvates, hydrates, isomorphs, isomers, polymorphs, co-crystals, pseudomorphs, neutral forms, acid addition salt forms, prodrugs and derivative(s) thereof.

[0037] The term "composition" or "formulation" or "preparation" is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients. The term "composition" or "dosage form" or " formulation" refers to finished pharmaceutical products that are suitable for administration, including, but not limited to, injections, etc.

[0038] The term “amount” as used herein refers to quantity or to concentration as appropriate to the context.

[0039] The term "carrier" or "vehicle" or "solvent" or “diluent” or “excipient” or “excipient(s)” as used herein refers to pharmacologically inert materials that provide a more or less fluid matrix, suitable for parenteral drug administration. Carriers, vehicles or diluent useful herein include any such materials known in the art, which are nontoxic and do not interact with other components of a pharmaceutical composition or drug delivery system in a deleterious manner.

[0040] The term “about” or “approximately” means within 10% of a given value or range or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Alternatively, the term “about” means within an acceptable standard error of the mean.

[0041] The term “comprising” or "comprises” or “including” or “having” or “containing” is inclusive or open-ended i.e., comprising what is specified in the present invention, but not excluding other or additional aspects, unrecited elements or method steps.When the term “further” or “additionally” is used herein, the unrecited elements, components may present along with the claimed cited element or components. It is to be construed as an open-ended term unless otherwise noted.

[0042] The term "optional" or "optionally" means that the subsequently described element, component or circumstance may or may not be present, so that the description includes instances where the element, component, or circumstance is included and instances where it is not.

[0043] As used herein, the term "microspheres" refers to a polymer or one or more combinations of polymers made into bodies of various sizes. The microspheres as used herein can be in any shape. In certain embodiments, the microspheres are substantially spherical shape. These structures of the microspheres may be generally spherical or spheroid in shape or bounded by imaginary spherical or spheroid shapes. In some embodiments, the surfaces of the microspheres provided herein appear smooth under magnification of up to 1000 times, such as up to 100 times, up to 10 times, 0 times or a range thereof. In certain embodiments, the exemplary microspheres described herein are not necessarily limited to being precisely spherical in shape (e.g., are particles).

[0044] The term “coacervation” as used herein means the separation of a macromolecular solution into two immiscible liquid phases. One phase is a dense coacervate phase, concentrated in the macromolecules and forming droplets, and the other phase is a polymer deficient phase. Coacervation is a result of a molecular dehydration of the polymer. Coacervation may be induced by a temperature change, addition of a non-solvent or addition of a micro-salt (simple coacervation), or by the addition of another polymer thereby forming an interpolymer complex (complex coacervation). Coacervates may be described as liquid crystals and mesophases and are more fluid than other systems with higher structural order, such as micelles. Such systems are in dynamic equilibrium and change in the conditions may result in either the reformation of a one phase system or the formation of a flocculate or precipitate. Burgess, D. J. (1994) Complex Coacervation: Microcapsule Formation. In: Dubin, P., Bock, J., Davis, R., Schulz, D. N. and Thies, C. (Eds.), Macromolecular Complexes in Chemistry and Biology, Springer-Verlag, Berlin, Heidelberg, New York, London, Paris, Tokyo, Hong Kong, Barcelona, Budapest, pp. 285-300.In microspheres fabrication, coacervation is achieved by adding a non-solvent or another polymer to copolymer solution to induce phase separation. The method primarily involves two steps. The first step is phase separation and drug encapsulation and the second step, solidification, entails pouring the emulsion into a hardening agent (e.g., n-heptane), and the solvent in the coacervate droplets is extracted by the hardening agent, leading to solidification into microspheres.

[0045] The term “free from moisture” as used herein means the during process or preparation the equipment and complete process does not contain the moisture. Also, the term "free from moisture" generally refers to a condition where a substance, environment, or surface contains minimal or no moisture. Further, the term "free from moisture" generally refers to a condition where a there is no presence of water. Further, the term "free from moisture" denotes a reaction medium with total moisture content of the reaction medium does not exceed about 0.1%.

[0046] The term “vessel” as used herein means the equipment or part of equipment or container.

[0047] In one embodiment of present invention the composition pH is from about 6 to about 8. In one embodiment of present invention a suitable pH adjuster may have been added to adjust the pH.

[0048] In another embodiment, the pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients such rate controlling agent, solubilizer, hardening agent, alcoholic solvent, suspending agent, coacervating agent, surfactant and vehicle or solvent or carrier, and the like or mixtures thereof. The choice of excipients depends on the desired characteristics of the composition and on the nature of other pharmacologically active compounds in the composition. Suitable excipients are known to those skilled in the art (refer Handbook of Pharmaceutical Excipients, edited by Rowe et al, 6th edition, 2009).

[0049] As used herein, the term “solubilizer” refers to a component of the present compositions to that makes soluble or increases the solubility in a carrier. Examples of solubilizer as methanol, dichloromethane, alcoholic solvent, non-aqueous solvent.

[0050] The term “drug polymer phase” as used herein means the one or more drug combined with one or more polymer.The term “coacervation phase” as used herein means the separation of colloidal systems into two liquid phases.

[0051] The term “hardening Phase” or “quenching medium” as used herein means the at completion of the coacervation agent addition, the coacervate is transferred into a quench liquid containing a hardening agent to solidify the semi-solid microparticles.

[0052] The term “phase inducer” as used herein in the context of coacervation, a phase inducer is typically a second polymer added to a solution containing the primary polymer intended to form the capsule wall material. The role of the phase inducer is to interact with the primary polymer, often through polymer-polymer incompatibility, leading to the formation of two distinct phases: a polymer-rich phase (coacervate) and a polymer-poor phase

[0053] The term “controlled release” as used herein means the pharmaceutical formulations designed to release active ingredients over an extended period, rather than all at once. This concept encompasses various types of release profiles, including modified release, sustained release, prolonged release, timed release, retarded release, extended release, and delayed release.

[0054] The term “burst release” as used herein means the pharmaceutical formulation where release of active ingredient quickly. The present invention overcome the problem of burst release.

[0055] Examples of rate controlling agent or polymer, or derivative or pharmaceutically acceptable form thereof include but are not limited to D, L-lactic and glycolic acids copolymer, PLA (Poly Lactic Acid), PLGA, PLA, PLGA (Poly Lactic-co-Glycolic Acid, ethylcellulose, albumin, gelatin, chitosan, polyalkyl cyanoacrylates, polyanhydrides, poly-8-caprolactone (PCL), or combination thereof and the like. Lurther include but are not limited to synthetic polymers, non-biodegradable polymers, biodegradable polymers, natural polymers, or combination thereof and the like. Suitable rate controlling agent or polymer selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0056] Examples of solubilizer include but are not limited to methanol, dichloromethane, ethyl acetate, alcoholic solvent, non-aqueous solvent, or combination thereof and the like. Suitablesolubilizer selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0057] Examples of hardening agent include but are not limited to hexane, octamethylcyclotetrasiloxane (OMCTS), n-heptane, or combination thereof and the like. Suitable hardening agent selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0058] Examples of alcoholic solvent include but are not limited to methanol, ethanol, Isopropanol or combination thereof and the like. Suitable alcoholic solvent selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0059] Examples of coacervating agent include but are not limited to silicone oil (poly(dimethylsiloxane), PDMS), toluene, 2-propanol, heptane, ethyl vinyl acetate (EVA), polyisobutylene (PIB), same oil, fluorochlorohydrocarbons, gelatin, acacia gum, or combination thereof and the like. Suitable coacervating agent selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0060] Examples of suspending agent include but are not limited to mannitol, acacia, calcium stearate, carbomer, cellulose or derivatice thereof, gelatin or combination thereof and the like. Suitable suspending agent selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0061] Examples of surfactant ionic and non-ionic include but are not limited to Span, Tween, Triton XI 00, cetyltrimethylammonium bromide, sodium dodecyl sulphate, or combination thereof and the like. Suitable suspending agent selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.

[0062] Examples of vehicle or solvent or carrier include but are not limited to water for injection, sterile water for injection, hydroalcoholic solvents or combination thereof and the like. Suitable vehicle or solvent or carrier selected from handbook of pharmaceutical excipients, edited by rowe et al, 6th edition, 2009.In one embodiment, the present invention composition can be administered to patients in need of treatment therewith by any appropriate route. Preferably the composition can be administered by intramuscularly in the gluteal region.

[0063] In one embodiment, the present invention composition may be in the form of injectable dosage forms, including but not limited to, suspension, solution, emulsion, nanosuspension, nanoemulsion, concentrated solutions for injections, ready to use or premix, ready to be dissolved in and / or diluted with a pharmaceutically acceptable vehicle, dry products ready to be dissolved in and / or diluted with a pharmaceutically acceptable vehicle, injectable microspheres, injectable microparticles, lyophilized powder for injection, spray dried powder for injection and the like.

[0064] In one of embodiment of the present invention, the drug polymer phase free from moisture.

[0065] In another embodiment of the present invention, the drug polymer phase and other phase free from moisture.

[0066] In another embodiment of the present invention, the drug polymer phase when transfer to another vessel(s) that complete process free from moisture.

[0067] In one of embodiment of the present invention relates to a novel coacervation method for preparation of microsphere formulation.

[0068] In another embodiment of the present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein the process of preparation of microsphere is free from moisture.

[0069] In another embodiment of the present invention relates to a novel coacervation method for preparation of controlled release microsphere formulation, wherein the process of preparation of microsphere is free from moisture.

[0070] The present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein before start of manufacturing process one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection(s) thereof.In another embodiment of the present invention relates to a novel coacervation method for preparation of microsphere formulation, wherein before transfer of phase(s) into vessel(s), one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection line thereof.

[0071] In one of embodiment of the present invention, a novel coacervation method for preparation of microsphere formulation comprises, pharmaceutically active ingredient or salt thereof and pharmaceutically acceptable excipients; wherein the process of preparation of microsphere is free from moisture.

[0072] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein pharmaceutically active ingredient or salt thereof is selected from group comprising peptide, polypeptide and oligonucleotide.

[0073] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein pharmaceutically active ingredient or salt thereof is selected from group comprising triptorelin pamoate, octreotide acetate, minocycline hydrochloride and exenatide.

[0074] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein microsphere formulation is for controlled release.

[0075] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein microsphere release is controlled for about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, about 63 days, about 70 days, about 77 days, about 84 days, about 91 days.

[0076] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein microsphere release is controlled for about 7 days to about 90 days, about 7 days to about 60 days, about 7 days to about 30 days and about 7 days to about 15 days.In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein microsphere release is controlled for about 28 days to about 56 days.

[0077] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein microsphere formulation comprises drug polymer phase, coacervation phase and hardening phase.

[0078] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein process comprises first step is preparation of drug polymer phase and the second step is coacervation phase.

[0079] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein preparation of drug polymer phase is free from moisture.

[0080] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein preparation of coacervation phase is free from moisture.

[0081] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein transfer of coacervating agent to coacervation phase is free from moisture.

[0082] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein transfer of drug polymer phase to coacervation phase is free from moisture.

[0083] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein before transfer into vessel(s), one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection line thereof.

[0084] In one of embodiment the present invention, the novel coacervation method for preparation of microsphere formulation, before start of preparation of microsphere clean-in-place (CIP),sterilize-in-place (SIP), partial blowdown by air to the equipment and the presence of moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof.

[0085] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, wherein before preparation of microsphere the equipment is clean-in-place (CIP) and sterilize-in-place (SIP), partial blowdown by air and the presence of moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof.

[0086] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, wherein before preparation of microsphere the equipment is clean-in-place (CIP) and sterilize-in-place (SIP), partial blowdown by air and the presence of moisture was removed by methanol from the vessel(s) and connection(s) thereof.

[0087] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation, wherein preparations further comprise hardening, washing, collecting and drying the microsphere.

[0088] In another embodiment of the present invention, further comprises prefdled syringe of diluent which contain carboxymethylcellulose sodium, mannitol, poloxamer 188 and water for injection.

[0089] The term “embryonic microsphere” as used herein means, the droplets of the drug-loaded polymer.

[0090] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:

[0091] 1. preparation of polymer phase;

[0092] 2. preparation of drug phase;

[0093] 3. preparation of drug polymer phase; and

[0094] Wherein the process of preparation for microsphere is free from moisture.

[0095] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:1. preparation of drug polymer phase;

[0096] 2. preparation of coacervation phase; and

[0097] wherein the process of preparation for microsphere is free from moisture.

[0098] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:

[0099] 1. preparation of drug polymer phase;

[0100] 2. preparation of coacervation phase; and

[0101] wherein presence of moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof.

[0102] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:

[0103] 1. before start of preparation of microsphere clean-in-place (CIP), sterilize-in-place (SIP), partial blowdown by air to the equipment and the presence of moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof.

[0104] 2. preparation of polymer phase;

[0105] 3. preparation of drug phase ;

[0106] 4. preparation of drug polymer phase; and

[0107] Wherein the process of preparation for microsphere is free from moisture.

[0108] In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:

[0109] 1. before start of preparation of microsphere clean-in-place (CIP), sterilize-in-place (SIP), partial blowdown by air to the equipment and the presence of moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof.

[0110] 2. preparation of polymer phase;

[0111] 3. preparation of drug phase ;

[0112] 3. preparation of drug polymer phase;

[0113] 4. preparation of coacervation phase; and

[0114] Wherein the process of preparation for microsphere is free from moisture.In one of embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, wherein preparation is free from moisture comprises:

[0115] 1. before start of preparation of microsphere clean-in-place (CIP), sterilize-in-place (SIP), partial blowdown by air to the equipment and the presence of moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof.

[0116] 2. the polymer was transferred into vessel and required quantity of solubilizer was transfer into the polymer vessel and stirred for appropriate time.

[0117] 3. the active ingredient was transferred to vessel and required quantity of solubilizer was transfer into the active ingredient vessel and stirred for appropriate time.

[0118] 4. step 3 were transferred to step 2 under stirring for appropriate time.

[0119] 5. required quantity of coacervating agent transfer to step 4 vessel under stirring at appropriate rpm.

[0120] 6. embryonic microsphere formed in the end of step 5, the embryonic microsphere in step 5 were transferred to vessel containing quenching medium under stirring.

[0121] 7. further above step prepared microsphere were separated, washed, dried and filled in appropriate vial.

[0122] In another embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:

[0123] 1. before start of preparation of microsphere clean-in-place (CIP), sterilize-in-place (SIP), partial blowdown by air to the equipment and the presence of moisture was removed by alcoholic solvent from the vessel and connection(s) thereof.

[0124] 2. The polymer was transferred into vessel and required quantity of solubilizer was transfer into the polymer vessel and stirred for appropriate time.

[0125] 3. The active ingredient was transferred to vessel and required quantity of solubilizer was transfer into the active ingredient vessel and stirred for appropriate time.

[0126] 4. Step 3 were transferred to step 2 under stirring for appropriate time, wherein preparation of drug polymer phase is free from moisture.

[0127] 5. Required quantity of coacervating agent transfer to step 4 vessel under stirring at appropriate rpm, wherein transfer of drug polymer phase to coacervation phase is free from moisture.

[0128] 6. Embryonic microsphere formed in the end of step 5, the embryonic microsphere in step 5 were transferred to vessel containing quenching medium under stirring.7. Further above step prepared microsphere were separated, washed, dried and fdled in appropriate vial.

[0129] In another embodiment the present invention, the novel coacervation method for preparation of controlled release microsphere formulation, comprises:

[0130] 1. before start of preparation of microsphere clean-in-place (CIP), sterilize-in-place (SIP), partial blowdown by air to the equipment and the presence of moisture was removed by alcoholic solvent from the vessel and connection(s) thereof.

[0131] 2. The polymer [D, L-lactic and glycolic acids copolymer] was transferred into vessel and required quantity of solubilizer [dichloromethane] was transfer into the polymer vessel and stirred for appropriate time.

[0132] 3. The active ingredient [octreotide acetate] was transferred to vessel and required quantity of solubilizer [methanol] was transfer into the active ingredient vessel and stirred for appropriate time.

[0133] 4. Step 3 were transferred to step 2 under stirring for appropriate time, wherein preparation of drug polymer phase is free from moisture.

[0134] 5. Required quantity of coacervating agent [dimethicone] transfer to step 4 vessel under stirring at appropriate rpm, wherein transfer of drug polymer phase to coacervation phase is free from moisture.

[0135] 6. Embryonic microsphere formed in the end of step 5, the embryonic microsphere in step 5 were transferred to vessel containing quenching medium under stirring.

[0136] 7. Further above step prepared microsphere were separated, washed, dried and fdled in appropriate vial.

[0137] In another embodiment of the present invention, the novel coacervation method for preparation of microsphere formulation for treatment of drug sensitive diseases.

[0138] The present invention is further illustrated by reference to the following experiments which is for illustrative purpose only and does not limit the scope of the invention in any way.

[0139] Example:

[0140]

[0141]

[0142] *Active ingredient solubilizer & Alcoholic Solvent - Methanol; Polymer solubilizer-Dichloromethane; Coacervating agent- Dimethicone

[0143] Manufacturing procedure:

[0144] 1. Clean-in-place (CIP), followed by sterilize-in-place (SIP), followed by partial blowdown by air and the presence of any moisture was removed by alcoholic solvent from the vessel(s) and connection(s) thereof used in the manufacturing process.

[0145] 2. The polymer was transferred into vessel and required quantity of solubilizer was transfer into the polymer vessel and stirred for appropriate time

[0146] 3. The active ingredient (octreotide acetate) was transferred to vessel and required quantity of solubilizer was transfer into the active ingredient vessel and stirred for appropriate time

[0147] 4. Step 3 were transferred to step 2 under stirring for appropriate time.

[0148] 5. Required quantity of coacervating agent transfer to step 4 vessel under stirring at appropriate rpm.

[0149] 6. Embryonic microsphere formed in the end of step 5, the embryonic microsphere in step 5 were transferred to vessel containing quenching medium under stirring.

[0150] 7. Further above step prepared microsphere were separated, washed, dried and fdled in appropriate vial.

[0151] Result:

[0152] Real Time Drug Release: Reference vs Test-1

[0153] Table 1:

[0154]

[0155] Test-1: Study Details

[0156] Study Design: An open label, randomized, single-period, two-treatment, parallel, balanced, single dose bioequivalence study.

[0157] Conditions (Fast I Fed): Fast

[0158] Sample size (No. of Subjects): 30 subjects, 15 subjects per treatment arm, ie: Test-1 to be administered in treatment arm 1 & Reference to be administered to treatment arm 2.

[0159] Analytes to measure: Octreotide in plasma

[0160] PK parameters to be observed: Log-transformed AUCo-28, AUC28-56, AUG, AUCo-®, and Cmax,

[0161] Sampling schedule: up to Day 91.

[0162] PK Summary Data (n#30):

[0163] Table 2:

[0164]

[0165] ef.: Reference Test-1: T-l GM: geometric means LSMD: least square means In data BE: Bioequivalence

[0166] Based on the above results tests were taken with changes in formulation and results were described in below table 3

[0167] Table 3:

[0168]

[0169]

[0170] $ White to white with a yellowish tint powder, DPP-Drug Polymer Phase, NP- Not performed T-Test, Test-1 without flushing of alcohol in DPP, Test-2* 0. l%w / w water in DPP, Test-3** 0.25%w / w water in DPP, Test-4*** 0.5% w / w water in DPP, Test-5 and Test-6 flushing with alcohol in DPP.

[0171] Real Time Drug Release:

[0172] Table 4:

[0173]

[0174] Ref.- Reference, DPP-Drug Polymer Phase, T-Test, Test-1 without flushing of alcohol in DPP, Test-2* 0. l%w / w water in DPP, Test-3** 0.25%w / w water in DPP, Test-4*** 0.5% w / w water in DPP, Test-5 and Test-6 flushing with alcohol in DPP.

[0175] Surprisingly, the present inventors overcome the initial burst release and found that those microspheres prepared by novel coacervation method, maintained controlled release which was a surprising and unexpected development.

[0176] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention.

Claims

WE CLAIM,1. A novel coacervation method for preparation of microsphere formulation comprises, pharmaceutically active ingredient or salt thereof and pharmaceutically acceptable excipients; wherein the process of preparation of microsphere is free from moisture.

2. The novel coacervation method for preparation of microsphere formulation according to claim 1, wherein pharmaceutically active ingredient or salt thereof is selected from group comprising peptide, polypeptide and oligonucleotide.

3. The novel coacervation method for preparation of microsphere formulation according to claim 1, wherein pharmaceutically active ingredient or salt thereof is selected from group comprising triptorelin pamoate, octreotide acetate, minocycline hydrochloride and exenatide.

4. The novel coacervation method for preparation of microsphere formulation according to claim 1, wherein microsphere formulation is for controlled release.

5. The novel coacervation method for preparation of microsphere formulation according to claim 1, wherein microsphere formulation comprises drug polymer phase, coacervation phase and hardening phase.

6. The novel coacervation method for preparation of microsphere formulation according to claim 1, wherein process comprises first step is preparation of drug polymer phase and the second step is coacervation phase.

7. The novel coacervation method for preparation of microsphere formulation according to claim 1 to claim 6, wherein preparation of drug polymer phase is free from moisture.

8. The novel coacervation method for preparation of microsphere formulation according to claim 1 to claim 7, wherein preparation of coacervation phase is free from moisture.

9. The novel coacervation method for preparation of microsphere formulation according to preceding claims, wherein transfer of coacervating agent to coacervation phase is free from moisture.

10. The novel coacervation method for preparation of microsphere formulation according to preceding claims, wherein transfer of drug polymer phase to coacervation phase is free from moisture.

11. The novel coacervation method for preparation of microsphere formulation according to preceding claims, wherein before transfer into vessel(s), one or more times alcoholic solvent flushing has to be carried out in vessel(s) and in connection line thereof.

12. The novel coacervation method for preparation of microsphere formulation according to preceding claims, before start to manufacturing, after CIP and SIP one or more times alcoholic solvent flushing has to be carried out into the vessel(s).

13. The novel coacervation method for preparation of microsphere formulation according to claim 11 and 12, wherein alcoholic solvent is methanol.

14. The novel coacervation method for preparation of microsphere formulation according to claim 11 and 12, wherein moisture content of less than about 0. l%w / w.

15. The novel coacervation method for preparation of microsphere formulation according to preceding claims, wherein preparations further comprise hardening, washing, collecting and drying the microsphere.

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