KR20120048810A - Pharmaceutical composition containing microspheres loaded with olanzapine as an active ingredient - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing olanzapine-containing polymeric microsphere is provided to minimize waste water. CONSTITUTION: A pharmaceutical composition for preventing or treating bipolar mania, bipolar disorder, seizure, obsessive/compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, extreme shyness, diabetic nerve pain or depression contains olanzapine-containing polymeric microsphere. A method for preparing the microsphere comprises: a step of mixing water insoluble organic solvent and dispersion solvent; a step of mixing the polymer compounds, olanzapine, and water insoluble organic solvent to prepare a dispersion phase; a step of the dispersion phase in the dispersion solvent to prepare O/W(oil-in-water type), O/O(oil-in-oil type), or W/O/W(water-in-oil-in-water type) emulsion; and a step of maintaining the emulsion at 0°C-10°C.

Description

Pharmaceutical composition containing microspheres loaded with olanzapine as an active ingredient

The present invention relates to a pharmaceutical composition comprising an olanzapine-containing polymer microspheres as an active ingredient, specifically, mixing a water-insoluble organic solvent and a dispersion solvent; Mixing a high molecular compound, olanzapine, and a water-insoluble organic solvent to form a dispersed phase; Mixing the dispersion phase with a dispersion solvent in which a water-insoluble organic solvent is mixed to prepare an emulsion, but maintaining the temperature of the emulsion at 0 ° C. to 10 ° C .; Schizophrenia and related schizophrenia containing the olanzapine-containing polymer microspheres prepared by the method comprising the step of removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the prepared emulsion at 0 ℃ to 10 ℃ Psychosis, bipolar mania, bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome , Extreme shyness, diabetic nerve pain and depression, and a pharmaceutical composition for the treatment or prevention of symptoms selected from the group consisting of.

Today, many antipsychotic drugs have been developed and used to treat central nervous system disorders or severe mental conditions. However, these drugs often cause side effects, with only 40% to 80% of all drug users responding only partially or not.

Olanzapine is a yellow crystalline solid that is almost insoluble in water and is widely used for the treatment of diseases of the central nervous system. Provided primarily by oral administration, to date, more than 5.6 million patients have been treated with olanzapine. Olanzapine is an antagonist of dopamine at the D-1 and D-2 receptors, and is also an antimuscarinic, anti-cholinergic, antagonist at the 5HT-2 receptor site. In addition, this compound has antagonist activity in alpha-receptors activated by noradrenaline. This activity is useful for treating mental conditions such as schizophrenia, schizophrenic disorders, and acute mania, because the compounds have a potential neuroleptic effect with relaxation, anxiety relief, or anti-vomiting. It is known to be effective in treating mild anxiety when administered in small doses.

Mental illnesses are not obedient and it is difficult to assess whether they are taking the right amount of medication. In addition, in some cases these patients are difficult to treat due to the overactive, confused, or rejective excited states they represent. Moreover, other underlying diseases besides psychosis such as postoperative delirium, behavioral disorders associated with mental retardation, emotional disorders, adaptation disorders, personality disorders, anxiety disorders can also induce the patient to be excited.

In this case, parenteral administration of antipsychotics is desirable when oral administration of the drug to the patient is impossible or its consistency is not reliable. However, frequent injections are not recommended for patients requiring long-term treatment due to the nature of the disease.

Therefore, in order to lower the frequency of administration, and to consistently administer the appropriate amount of drug and to evaluate its compliance, it is desirable to formulate the drug into a form that is capable of continuous drug release in the blood for a long time and can be administered intramuscularly.

In general, the method used for delaying the release of the drug is to prepare the active drug material in ester form, but in the case of olanzapine, the formation of the ester product is not easy. In addition, olanzapine is a metastable drug, which has a poor discoloration tendency, and is particularly susceptible to hydrolysis in a solution or a wet environment even at room temperature or refrigerated.

Therefore, there is an urgent need to develop a type of formulation that can guarantee the homogeneity and stability of the final formulation and effectively delay the release of olanzapine.

Conventional injections, such as fluids, suspensions and emulsions, are quickly removed from the body after intramuscular or subcutaneous administration, so frequent injections have been essential for the treatment of chronic diseases. Microencapsulation, which is designed to solve this problem, refers to a manufacturing process for encapsulating a drug in a microsphere composed of a high molecular compound (in the following description, a microsphere includes a nanosphere). Since it has a size of usually μm, it can be administered to a human body or an animal by intramuscular or subcutaneous injection, and can be manufactured to have various drug release rates, thereby controlling the drug delivery period. Therefore, a single dose can maintain effective drug concentrations for long periods of time, minimizing the total drug dose required for treatment, and improving patient compliance with drug treatment, leading to drug-containing polymers from leading pharmaceutical companies around the world. Has shown great interest in the production of microspheres.

Poly-d, l-lactideco-glycolide (PLGA) is most widely used as a polymer compound in preparing polymer microspheres through microencapsulation. PLGA is a biocompatible polymer compound that is hydrolyzed in vivo and converted into non-toxic lactic acid and glycolic acid. Therefore, the pharmaceutical industry is putting a lot of effort into the development of pharmaceutical formulations using PLGA. Examples of microsphere products made from PLGA are currently available such as Risperdal Consta, Sandostatin LAR and Vivitrol. And the Lupron Depot. Each of these is administered to the patient once to control the release of risperidone, octreotide acetate, naltrexone and leuprolide acetate from 2 weeks to 4 months.

Such drug-containing polymer microspheres are conventionally prepared by solvent evaporation or solvent extraction using an organic solvent such as methylene chloride and ethyl acetate.

First, a brief description of the solvent evaporation method (see US Pat. Nos. 6,471,996, 5,985,309 and 5,271,945), dispersing or dissolving the drug in an organic solvent in which the polymer compound is dissolved, and then emulsifying in a dispersion medium such as water After preparing a type (O / W) oil-in-water emulsion, the organic solvent in the emulsion is diffused into a dispersion medium to form a drug-containing polymer microsphere by evaporating the organic solvent through an air / water interface. In this case, in order to promote diffusion of the organic solvent into the dispersion medium, techniques such as reduced pressure, temperature rise, and extraction of an organic solvent using excess water are used. The dispersing organic solvent commonly used to dissolve PLGA polymer compounds is methylene chloride, which can dissolve PLGA copolymers with various molecular weights and lactide: glycolide ratios, and has a low water solubility of 1.32% by weight. Because it does not mix well with water, it is suitable for making oil-in-water type emulsions. Due to the low boiling point of 39.8 ° C., a small amount of methylene chloride molecules diffused from the emulsion droplets into the water evaporate well through the water and air interface. If this process is repeated continuously, microspheres are produced as methylene chloride is removed from the emulsion droplets. Finally, the low boiling point has the advantage that it is very easy to dry out the residual methylene chloride present in the microspheres.

As such, although methylene chloride is an optimal organic solvent for making kerosene, which has a strong volatility, does not mix well with water and has a much lower boiling point than water, it has the following serious problems: (a) Experimentally confirmed carcinogenesis It is a substance; (b) Destroys the ozone layer in the atmosphere, causing environmental toxicity, and consequently increases human skin cancer. (c) It is one of the 38 most dangerous toxic hazardous substances defined by the Agency for Toxic Substances and Disease Registry of the US Department of Health and Human Services. (d) The water solubility is about 1.32% by weight, so that only a small fraction of the total amount of methylene chloride used is dissolved in water and evaporated, which takes considerable time to completely remove the methylene chloride in the emulsion droplets. For example, U. S. Patent No. 6,884, 435 agitates the emulsion overnight to remove methylene chloride from the emulsion, and may increase the reactor temperature or introduce reduced pressure conditions to shorten the microsphere preparation time (US Patents 3,691,090, 3,891,570, 6,270,700 and 6,572,894).

On the other hand, the solvent extraction method used in the preparation of drug-containing polymer microspheres is a method of effectively extracting the organic solvent in the emulsion droplets using a large amount of solubilizing solvent. When the organic solvent is extracted from the emulsion droplets, the molten polymer compound is cured to convert the emulsion droplets into microspheres. The solubilizing solvent generally used is water, and the degree of water solubility of the organic solvent greatly affects the amount of water required. For example, methylene chloride has a water solubility of 1.32% by weight so very large amounts of water can be used to extract methylene chloride in the emulsion. However, in this case, since a large amount of wastewater containing methylene chloride is generated and the treatment of such wastewater is also a problem, ethyl acetate having a higher water solubility than methylene chloride is mainly used in the solvent extraction method. Ethyl acetate has a water solubility of 8.7% by weight and can be extracted with a relatively small amount of water compared to methylene chloride, and has the advantage of being a non-halogenated organic solvent. However, the boiling point of ethyl acetate is 77 ° C., which is much higher than 39.8 ° C., which is the boiling point of methylene chloride, and has a disadvantage in that it is relatively difficult to remove residual solvent when dried. In addition, PLGA high molecular weight compounds having a specific molecular weight and lactide: glycolide ratio are insoluble in ethyl acetate.

Accordingly, U.S. Patent Nos. 4,389,840, 4,530,840, 6,544,559, 6,368,632, and 6,572,894, and the like disclose a technique for simultaneously utilizing a solvent evaporation method and a solvent extraction method. That is, after the emulsion is made, some organic solvents are removed through evaporation and the remaining organic solvents are removed by solvent extraction. For example, in US Pat. No. 4,389,840, a drug and a PLGA polymer compound are dissolved in methylene chloride and then emulsified in water to prepare an oil-in-water emulsion, and then 40 to 60% by weight of methylene chloride is evaporated.

Disclosed is a process for producing microspheres by removing via and extracting the remaining methylene chloride with a large amount of water.

However, all of these conventional methods require the use of a very large amount of water (more than 10 times the water solubility of organic solvents) because the water solubility of the organic solvents used is not high enough. Therefore, a very large capacity reactor is required for this purpose, and a large amount of wastewater containing an organic solvent is generated, thereby facing an inefficiency problem in which an additional cost for wastewater treatment is increased. In addition, there is a problem that it is difficult to effectively remove the organic solvent remaining in the microspheres.

The present inventors have disclosed a method for preparing drug-containing polymer microspheres comprising the step of converting a water-insoluble organic solvent into a water-soluble organic solvent by adding ammonia solution. By the above method, polymer microspheres can be produced easily and quickly while minimizing waste water generation. However, even with this method, there is a problem that the amount of organic solvent remaining in the polymer microspheres accounts for 1% or more.

When a significant amount of organic solvent remains in the microspheres, the phenomenon of aggregation between the microspheres occurring during drying is prominent. Therefore, after drying, the microspheres are not individually dispersed, which may cause a problem in the injection process, decrease in drug release reproducibility, and it is difficult to obtain a product license from the regulatory authority because the amount of residual solvent exceeds the permission limit. .

Therefore, it is urgent to develop a type of formulation that can guarantee continuous homogeneity and stability of the final formulation and minimize the amount of remaining organic solvent in the prepared polymer microspheres, effectively releasing olanzapine.

Accordingly, the present inventors studied a method of reducing the amount of residual solvent of the olanzapine-containing polymer microspheres prepared by the method for preparing polymer microspheres which remove the water-insoluble organic solvent using an acid or a base. It was found that the concentration of the residual organic solvent in the prepared polymer microspheres was further reduced when the solvent was previously added to the dispersion solvent. In addition, during the study to solve the decomposition of some polymer compounds according to the administration of olanzapine found that the problem of decomposition of the polymer compound is overcome when the step of removing the water-insoluble organic solvent using an acid or a base at a low temperature The present invention has been completed.

Accordingly, an object of the present invention is to mix a water-insoluble organic solvent and a dispersion solvent; Mixing a high molecular compound, olanzapine, and a water-insoluble organic solvent to form a dispersed phase; The dispersion phase is mixed with a dispersion solvent in which a water-insoluble organic solvent is mixed to form an oil-in-water (O / W) type, an oil-in-oil (O / O) type or a water-in oil- (W / O / W) type. preparing an in-water emulsion, but maintaining the temperature of the emulsion at 0 ° C to 10 ° C; And schizophrenia comprising the olanzapine-containing polymer microspheres prepared by the method comprising the step of removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the prepared emulsion at 0 ℃ to 10 ℃ And related psychosis, bipolar mania, bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress symptoms It provides a pharmaceutical composition for the treatment or prevention of symptoms selected from the group consisting of syndrome, extreme shyness, diabetic nerve pain and depression.

In addition, another object of the present invention is to mix a water-insoluble organic solvent and a dispersion solvent; Mixing a high molecular compound, olanzapine, and a water-insoluble organic solvent to form a dispersed phase; The dispersion phase is mixed with a dispersion solvent in which a water-insoluble organic solvent is mixed to form an oil-in-water (O / W) type, an oil-in-oil (O / O) type or a water-in oil- (W / O / W) type. preparing an in-water emulsion, but maintaining the temperature of the emulsion at 0 ° C to 10 ° C; Removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the prepared emulsion at 0 ° C to 10 ° C; And schizophrenia and related psychosis, bipolar mania, which comprises an olanzapine-containing polymer microspheres prepared by the method comprising the steps of obtaining the polymer microspheres from which the water-insoluble organic solvent prepared is removed and redispersing them in a heated dispersion solvent. (bipolar mania), bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, extreme shame To provide a pharmaceutical composition for the treatment or prevention of symptoms selected from the group consisting of extreme shyness, diabetic nerve pain and depression.

It is another object of the present invention to provide a pharmaceutical formulation comprising the pharmaceutical composition.

In order to achieve the above object, the present invention comprises the steps of mixing a water-insoluble organic solvent and a dispersion solvent; Mixing a high molecular compound, olanzapine, and a water-insoluble organic solvent to form a dispersed phase; The dispersion phase is mixed with a dispersion solvent in which a water-insoluble organic solvent is mixed to form an oil-in-water (O / W) type, an oil-in-oil (O / O) type or a water-in oil- (W / O / W) type. preparing an in-water emulsion, but maintaining the temperature of the emulsion at 0 ° C to 10 ° C; And schizophrenia comprising the olanzapine-containing polymer microspheres prepared by the method comprising the step of removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the prepared emulsion at 0 ℃ to 10 ℃ And related psychosis, bipolar mania, bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress symptoms It provides a pharmaceutical composition for the treatment or prevention of symptoms selected from the group consisting of syndrome, extreme shyness, diabetic nerve pain and depression.

In order to achieve another object of the present invention, the present invention comprises the steps of mixing a water-insoluble organic solvent and a dispersion solvent; Mixing a high molecular compound, olanzapine, and a water-insoluble organic solvent to form a dispersed phase; The dispersion phase is mixed with a dispersion solvent in which a water-insoluble organic solvent is mixed to form an oil-in-water (O / W) type, an oil-in-oil (O / O) type or a water-in oil- (W / O / W) type. preparing an in-water emulsion, but maintaining the temperature of the emulsion at 0 ° C to 10 ° C; Removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the prepared emulsion at 0 ° C to 10 ° C; And schizophrenia and related psychosis, bipolar mania, which comprises an olanzapine-containing polymer microspheres prepared by the method comprising the steps of obtaining the polymer microspheres from which the water-insoluble organic solvent prepared is removed and redispersing them in a heated dispersion solvent. (bipolar mania), bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, post traumatic distress syndrome, extreme shame It provides a pharmaceutical composition for the treatment or prevention of symptoms selected from the group consisting of extreme shyness, diabetic nerve pain and depression.

In order to achieve another object of the present invention, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition.

Hereinafter, the content of the present invention will be described in more detail.

The pharmaceutical composition of the present invention

(a) mixing a water-insoluble organic solvent and a dispersion solvent;

(b) mixing the high molecular compound, olanzapine and a water-insoluble organic solvent to form a dispersed phase;

(c) O / W (oil-in-water), O / O (oil-in-oil) by mixing the dispersed phase of step (b) with the dispersion solvent mixed with the water-insoluble organic solvent of step (a) Preparing a) -type or water-in-oil-in-water (W / O / W) type emulsion, and maintaining the temperature of the emulsion at 0 ° C to 10 ° C; And

(d) removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the emulsion prepared in step (c) at 0 ° C to 10 ° C.

It characterized in that it comprises an olanzapine-containing polymer microspheres prepared by a method comprising as an active ingredient.

The above steps are described in detail.

In step (a), a water-insoluble organic solvent and a dispersion solvent are mixed.

The water-insoluble organic solvent of the present invention can dissolve the polymer compound used for the preparation of the polymer microspheres known in the art, and is hydrolyzed by an acid or a base, and the hydrolysis products are all soluble in water. Can be used without In general, compounds having amide, ester, anhydride and halogen acid structures are well known to be hydrolyzed by acid / base. The compound having an anhydride structure undergoes a hydrolysis reaction to produce a water-soluble carboxylic acid, and the compound having an ester structure is hydrolyzed to a water-soluble carboxylic acid and an alcohol. Compounds having a halogen acid structure are hydrolyzed to water-soluble carboxylic acids and halogen acids (HF, HCl, HBr, HI, etc.). In the case of a compound having an amide structure, the amide is hydrolyzed into carboxylic acid and an amine, so that the amide is included in the water-insoluble organic solvent of the present invention when the amine is a product dissolved in water.

The water-insoluble organic solvent in the present invention is a compound having an acid halogen structure, a compound having an anhydride structure, a phosphoric anhydride compound, a compound having an ester structure, carboxyl Carboxylic ester compounds, phosphoric ester compounds, sulfuric acid ester compounds, nitrate ester compounds, boric acid ester compounds, amide-containing compounds and carboxylic amides compounds, preferably For example, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl formate, ethyl formate ( ethyl formate, isopropyl formate, propyl formate ), Butyl formate, methyl dichloroacetate, methyl chloroacetate, ethyl chloroacetate, ethyl dichloroacetate, methyl fluoroacetate fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, ethyl difluoroacetate, maleic anhydride, acetic anhydride , Propionic anhydride, phosphoric anhydride, acetamide, propionamide, butylamide and carboxyl amide.

More preferably, ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl formate, propyl formate Acetic anhydride or propionic anhydride.

The dispersion solvent used in the present invention includes an aqueous dispersion solvent or a non-aqueous dispersion solvent containing an emulsifier, and when preparing the O / W and W / O / W emulsion, the aqueous dispersion solvent, O / O emulsion production In the case of non-aqueous dispersion solvent may be used. Aqueous dispersants include hydrophilic emulsifiers such as polyvinyl alcohol and polysorbate series (eg polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85). An aqueous solution containing an emulsifier such as) or a cosolvent thereof may be used. As the non-aqueous dispersion solvent, a lipophilic emulsifier such as silicone oil, vegetable oil, toluene or xylene containing an emulsifier such as glycerin esters of fatty acids or lecithin can be used. The concentration of the emulsifier in the dispersion solvent may be 0.05 to 15% (w / v).

The amount of the water-insoluble organic solvent mixed in the dispersion solvent may vary depending on the type of the polymer compound used to prepare the polymer microspheres, the type of the encapsulated drug, and the type of the dispersion solvent. Preferably, the water-insoluble organic solvent has water solubility (water solubility). If the amount is too small, the surface structure of the polymer microspheres becomes porous, and the initial release amount of the drug is increased, and if the water is added above the water solubility, it is difficult to remove the organic solvent, thereby increasing the concentration of the residual organic solvent.

In step (b), the polymer compound, olanzapine, and a water-insoluble organic solvent are mixed to form a dispersed phase.

"Dispersed phase" of the present invention refers to a mixture of a polymer compound and a drug dissolved in a water-insoluble organic solvent.

Olanzapine is a thienobenzodiazepine family of atypical antipsychotics used to treat schizophrenia, bipolar disorder and central nervous system disease. Olanzapine of the present invention has a structure of formula (1) and can be isolated and purified from nature, commercially available and can be prepared by chemical synthesis methods known in the art.

<Formula 1>

Examples of the water-insoluble organic solvent of step (b) are as described above in step (a).

The water-insoluble organic solvent of step (b) may preferably be the same kind of organic solvent as used in step (a), and if necessary, the water-insoluble organic solvent is a common mixture of one or more other organic solvents. By using a medium, the solubility of the drug to be enclosed in the microspheres can be adjusted or the curing rate of the emulsion droplets can be controlled as desired.

The polymer compound used in the present invention may be used without limitation as long as it is a polymer compound known in the art. PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalate, polyhydroxybutyrate, poly Amino acids, copolymers of lactic acid and amino acids, and mixtures thereof, more preferably polylactide-co-glycolide (PLGA).

Also preferably, the polymer compound used in the present invention may be a polymer compound whose terminal is treated so as not to cause hydrolysis by an acid or a base, and for example, terminal PL esterified or esterified PCL (polycaprolactone) ), Esterified polyanhydrides.

The polymer compound may be used in an amount of 1 to 500 parts by weight, preferably 1 to 50 parts by weight, based on 1 part by weight of olanzapine.

In step (c), the dispersed phase of step (b) is mixed with the dispersion solvent in which the water-insoluble organic solvent of step (a) is mixed to form an oil-in-water (O / W) type and oil-in (O / O). Prepare oil-type or water / in / water-in-water emulsions, but maintain the temperature of the emulsion at 0 ° C to 10 ° C.

In the preparation of the emulsion, in order to prepare an oil-in-water (O / W) type emulsion, a polymer compound, an olanzapine, and a water-insoluble organic solvent are mixed to form a dispersed phase, which is mixed with a dispersion solvent to which a water-insoluble organic solvent is added. In order to prepare an O / O (oil in oil) emulsion, a polymer compound, an olanzapine, and an organic solvent are mixed to form a dispersed phase, which is mixed with a dispersion solvent using an organic solvent that is not mixed with the previously used organic solvent. To prepare W / O / W (water-in-oil-in-water) emulsion, an aqueous solution of olanzapine is emulsified in a water-insoluble organic solvent in which a high molecular compound is dissolved. A water-in-oil-type emulsion may be prepared by mixing a water-in-oil-type emulsion and then mixing it in a dispersion solvent to which a water-insoluble organic solvent is added.

The volume ratio of the dispersed phase mixed in step (c) and the dispersed solvent in which the water-insoluble organic solvent is mixed may be preferably 1: 3 to 100, and most preferably 1: 4 to 20.

If the ratio of the dispersion solvent is less than the above range, the emulsion is not formed well, if it is larger than the above range there is a problem that the waste solution is excessively increased.

In step (d), the oil prepared in step (c) is added with a base or an acid while maintaining 0 ° C to 10 ° C to remove the water-insoluble organic solvent from the oil.

In the present invention, the step of removing the water-insoluble organic solvent from the emulsion by adding a base or an acid solution is preferably performed by a hydrolysis reaction. Hydrolysis is a reaction in which water is added and decomposed into two substances. In the case of a compound having an ester structure, it is hydrolyzed to carboxylic acid and an alcohol, and in the case of an anhydride structure, it is hydrolyzed to a carboxylic acid. In the case of a compound having a hydrolysis, it is hydrolyzed to carboxylic acid and an amine, and in the case of a compound having a halogen acid structure, the compound is hydrolyzed to carboxylic acid and a halogen acid (HF, HCl, HBr, HI, etc.). This converts the water-insoluble organic solvent dispersed in a small amount (or dissolved) in one layer (e.g., water phase) into a water-soluble organic solvent that is completely soluble in water, and water-insoluble as much as converted. Allow the organic solvent to diffuse into the aqueous layer. This process is continuously carried out to remove the water-insoluble organic solvent in the emulsion to cure the emulsion droplets to the microspheres can be prepared olanzapine-containing polymer microspheres. The removal of the water-insoluble organic solvent in the emulsion above not only completely or substantially eliminates (in an undetectable level) the water-insoluble organic solvent, but also reduces the water-insoluble organic solvent relative to the initial level before acid or base addition. It includes. At this time, due to the rapid curing of the emulsion droplets, the interaction between emulsion droplets is suppressed to obtain the desired polymer microspheres without aggregation. At this time, the acid catalyzes the reaction, and the base is consumed in the reaction, and once added, the reaction does not significantly affect the reaction even if the amount is smaller or higher than that of the water-insoluble organic solvent. However, if too many moles of acid or base are added, there may be a problem in the stability of the olanzapine and the polymer compound, so an appropriate amount should be considered.

Preferably, the base solution may be added such that the molar number of the water-insoluble organic solvent and the molar number of the base solution are 1: 0.1 to 10, more preferably 1: 0.2 to 5, and still more preferably 1: 0.3 To 3, most preferably 1: 0.5 to 1.5.

The temperature of the emulsion of step (c) and step (d) may vary depending on the type of polymer compound, water-insoluble organic solvent, base or acid, but preferably 0 ° C to 10 ° C, most preferably 0 ° C to 4 ° C. May be ° C.

If the temperature of the emulsion exceeds 10 ℃, the decomposition of the polymer compound occurs during the manufacturing process of the olanzapine-containing polymer microspheres, and if the temperature is lowered below 0 ℃, the water-soluble dispersion solvent is frozen, it may not be well formed.

The base is preferably sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium hydroxide (KOH), ammonium hydroxide (NH ₄ OH), copper hydroxide (Cu (OH) ₂ ), and iron hydroxide (Fe (OH) ₃ ). And acid is preferably hydrochloric acid (HCl), nitric acid (HNO ₃ ), sulfuric acid (H ₂ SO ₄ ), acetic acid (CH ₃ COOH), boric acid (H ₃ BO ₃ ) and carbonic acid (H ₂ CO ₃ ) Can be.

The olanzapine-containing polymer microspheres prepared as described above do not require a conventional solvent evaporation or solvent extraction process, and can be easily produced in a short time while minimizing wastewater generation using a small amount of water, and the remaining organic particles in the polymer microspheres prepared The concentration of solvent was low and the decomposition of the polymer compound was also prevented. In addition, the rate of release of olanzapine in the body can be controlled to eliminate the discomfort and disadvantages of frequent drug intake or injection.

On the other hand, the present invention comprises the steps of (a) mixing a water-insoluble organic solvent and a dispersion solvent;

(b) mixing the high molecular compound, olanzapine and a water-insoluble organic solvent to form a dispersed phase;

(c) O / W (oil-in-water), O / O (oil-in-oil) by mixing the dispersed phase of step (b) with the dispersion solvent mixed with the water-insoluble organic solvent of step (a) Preparing a) -type or water-in-oil-in-water (W / O / W) type emulsion, and maintaining the temperature of the emulsion at 0 ° C to 10 ° C;

(d) removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the emulsion prepared in step (c) at 0 ° C to 10 ° C; And

(e) obtaining the polymer microspheres from which the water-insoluble organic solvent prepared in step (d) is removed and redispersing in a warmed dispersion solvent

Schizophrenia and related psychoses, bipolar mania, bipolar disorders, seizures, obsessive / compulsive disorders, including For the treatment or prevention of symptoms selected from the group consisting of generalized anxiety disorder, post traumatic distress syndrome, extreme shyness, diabetic nerve pain and depression It provides a pharmaceutical composition.

The above steps are described in detail.

Steps (a) to (d) are as described above.

In step (e), the polymer microspheres from which the water-insoluble organic solvent prepared in step (d) is removed are redispersed in a warmed dispersion solvent.

The dispersion solvent used in the redispersion process of the present invention includes an aqueous dispersion solvent or a non-aqueous dispersion solvent containing an emulsifier, and when preparing O / W and W / O / W emulsions, the aqueous dispersion solvent is O / In preparing O type emulsion, a non-aqueous dispersion solvent may be used. Aqueous dispersants include hydrophilic emulsifiers such as polyvinyl alcohol and polysorbate series (eg polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85). An aqueous solution containing an emulsifier such as) or a cosolvent thereof may be used. As the non-aqueous dispersant, a lipophilic emulsifier such as silicone oil, vegetable oil, toluene or xylene containing an emulsifier such as glycerin esters of fatty acids or lecithin may be used. The concentration of the emulsifier in the redispersion solvent may be 0.05 to 15% (w / v).

The temperature of the heated dispersion solvent may vary depending on the type and amount of the water-insoluble organic solvent and the polymer compound, preferably 20 ° C. to 80 ° C., more preferably 30 ° C. to 50 ° C., and most preferably. Preferably from 30 ° C to 40 ° C. When the temperature of the dispersion solvent is lowered below 20 ° C, the amount of residual organic solvent may increase, and when it exceeds 80 ° C, deformation of the polymer microspheres may occur.

The polymeric microspheres redispersed in the heated dispersion solvent further reduce the concentration of organic solvent in the microspheres.

The olanzapine-containing polymer microspheres contained as an active ingredient in the pharmaceutical composition of the present invention do not require a conventional solvent evaporation or solvent extraction process, and can be easily manufactured in a short time while minimizing waste water generation using a small amount of water. The concentration of residual organic solvent in the prepared polymer microspheres was low and the decomposition of the polymer compound was also prevented. In addition, the composition of the present invention can control the release rate of the olanzapine in the body to eliminate the discomfort and disadvantages of frequent drug intake or injection.

Olanzapine of the present invention is a thienobenzodiazepine family of atypical antipsychotic drugs used for the treatment of schizophrenia, bipolar disorder and central nervous system diseases. Examples of diseases that can be treated with olanzapine include schizophrenia and related psychosis, bipolar mania and / or bipolar disorder, seizure, obsessive / compulsive disorder, and panic anxiety disorder ( generalized anxiety disorders, post traumatic distress syndrome, extreme shyness, diabetic nerve pain, stop smoking and depression, but are not limited to these.

Thus, the composition of the present invention is schizophrenic and related psychosis, bipolar mania, bipolar disorder, seizure, obsessive / compulsive disorder, generalized anxiety disorder, trauma There is efficacy in the treatment or prevention of symptoms selected from the group consisting of post traumatic distress syndrome, extreme shyness, diabetic nerve pain and depression. In addition, the olanzapine-containing polymer microspheres contained as an active ingredient of the present invention do not require a conventional solvent evaporation or solvent extraction process, and can be easily manufactured in a short time while minimizing waste water generation using a small amount of water. The concentration of residual organic solvent in the polymer microspheres was very low and the decomposition of the polymer compound was also prevented. In addition, the composition of the present invention can control the release rate of the olanzapine in the body to eliminate the discomfort and disadvantages of frequent drug intake or injection.

The total effective amount of the pharmaceutical composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol which is administered in multiple doses for a long time. . The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the extent of the disease. Preferably the preferred total dose of the composition of the present invention may be about 0.01 μg to 500 mg, most preferably 0.1 μg to 100 mg per kg of patient body weight per day. However, the dosage of the composition is determined in consideration of various factors such as the age, weight, health condition, sex, severity of the disease, diet and excretion rate, as well as the route and frequency of treatment of the pharmaceutical composition is determined In view of this, one of ordinary skill in the art will be able to determine the appropriate effective dosage for the particular use of the composition as a therapeutic agent.

The pharmaceutical composition according to the present invention is not particularly limited to its formulation, route of administration and method of administration as long as the effect of the present invention is achieved. For example, the pharmaceutical compositions of the present invention may be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration. Can be.

Accordingly, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of the present invention. The pharmaceutical formulation of the present invention is characterized by comprising the pharmaceutical composition of the present invention. The pharmaceutical formulation of the present invention is not particularly limited in its dosage form as long as it shows the effect according to the present invention.

In the case of preparations for oral administration, the compositions of the present invention may be formulated using methods known in the art as powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions and the like. Can be. Formulations for parenteral administration may be formulated by methods known in the art in the form of injections, creams, lotions, external ointments, oils, humectants, gels, aerosols and nasal inhalants.

Preferably the pharmaceutical formulation of the invention may be an injection. Injections of the invention may preferably be intravenous, subcutaneous or intramuscular injections. Suitable carriers when formulated as injectables include pharmaceutically acceptable isotonic agents, solubilizers, analgesics, stabilizers, buffers, preservatives and the like known in the art. The term "pharmaceutically acceptable" refers to a physiologically acceptable and, when administered to a human or animal, usually does not cause an allergic reaction, such as gastrointestinal disorders, dizziness, or the like. Suitable stabilizers include sodium bisulfite, sodium sulfite and ascorbic acid, and the like, and preservatives include benzalkonium chloride, methyl or propyl-paraben and chlorobutanol.

These formulations are described in Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995, a prescription generally known in all pharmaceutical chemistries.

In one embodiment of the present invention is to measure the residual solvent of the polymer microspheres prepared according to the existing method (Korean Patent No. 10-0918092), prepared by using a dispersion solvent in which a variety of concentrations of water-insoluble organic solvent is added in advance The residual solvent of the prepared polymer microspheres was measured. As a result, when the organic solvent was added to the dispersion solvent in advance, it was confirmed that the concentration of the residual solvent was lowered up to a level of 25% (see Example 1).

In another embodiment of the present invention was compared the residual solvent concentration according to the dispersion solvent temperature of the redispersion step. In the process of preparing the polymer microspheres, add 1 step to the time when the reaction is terminated by adding a base or acid solution. And the concentration of the residual solvent was measured by varying the temperature of the second step to 33 ° C. or keeping it at room temperature.

As a result, it was confirmed that the amount of residual solvent was significantly reduced when the second stage temperature was maintained high regardless of whether the first stage was heated or not. These results were the same when the type of the polymer compound was changed or the capacity of the polymer compound was increased. It was also confirmed that olanzapine-containing polymer microspheres in which olanzapine was well enclosed in the polymer microspheres were prepared (see Example 2).

In another embodiment of the present invention, the residual solvent of the polymer microspheres prepared by simultaneously applying the conditions of maintaining the dispersion solvent temperature of the two stages of redispersion and the condition of using the dispersion solvent to which the water-insoluble organic solvent is added in advance Measured. The amount of water-insoluble organic solvent added in advance to the dispersion solvent was set in various ways and the results were compared. As a result, it was confirmed that the polymer microspheres containing the olanzapine were stably prepared, and the amount of the residual solvent was reduced in a concentration-dependent manner depending on the amount of the water-insoluble organic solvent previously added to the dispersion solvent. In addition, it was confirmed that the spherical polymer microspheres were stably produced even if the organic solvent was previously added to the dispersion solvent (see Example 3).

In another embodiment of the present invention, the olanzapine-containing polymer microspheres were prepared by varying the ratio of the dispersed phase and the solvent, and the concentration change of the residual solvent was measured accordingly. As a result, when the ratio of the dispersed phase and the solvent is 1: 4 or 1: 6, the residual amount of the solvent (EA or EF) is reduced compared to the case of 1:10, but the residual amount of ethanol was confirmed to increase. Therefore, it was confirmed that the concentration of the residual solvent of the polymer microspheres can be controlled by controlling the ratio of the dispersed phase and the dispersed solvent. In addition, it was confirmed that there is no difference in controlling the ratio of the dispersed phase and the dispersion solvent depending on which of the amount of the powder phase and the amount of the dispersion solvent was adjusted (see Example 4).

In another embodiment of the present invention by varying the ratio of the dispersed phase and the solvent and the amount of the organic solvent premixed in the dispersion solvent by combining the conditions of the embodiments and maintaining the temperature of the redispersion step at 40 ℃ It was prepared to measure the change in properties accordingly. The dispersed phase is fixed with 4 ml of ethyl formate in which 250 mg of a polymer compound is dissolved, and the amount of the dispersion solvent is 20 ml, 30 ml, and 40 ml, and the amount of organic solvent added to the dispersion solvent in advance is 0% to 10%. Polymer microspheres were each prepared by increasing up to.

As a result, when the organic solvent was added to the dispersion solvent in advance, it was confirmed that the concentration of the residual solvent was suppressed to a predetermined level or less despite the change of other conditions. It was confirmed that there was no increase in residual ethanol increase when mixed.

In addition, the yield of the polymer microspheres was generally good, and it was confirmed that there was no change in the molecular weight of the polymer compound before and after the preparation of the polymer microspheres (see Example 5).

In another embodiment of the present invention was prepared by reflecting all the conditions of the above examples to prepare the polymer microspheres containing the olanzapine and the residual solvent amount, the Olanzapine encapsulation rate, the yield of the polymer microspheres and the molecular weight of the polymer compound was measured.

As a result, the residual solvent concentration was measured very low, and it was confirmed that most of the olanzapine encapsulation rate and the yield of the polymer microspheres were more than 70% (see Example 6-2).

As a result of measuring the molecular weight change before and after the preparation of the microspheres of the polymer compound of the prepared olanzapine-containing polymer microspheres, the decomposition of the polymer compound used to prepare the polymer microspheres occurs in the process of preparing the polymer microspheres containing the olanzapine It confirmed that (see Example 6-3).

This is a problem that did not appear in the manufacturing process of the polymer microspheres containing no olanzapine, as confirmed in Example 5, it was assumed that the olanzapine is involved in the ester bond decomposition of the polymer compound in the manufacturing process of the polymer microspheres.

The organic solvent and PLGA can be decomposed by the same mechanism by the base. However, since the amount of the organic solvent is larger than PLGA and is extremely low molecular weight, the decomposition by the added base mostly degrades the organic solvent. However, when the temperature is high when reacting with the base, the flexibility of the PLGA may be increased, and the difference in reactivity between the organic solvent and the PLGA may be reduced. In consideration of this point, it is expected that the degradation of PLGA may be prevented in the case of lowering the temperature of the first stage, thereby preparing polymer microspheres with the first stage of 4 ° C.

As a result of measuring the PLGA molecular weight before and after the preparation of the polymer microspheres prepared at the first stage temperature at 4 ° C, it was confirmed that the degree of molecular weight reduction of PLGA was significantly reduced compared to the case where the first stage temperature was set at room temperature. In addition, as a result of measuring the encapsulation rate and the yield of the microspheres of the polymer microspheres prepared at a one-stage temperature of 4 ° C., it was confirmed that the encapsulation rate and the yield of the polymer microspheres were mostly 70% or more, as good as in the case of room temperature (Example 6 -4).

In another embodiment of the present invention, polymer microspheres were prepared using a water-insoluble organic solvent different from that used in the above examples.

Polymer microspheres were prepared using ethyl acetate as a water-insoluble organic solvent, and the amount of residual solvent, the amount of olanzapine encapsulation and the yield of polymer microspheres were measured. It confirmed that it was good in% or more (refer Example 7-2).

In another embodiment of the present invention, the olanzapine-containing polymer microspheres were prepared, tested for dispersibility and injectability, and then injected into a rat and pharmacokinetic test was performed by measuring the concentration of olanzapine in blood.

As a result, the composition containing the olanzapine-containing polymer microspheres of the present invention was confirmed that it can be used as an injection because of good dispersibility and injectability, and it was confirmed that the olanzapine in the blood was continuously released until 80 days when injected into a let (Example) 8).

As described above, the present invention provides an olanzapine-containing polymer microspheres prepared by a method comprising mixing a water-insoluble organic solvent and a dispersion solvent and removing the water-insoluble organic solvent from an emulsion using a base or an acid. It provides a pharmaceutical composition for the treatment or prevention of schizophrenia, bipolar disorder and central nervous system disease comprising. The production method of the present invention does not require a conventional solvent evaporation or solvent extraction process, and can easily prepare the olanzapine-containing polymer microspheres in a short time while minimizing the generation of wastewater using a small amount of water and in the prepared polymer microspheres It is possible to keep the concentration of residual solvent low and to prevent the decomposition of high molecular compounds during the manufacturing process, which is effective for the preparation of sustained-release drugs.

1 is a graph showing the measurement results of the residual solvent of the polymer microspheres prepared without adding a water-insoluble organic solvent to the dispersion solvent in advance.
2 is an electron micrograph of the polymer microspheres containing olanzapine. Figure 2A is a photograph of the polymer microspheres prepared by maintaining the temperature at 33 ℃ during the manufacturing process and Figure 2B is a photograph of the polymer microspheres prepared without the heating step. In both cases, the polymeric microspheres were well-formed and spherical, and olanzapine was well encapsulated into the polymeric microspheres.
3 is an electron micrograph of polymer microspheres prepared by maintaining a two-step temperature at 40 ℃ and increasing the amount of olanzapine and the polymer compound. Figure 3A is a picture of polymer microspheres when the amount of olanzapine is 60mg, Figure 3B is a picture of polymer microspheres when the amount of olanzapine is 80mg.
Figure 4 is a graph showing the concentration of the residual solvent in the polymer microspheres according to the concentration of the organic solvent previously added to the dispersion solvent.
FIG. 5 is an electron micrograph of polymer microspheres prepared by varying the concentration of an organic solvent added in advance to a dispersion solvent (Add: amount of water-insoluble organic solvent (ethyl formate) previously added to the dispersion solvent).
6 is a standard calibration curve prepared for measuring the molecular weight of polymer compounds before and after preparation of polymer microspheres.
7 is an electron micrograph of the polymer microspheres containing the olanzapine (Production number is the production number of the olanzapine-containing polymer microspheres of Example 8).
8 is a graph showing the result of measuring the concentration of olanzapine concentration after injecting a composition containing olanzapine-containing polymer microspheres into a pellet (manufacture number is a preparation number of the olanzapine-containing polymer microspheres of Example 8).
9 is a graph showing the results of measuring the concentration of olanzapine concentration after injection of a composition containing olanzapine-containing polymer microspheres (Production number is the production number of the olanzapine-containing polymer microspheres of Example 8).

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

&Lt; Example 1 >

Comparative experiment of residual solvent concentration according to the concentration of water-insoluble organic solvent mixed in the dispersion solvent

<1-1> Residual Solvent Measurement in Manufacturing Polymer Microspheres by Conventional Methods

An emulsion was prepared by dissolving 0.25 g of 7525 2.5E PLGA polymer in 4 ml of ethyl formate (EF) and emulsifying in 40 ml of 0.5% polyvinyl alcohol (PVA). 3.4 ml of 28% NH ₃ solution to be reacted with EF was added to the emulsion for 30 minutes, and distilled water was added and filtered. The microspheres were separated and again redispersed in 80% 0.1% PVA and stirred. 7525 2.5E PLGA polymer information used for this experiment is as follows.

7525 2.5E PLGA Polymer Information Polymer name and brand Company Name Lactide: Glycolide Inherent viscosity 7525DLG2.5E
(LAKESHORE
BIOMTERIALS) SurModics Pharmaceuticals Co.
(United States of America) 75: 25 0.25 dL / g

Microsphere residual solvent analysis was performed using the following gas chromatography (GC) method. GC instrument was used GC-2010 of shimadzu (Japan) and ZB-624 of phenomenex (USA) for the column. The temperature of the SPL was maintained at 200 ° C. and the split ratio of the sample was 15. Carrier gas used high purity nitrogen gas. The pressure was maintained for 2 minutes at 54.3 kPa (flow rate 1.3 ml / min) and 3 minutes at 40 kPa at a rate of -50 ° C. The pressure was then raised to 100 kPa at rate 80 and maintained for 2 minutes. The column temperature was maintained at 80 ° C. for 5.1 minutes and raised to 180 ° C. at 200 ° C. per minute for 2 minutes. A flame ionization detector (FID) was used as the detector and the temperature was 220 ° C. About 50 mg of polymer microspheres samples were taken, weighed accurately and completely dissolved in 2 ml tetrahydrofuran. After diluting it four times with pentanol, the precipitated polymer was filtered through a filter and injected into GC.

As a result, as shown in [FIG. 1], it was confirmed that the residual solvent came out at 1.5% or more.

<1-2> Residual solvent concentration according to the concentration of water-insoluble organic solvent mixed in the dispersion solvent

The residual organic solvent concentration remaining in the polymer microspheres was measured depending on whether the water-insoluble organic solvent was previously mixed with the dispersion solvent.

Polymeric microspheres were prepared according to the polymer microspheres production conditions as shown in Table 2 below.

Polymer microsphere manufacturing conditions number The amount of organic solvent (EF) mixed in the dispersion solvent Amount of drug (olanzapine) Amount of NaOH EF Residual% Ethanol residual% A 0ml 0mg 5ml 0.62 0.48 B 0.5ml 0mg 5.6 ml 0.34 0.52 C 1.0ml 0mg 6.2ml 0.16 0.46 D 0ml 60mg 5ml 0.55 0.94 E 0.5ml 60mg 5.6 ml 0.31 1.03 F 1.0ml 60mg 6.2ml 0.21 0.87

First, 0.35 g of 7525 2.5E polylactide-co-glycolide (PLGA) polymer and olanzapine according to [Table 1] were dissolved in 4 ml of ethyl formate (EF), followed by EF organic solvent according to [Table 1]. Emulsion was prepared by emulsifying in 20 ml of 0.5% poly (vinyl alcohol) (PVA) added in advance. An equivalent of 10 N NaOH to be reacted with EF was added to the emulsion to react for 30 minutes, and distilled water was added, followed by filtration. The microspheres were separated and again redispersed in 80 ml of 0.1% PVA and stirred.

As a result, as shown in [Table 2], when the organic solvent was added to the dispersion solvent, the concentration of the residual organic solvent was confirmed to be low.

<Example 2>

Comparison of Residual Solvent Concentration According to Dispersion Solvent Temperature in Redispersion Stage

In the preparation of the polymer microspheres, it was expected that the reaction of acid or base to remove the water-insoluble organic solvent would bring about a temperature change of the aqueous phase, which would affect the amount of residual solvent. Therefore, the process of preparing the polymer microspheres is defined as one step until the reaction is terminated by adding a base or acid solution, and two steps are defined until the completion of the agitation by re-dispersing the microspheres separated through filtration into the PVA solution after completion of the reaction. It was. At this point, the temperature was investigated to play an important role in reducing residual solvent.

<2-1> 2.5E PLGA Polymer using Microsphere  Comparative experiment of residual solvent concentration according to dispersion solvent temperature in redispersion stage

Polymer microsphere manufacturing process is as follows. 60 mg olanzapine and 250 mg 7525 2.5E PLGA were dissolved in 4 ml ethyl formate. This dispersed phase was emulsified in 20 ml of 0.5% PVA aqueous solution in which 1 ml of ethyl formate was previously dissolved. Thereafter, 6.2 ml of 10N NaOH was added to induce a reaction for 30 minutes, thereby preparing polymer microspheres. The polymer microspheres were separated, redispersed in 0.1% PVA 80ml and stirred, and the polymer microspheres were separated and dried in vacuo.

In the above process, steps 1 and 2 were performed under the temperature conditions of the following [Table 3], and the residual solvent was measured in the same manner as in <Example 1>.

7525 Residual Solvent Concentration According to Manufacturing Conditions in Manufacturing Polymer Microspheres Using 2.5E PLGA Manufacture conditions Residual EF (%) Residual EtOH (%) Step 1: heat to 33 ° C
Step 2: heat to 33 ° C 0.12 0.33 Step 1: do not heat
Step 2: heat to 33 ° C 0.09 0.36 Step 1: heat to 33 ° C
Step 2: do not heat 0.10 0.68

As a result, as shown in [Table 3], when the second stage was not heated, the residual amount of ethanol in the polymer microspheres exceeded 0.5%. It was confirmed that the shrinkage. Moreover, when the temperature of 1st stage was kept at 33 degreeC, and the case where it was not, it was confirmed that there is no big difference in the density | concentration of a residual solvent as long as the 2nd water phase temperature is maintained at 33 degreeC.

This confirms that the two-stage water temperature control plays an important role in removing residual solvent.

<2-2> 6535 4.5A PLGA Polymer using Microsphere  Comparative experiment of residual solvent concentration according to dispersion solvent temperature in redispersion stage

In general, as the PLGA molecular weight increases, the amount of organic solvent remaining in the polymer microspheres increases. Therefore, it was tested whether the method of the present invention could overcome the residual organic solvent problem even when using a high molecular weight 6535 4.5A PLGA.

The PLGA polymer information used is shown in [Table 4].

6535 4.5A PLGA Polymer Information Polymer name and brand Company Name Lactide: Glycolide Inherent viscosity 6535DLG4.5A
(LAKESHORE
BIOMTERIALS) SurModics Pharmaceuticals Co.
(United States of America) 64: 36 0.49 dL / g

Polymer microsphere manufacturing process is the same as in <Example 2-1> and only the polymer used was changed from 7525 2.5E PLGA to 6535 4.5A PLGA.

In the above process, steps 1 and 2 were performed under the temperature conditions of the following [Table 5], and the residual solvent was measured in the same manner as in <Example 1>.

In addition, the state of the prepared polymer microspheres was confirmed through electron microscopy (SEM, Hitachi S-3000N, Japan, HV 20kv, Working Distance 15mm, Beam current 40).

6535 Residual Solvent Concentration According to Manufacturing Conditions in Manufacturing Polymer Microspheres Using 4.5A PLGA Manufacture conditions Residual EF (%) Residual EtOH (%) Step 1: heat to 33 ° C
Step 2: heat to 33 ° C 0.08 0.55 Step 1: do not heat
Step 2: do not heat 0.26 1.12

As a result, even when 6535 4.5A was used as shown in [Table 5], it was confirmed that the residual amounts of ethyl formate and ethanol were significantly reduced when the two-phase water temperature was maintained at 33 ° C.

In addition, as a result of photographing the polymer microspheres with an electron microscope, it was confirmed that the polymer microspheres in which 60 mg olanzapine was well encapsulated into the polymer microspheres were prepared (see FIG. 2).

<2-3> Comparison of Residual Solvent Concentration According to Dispersion Solvent Temperature in Redispersion Stages with High Polymer Usage

In the case of increasing the concentration of PLGA in the dispersed phase, it was examined whether the residual solvent concentration in the polymer microspheres can be reduced by changing the dispersion solvent temperature.

60 mg or 80 mg of olanzapine and 400 mg of 6535 4.5A PLGA were dissolved in 4 ml of ethyl formate to form a dispersed phase. Thereafter, polymer microspheres were prepared in the same manner as in <Example 2-1>, and the residual solvent concentration was measured in the same manner as in <Example 1>.

Two-step temperature in the above process is as described in [Table 6].

6535 Residual Solvent Concentration According to Manufacturing Conditions in Manufacturing Polymer Microspheres Using 4.5A PLGA Batch name 2 stage temperature (℃) Olanzapine amount (mg) Ethyl Formate Residue% Ethanol residual% One 33 60 0.91 0.13 2 33 80 1.43 0.1 or less 3 40 60 0.1 or less 0.1 or less 4 40 80 0.1 or less 0.1 or less 5 50 60 0.1 or less 0.1 or less 6 50 80 0.1 or less 0.1 or less

As a result, as shown in [Table 6], even when the amount of PLGA was increased to 400 mg, it was confirmed that the concentration of the residual solvent could be kept low when the temperature was maintained at 40 ° C. or higher.

In addition, the state of the polymer microspheres of batch No. 3 and 4 in Table 6 was confirmed by electron microscopy (SEM, Hitachi S-3000N, Japan, HV 20kv, Working Distance 15mm, Beam current 40).

As a result, it was confirmed that the polymer microspheres encapsulated with the administered olanzapine were prepared (see FIG. 3).

< Example  3>

Mixed with dispersion solvent Water insoluble  Residual solvent concentration comparison experiment according to the organic solvent concentration 1

When the organic solvent was previously added to the dispersion solvent in <Example 1>, it was confirmed that the concentration of the residual organic solvent was lowered. Accordingly, while maintaining the dispersion solvent temperature of the redispersion step, the amount of the water-insoluble organic solvent mixed in the dispersion solvent was changed and the amount of the residual solvent was measured and compared.

500 mg of 4.5A PLGA (Lactide: Glycolide = 85: 15, 0.45 dL / g, SurModics Pharmaceuticals Co., USA) is dissolved in 4 ml of ethyl formate to form a dispersed phase, which is then dispersed in 0, 1, 2 or 4 ml of ethyl fort. Emulsions were made by emulsifying each of 20 ml of 0.5% PVA aqueous solution to which the mate was previously added. Thereafter, 6.2 ml of 10N NaOH was added to induce a reaction for 30 minutes, thereby preparing polymer microspheres. The polymer microspheres were separated and redispersed and stirred in 80 ml of 0.1% PVA at 40 ° C., and the polymer microspheres were separated and dried in vacuo.

After preparing the polymer microspheres, the residual solvent was measured in the same manner as in <Example 1>, and the polymer microspheres prepared in the same manner as in <Example 2-2> were photographed.

As a result, as shown in FIG. 4, it was confirmed that the concentration of the solvent remaining in the polymer microspheres decreased as the concentration of the organic solvent added in advance to the dispersion solvent increased. In addition, as shown in FIG. 5, the spherical polymer microspheres are stably prepared even when the organic solvent is added to the dispersion solvent in advance, and the size of the polymer microspheres prepared is decreased as the concentration of the organic solvent added in advance to the dispersion solvent increases. It was confirmed.

< Example  4>

Comparison of Residual Solvent Concentration According to the Ratio of Disperse Phase and Dispersion Solvent

<4-1> Polymer by changing the ratio of dispersed phase and solvent Microsphere  Produce

In order to determine the change of the amount of residual solvent according to the change of the ratio of the dispersed phase and the dispersed solvent, the ratio of the dispersed phase (O) and the dispersed solvent (W) is 1:10, 1: 6 or 1: Adjusted to 4 to prepare a polymer microspheres, respectively. The proportion of the dispersed phase and the solvent was adjusted to adjust the amount of the powder phase or the amount of the dispersed solvent, respectively. In addition, the organic solvent constituting the dispersed phase was also tested using ethyl acetate and ethyl formate, respectively, and the solvent decomposition reagent was also tested using NaOH and ammonia, respectively.

O / W ratio and solvent decomposition method used in the experiment O / W ratio Disperse phase ( ml ) Dispersion solvent ml ) Solvent Decomposition EA -One 1: 4 40 160 NaOH EA -2 1: 6 27 160 NaOH EA -3 1:10 16 160 NaOH EA -4 1: 6 27 160 NaOH EA -5 1: 4 16 64 NaOH EA -6 1: 6 16 96 NaOH EF -One 1: 4 42.5 170 NH3 EF -2 1: 6 28.3 24 NH3 EF -3 1:10 17 170 NH3 EF -4 1: 4 17 68 NH3 EF -5 1: 6 17 102 NH3 EF -6 1: 4 40 160 NaOH EF -7 1: 6 27 160 NaOH EF -8 1:10 16 160 NaOH EF -9 1: 4 16 64 NaOH EF -10 1: 6 16 96 NaOH

1 g of polymer blend (4A: 2A = 6: 4) and 0.333 g of olanzapine were added, an equivalent amount of ethyl acetate or ethyl formate was added thereto, followed by complete dissolution. Then, 0.5% PVA was added thereto and stirred at room temperature. Polymeric microspheres were prepared by adding the equivalent of 10M NaOH or ammonia solution and stirring for 30 minutes. The prepared polymer microspheres were obtained by filtration and redispersed in 0.1% PVA, stirred, washed with distilled water and lyophilized.

<4-2> manufactured polymer Microsphere  Yield and residual solvent measurement

The residual solvent of the polymer microspheres prepared in <Example 4-1> was measured in the same manner as in <Example 1>.

The yield of the polymer microspheres is obtained by placing the polymer microspheres recovered in a weighing dish in advance and measuring the weight after vacuum drying to obtain the weight of the recovered polymer microspheres by the following equation.

Yield (%) = (weight of recovered polymer microspheres) / (sum of polymer and drug weight used in manufacturing) X 100

Yield and residual solvent amount of the prepared polymer microspheres Residual solvent
amount(%) yield
(%) EA EtOH EA -One 0.023 1.273 62.5 EA -2 0.058 1.249 38.9 EA -3 1.289 0.180 79.8 EA -4 0.113 0.997 53.9 EA -5 0.057 0.506 54.5 EA -6 0.133 0.366 68.6 EF -One 0.249 0.199 66.8 EF -2 0.048 0.027 26.3 EF -3 1.486 0.136 92.6 EF -4 0.530 0.070 77.9 EF -5 0.210 N.D. 62.0 EF -6 N.D. 1.281 43.5 EF -7 0.020 0.192 44.3 EF -8 0.365 N.D. 71.0 EF -9 0.227 0.714 52.2 EF -10 0.739 0.562 59.5

As a result, as shown in [Table 8], when the ratio of the dispersed phase and the solvent is 1: 4 or 1: 6, the residual amount of the used solvent (EA or EF) is reduced compared to the case of 1:10, but the residual amount of ethanol It was confirmed to increase. It was confirmed that there was no difference in controlling the ratio of the dispersed phase and the dispersion solvent according to which of the amount of the powder phase and the amount of the dispersion solvent was adjusted.

< Example  5>

Changes in Polymer Microspheres with the Changes of Dispersed Phase and Dispersion Solvent Ratio, Preconcentration of Organic Solvents, and Temperature during Redispersion

<5-1> polymer Microsphere  Preparation and Residual Solvent Measurement

In the above <Example 1> to <Example 4> the concentration of the water-insoluble organic solvent mixed in the dispersion solvent, the residual solvent temperature change in the redispersion step (second step) and the ratio of the dispersion phase and the dispersion solvent in the residual solvent The concentration of was measured.

Reflecting all these factors, polymer microspheres were prepared and the residual solvent concentration was measured.

The dispersed phase used a solution in which 250 mg of 4.5A PLGA was dissolved in 4 ml of ethyl formate. As a dispersion solvent, 20, 30, 40 ml of 0.5% PVA was used, and the water-insoluble organic solvent (ethyl formate) previously added to the dispersion solvent was added from 0 ml to 4 ml depending on the amount of the dispersion solvent. Solvent decomposition was performed using 10N NaOH, which was calculated to be added in a 1: 1 equivalent amount considering the total amount of ethyl formate added. In the preparation of the polymer microspheres, the reaction proceeds at room temperature until the step of terminating the reaction by adding a base or an acid solution (step 1), and terminating stirring by re-dispersing the polymer microspheres separated through filtration into the PVA solution ( 40 ° C. was maintained until step 2).

Residual solvent analysis of the prepared polymer microspheres was measured in the same manner as in <Example 1>. The same manufacturing process and residual solvent analysis were repeated twice to indicate all of the values.

Residual Solvent Amount of Prepared Polymeric Microspheres One
step
Room temperature
(RT)
to
maintain Dispersion solvent
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Residual EF (%) Residual Ethanol (%) #One #2 #One #2 20 0 0.175 0.113 0.063 0.080 One 0.053 0.015 0.044 0.049 2 0.036 0.006 0.044 0.056 30 0 0.285 0.291 0.038 0.052 One 0.156 0.119 0.056 0.052 2 0.059 0.028 0.037 0.032 3 0.042 0.020 0.078 0.041 40 0 0.932 1.204 0.058 0.105 One 0.231 0.225 0.038 0.053 2 0.164 0.079 0.040 0.043 3 0.111 0.061 0.055 0.042 4 0.040 0.038 0.023 0.112

As a result, as shown in [Table 9], it was confirmed that the concentration of the residual solvent decreased when the ethyl solvent was added to the dispersion solvent as compared with the case where no ethyl formate was added at all. In particular, the ratio of the dispersed phase and the dispersion solvent was 1:10. (Dispersion solvent PVA amount 40ml) When EF was not added to the dispersion solvent in advance, it was confirmed that the amount of the residual solvent increases.

<5-2> polymer Microsphere Yield  Measure

The yield of the polymer microspheres prepared in Example 5-1 was measured. The measurement was carried out in the same manner as in <Example 4-2>.

As a result, as shown in [Table 10], it was confirmed that there was no problem in the yield of the polymer microspheres under all conditions.

Yield of prepared polymer microspheres One
step
Room temperature
(RT)
to
maintain Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Yield (%) #One #2 20 0 79.56 70.24 One 66.48 63.88 2 76.68 66.52 30 0 69.96 70.24 One 40.04 75.76 2 77.56 74.64 3 88.28 74.16 40 0 67.68 72.4 One 67.28 82.8 2 39.6 82.2 3 77.04 79.64 4 55.96 77.92

<5-3> polymer Microsphere  4.5A before and after manufacture PLGA Change in molecular weight of GPC )

In order to measure the molecular weight change of PLGA in the polymer microspheres prepared in <Example 5-1>, the molecular weight of 4.5A PLGA before and after polymer microspheres was measured by gel permeation chromatography (GPC). .

For GPC, Agilent 1100 (Agilent Technologies, Inc, USA) was used, and tetrahydrofuran was used as the mobile phase. The analytical column was PLgel 5um 100Å 79911GP-504 manufactured by Agilent, and the flow rate was maintained at 1 ml / min. Standard laboratories (molecular weight: 3390000, 1290000, 426600, 151700, 72200, 28500, 9860, 4950, 1300) of Polymer Laboratories were used to prepare the standard calibration curve. Assay samples were used by filtering 8 mg of polymer microspheres in 2 ml of tetrahydrofuran. GPC injection amount was 50ul.

Standard calibration curves as shown in FIG. 6 were obtained using standard products. Based on this, the molecular weight of 4.5A PLGA and 4.5A PLGA of the prepared polymer microspheres were determined. As a result, as shown in [Table 11], the molecular weight of 4.5A PLGA of the polymer microspheres of the present invention was 55421 to 58409, and it was confirmed that no significant change was observed compared to 57542, which is 4.5A molecular weight before manufacture.

As a result, it was confirmed that the polymer microspheres of the present invention did not exhibit decomposition of the 4.5A PLGA polymer.

Molecular weight comparison of 4.5A PLGA One
step
Room temperature
(RT)
to
maintain Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) GPC Mw Polydispersity 20 0 57901 1.4594 One 57294 1.5004 2 55743 1.5865 30 0 57498 1.5405 One 55573 1.6392 2 57486 1.5552 3 55421 1.649 40 0 57788 1.4495 One 57704 1.5207 2 57994 1.5454 3 57423 1.4922 4 58409 1.4399 4.5A PLGA before microsphere manufacturing 57542 1.6122

< Example  6>

Olanzapine  Containing polymer Microsphere  Produce

<6-1> Olanzapine  Containing polymer Microsphere  Produce

Olanzapine-containing polymer microspheres were prepared under the conditions according to [Table 12].

After dissolving 60 mg of olanzapine and 250 mg of 4.5A PLGA in 4 ml of ethyl formate, the dispersion phase was emulsified by putting into an dispersion solvent (0.5% PVA) previously added with ethyl formate according to [Table 12]. Then, 10N NaOH solution was added to cause a reaction for 30 minutes, distilled water was added, and the polymer microspheres were separated by filtration. The separated polymer microspheres were redispersed in 0.1% PVA solution and dried in vacuo. In the preparation of the polymer microspheres, the reaction proceeds at room temperature until the step of terminating the reaction by adding a base or an acid solution (step 1), and terminating stirring by re-dispersing the polymer microspheres separated through filtration into the PVA solution. 40 ° C. was maintained until step 2).

Olanzapine-containing polymer microspheres production conditions One
step
Temperature PLGA Class Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Olanzapine (mg) 2
step
Temperature menstruum
For disassembly
NaOH Room temperature
(RT) 6535DLG4.5A 30 2 60 40 ℃ 7.4 3 60 40 ℃ 8.6 40 3 60 40 ℃ 8.4 4 60 40 ℃ 9.6

<6-2> Residual solvent , Olanzapine Inclusion rate  And polymers Microsphere Yield  Measure

The residual solvent amount of the polymer microspheres prepared in <Example 6-1> was measured in the same manner as in <Example 1>.

The yield of the prepared polymer microspheres was calculated according to the following equation after weighing the polymer microspheres prepared in a drying container by lyophilization.

Yield (%) = (Polymer Microsphere Weight) / (Sum of Polymer and Drug Weight Used in Manufacturing) X 100

The encapsulation amount and the encapsulation rate of the prepared polymer microspheres were measured as follows.

10 mg of the dried polymer microspheres were dissolved in an acetonitrile: water = 50: 50 (v / v) solution, and then diluted in an appropriate multiple. After the filter was analyzed by UPLC (Ultra Performance Liquid Chromatography), the amount of inclusion and the rate of inclusion were calculated. The UPLC analyzer used ACQUITY from Waters (Germany), and the column was HSS C18 (Waters ACQUITY UPLC, Germany). The mobile phase was used as a mixture of ammonium acetate buffer and acetonitrile 50:50, the diluent used a mixture of acetonitrile and water 50:50.

Fill amount (%) = (detected drug weight / microsphere weight) X 100

Inclusion Rate (%) = Inclusion Amount / (Theoretical Inclusion Amount) X 100

Theoretical loading (%) = (weight of drug used in manufacturing) / (sum of polymer and drug used in manufacturing) X 100

As a result, the amount of residual solvent was kept low as shown in [Table 13], and it was confirmed that the encapsulation rate and yield were mostly good as 70% or more as shown in [Table 14].

Residual Solvent Amount of Prepared Polymeric Microspheres One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Residual EF (%) Residual Ethanol (%) #One #2 #One #2 Room temperature
(RT) 30 2 0.023 0.006 0.199 0.163 3 0.013 0.003 0.168 0.116 40 3 0.022 0.011 0.208 0.140 4 0.013 0.014 0.201 0.145

Encapsulation rate and yield of the prepared polymer microspheres One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Inclusion Rate (%) Yield (%) #One #2 #One #2 Room temperature
(RT) 30 2 80.719 76.789 73.613 72.616 3 80.215 69.635 74.226 72.958 40 3 80.858 74.364 71.613 75.723 4 74.205 68.040 72.613 75.942

<6-3> polymer Microsphere  4.5A before and after manufacture PLGA  Molecular weight change ( GPC )

In order to measure the change in molecular weight of PLGA in the polymer microspheres prepared in <Example 6-1>, the molecular weight of 4.5A PLGA before and after polymer microspheres was measured by gel permeation analysis (GPC).

The measurement was performed in the same manner as in <Example 5-3>.

As a result, as shown in [Table 15], it was confirmed that the molecular weight of 4.5A PLGA was reduced by 50% or more before and after the preparation of the polymer microspheres. As confirmed in <Example 5-3>, when olanzapine was not contained, there was no molecular weight change. Therefore, it was found that olanzapine is involved in the ester bond decomposition of the polymer during the preparation of the polymer microspheres.

Molecular weight comparison of 4.5A PLGA One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) GPC Mw Polydispersity Room temperature
(RT) 30 2 24746 1.994 3 24456 2.0477 40 3 27685 1.9483 4 27732 1.8286 4.5A PLGA before microsphere manufacturing 56694 1.6061

<6-4> Polymer when 1st stage temperature is maintained at 4 ℃ Microsphere  4.5A before and after manufacture PLGA  Molecular weight change, Inclusion rate  And Yield  Measure

The organic solvent and PLGA can be decomposed by the same mechanism by the base. However, since the amount of the organic solvent is larger than PLGA and is extremely low molecular weight, the decomposition by the added base mostly degrades the organic solvent. However, when the temperature is high when reacting with the base, the flexibility of the PLGA may be increased, and the difference in reactivity between the organic solvent and the PLGA may be reduced. In view of this, the experiment was conducted in anticipation that the decomposition of PLGA could be prevented when the first stage temperature was lowered to 4 ° C.

According to the method for preparing polymer microspheres of the present invention, olanzapine-containing polymer microspheres were prepared under the conditions according to [Table 16].

Conditions for Preparation of Olanzapine-Containing Polymer Microspheres2 One
step
Temperature PLGA Class Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Olanzapine
(mg) 2
step
Temperature menstruum
For disassembly
NaOH 4 ℃ 6535DLG4.5A 20 One 60 40 ℃ 6.2 2 60 40 ℃ 7.4 30 3 60 40 ℃ 8.6 40 4 60 40 ℃ 9.6

4.5A PLGA molecular weight change was measured before and after the preparation of the polymer microspheres in the same manner as in <Example 6-3> with respect to the polymer microspheres prepared according to the conditions of [Table 16].

As a result, as shown in [Table 17], 4.5A PLGA molecular weight reduction was confirmed to decrease to 10% or less.

Molecular weight comparison of 4.5A PLGA One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) GPC Mw Polydispersity 4 ℃ 20 One 51752 1.6803 2 50594 1.5895 30 3 54116 1.5211 40 4 49362 1.7797 4.5A PLGA before microsphere manufacturing 56694 1.6061

In addition, the encapsulation rate and yield were measured in the same manner as in <Example 6-4> of the polymer microspheres prepared according to the conditions of [Table 16].

As a result, as shown in [Table 18], the encapsulation rate and the yield were mostly 70% or more, which was as good as in the case of room temperature.

As a result, it was confirmed that the olanzapine-containing polymer microspheres of the present invention can be produced by keeping the temperature of the first step low.

Olanzapine inclusion rate analysis and polymer microsphere yield One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Inclusion Rate (%) Yield (%) #One #2 #One #2 4 ℃ 20 One 78.803 76.834 75.581 75.552 2 83.261 82.174 72.355 77.968 30 3 82.852 78.537 73.258 74.474 40 4 78.879 74.754 68.484 73.000

< Example  7>

Ethyl acetate Water insoluble  Organic solvent Olanzapine  Containing polymer Microsphere  Produce

<7-1> Olanzapine  Containing polymer Microsphere  Produce

Olanzapine-containing polymer microspheres were prepared using the water-insoluble organic solvent (ethyl formate) and other water-insoluble organic solvents used in Example 6.

The water-insoluble organic solvent used was ethyl acetate (EA), and the preparation conditions were prepared under the conditions shown in [Table 19].

After dissolving 60 mg of olanzapine and 250 mg of 4.5A PLGA in 4 ml of ethyl acetate, the dispersed phase was emulsified in an emulsion of 0.5% PVA to which ethyl acetate was added, prepared according to [Table 19]. Then, 10N NaOH solution was added to cause a reaction for 30 minutes, distilled water was added, and the polymer microspheres were separated by filtration. The separated polymer microspheres were redispersed in 0.1% PVA solution and dried in vacuo. In the preparation of the polymer microspheres, the step of terminating the reaction by adding a base or an acid solution (step 1) proceeds at 4 ° C. After completion of the reaction, the polymer microspheres separated through filtration are redispersed in a PVA solution to terminate stirring. It maintained 40 degreeC until (step 2).

Olanzapine-containing polymer microspheres production conditions One
step
Temperature PLGA Class Dispersion solvent
PVA
Volume (ml) The amount of EA added in advance to the dispersion solvent (ml) Olanzapine (mg) 2
step
Temperature menstruum
For disassembly
NaOH (ml) 4 ℃ 6535DLG4.5A 30 2 60 40 ℃ 7.4 3 60 40 ℃ 8.6 40 3 60 40 ℃ 8.4 4 60 40 ℃ 9.6

<7-2> Residual solvent , Olanzapine Inclusion rate  And polymers Microsphere Yield  Measure

The residual solvent amount of the polymer microspheres prepared in <Example 7-1> was measured in the same manner as in <Example 1>.

The measurement was performed by the same method as in <Example 6-2>.

As a result, the amount of residual solvent was kept low as shown in [Table 20], and the sealing rate and yield were as shown in [Table 21], and most of the sealing rate was 85% or more, and the yield was mostly 70% or more. .

Residual Solvent Amount of Prepared Polymeric Microspheres One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Residual EA (%) Residual Ethanol (%) #One #2 #One #2 4 ℃ 30 2 0.151 0.153 0.513 0.410 3 0.134 0.120 0.578 0.506 40 3 0.085 0.091 0.280 0.242 4 0.129 0.130 0.310 0.458

Encapsulation rate and yield of the prepared polymer microspheres One
step
Temperature Dispersion solvent
PVA
Volume (ml) Amount of EF added in advance to the dispersion solvent (ml) Inclusion Rate (%) Yield (%) 4 ℃ 30 2 90.952 71.05 3 88.892 71.45 40 3 85.335 75.71 4 88.993 67.32

< Example  8>

Olanzapine  Containing polymer Microsphere  Pharmacokinetic Test

<8-1> Olanzapine  Containing polymer Microsphere  Produce

According to the composition of Table 22, olanzapine-containing polymer microspheres were prepared using various PLGA.

1000 mg PLGA and olanzapine were dissolved in an organic solvent (ethyl formate) to prepare a dispersed phase. The ratio of the dispersed phase to the solvent was 1: 5, and the solvent was mixed with 0.5% PVA in a ratio of 10: 1 ethyl formate. After dispersing the emulsion into a dispersion solvent cooled to 4 ℃ to prepare an emulsion, 10M NaOH was administered according to [Table 22] and the reaction was induced for 30 minutes to prepare a polymer microspheres. The resulting polymer microspheres were washed with distilled water, redispersed in a 0.1% PVA solution at 40 ° C. and stirred, and the polymer microspheres were separated and dried in vacuo.

The state of the prepared polymer microspheres was confirmed by electron microscopy (SEM, Hitachi S-3000N, Japan, HV 20kv, Working Distance 15mm, Beam current 40).

Composition of olanzapine-containing polymer microspheres Manufacturing number PLGA type (1000 mg) Dispersion solvent
(ml) Olanzapine
(mg) NaOH amount 0.5%
PVA One 8515 4.5E 30 667 56 150 2 100 DL 2E 30 667 56 150 3 100 DL 4.5E 30 667 56 150 4 100 DL 2E 10 240 18.6 50

As a result of electron microscope observation, it was confirmed that olanzapine was well encapsulated into the polymer microspheres and all the polymer microspheres were spherically prepared (see FIG. 7).

<8-2> Scanning  And dispersibility test

The olanzapine-containing polymer microspheres prepared in Example 8-1 were suspended in physiological saline containing carboxymethyl cellulose (CMC) and Tween 20 at a concentration of 30% (w / v), and then 1 ml using a 19G needle syringe. Were sucked into the syringe and flushed again to see if injection was possible.

As a result, as shown in [Table 23], it was confirmed that the olanzapine-containing polymer microspheres of the present invention had good injectability and dispersibility.

Scanning and Dispersion Test Results Manufacturing number Evaluation results One + 2 + 3 +

<8-3> Olanzapine  Containing polymer Microsphere  Sustainability Assessment

The olanzapine-containing polymer microspheres prepared in Example 8-1 were suspended in an excipient solution (saline containing carboxymethyl cellulose and Tween 20) and administered by intramuscular injection at 40 mg / kg in 9-week-old female SD rats. It was. Thereafter, blood was collected at predetermined times to measure the concentration of olanzapine in the blood.

As a result, as shown in [8] and [9], it was confirmed that the olanzapine-containing polymer microspheres of the present invention release the olanzapine up to 80 days.

< Formulation example  1> Preparation of Injection

Olanzapine-containing polymer microspheres 20 mg

Carboxymethyl Cellulose (CMC) 30 mg

Polysorbate 20 (twin 20) 1.5mg

Physiological saline for injection 2949 mg

According to the conventional method for preparing an injection, the amount of the above-mentioned ingredient was prepared per ampoule (3 ml).

Accordingly, the present invention provides a schizophrenia comprising olanzapine-containing polymer microspheres prepared by a method comprising mixing a water-insoluble organic solvent and a dispersion solvent and removing the water-insoluble organic solvent from an emulsion using a base or an acid. It provides a pharmaceutical composition for the treatment or prevention of bipolar disorder and central nervous system diseases. The production method of the present invention does not require a conventional solvent evaporation or solvent extraction process, and can easily prepare the olanzapine-containing polymer microspheres in a short time while minimizing the generation of wastewater using a small amount of water and in the prepared polymer microspheres It is possible to keep the concentration of residual solvent low and to prevent the decomposition of the polymer compound during the manufacturing process, which is effective in the manufacture of sustained-release pharmaceutical products, and thus has high industrial applicability.

Claims (17)

(a) mixing a water-insoluble organic solvent and a dispersion solvent;
(b) mixing the high molecular compound, olanzapine and a water-insoluble organic solvent to form a dispersed phase;
(c) O / W (oil-in-water), O / O (oil-in-oil) by mixing the dispersed phase of step (b) with the dispersion solvent mixed with the water-insoluble organic solvent of step (a) Preparing a) -type or water-in-oil-in-water (W / O / W) type emulsion, and maintaining the temperature of the emulsion at 0 ° C to 10 ° C; And
(d) removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the emulsion prepared in step (c) at 0 ° C to 10 ° C.
Schizophrenia and related psychoses, bipolar mania, bipolar disorders, seizures, obsessive / compulsive disorders, including For the treatment or prevention of symptoms selected from the group consisting of generalized anxiety disorder, post traumatic distress syndrome, extreme shyness, diabetic nerve pain and depression Pharmaceutical compositions.
(a) mixing a water-insoluble organic solvent and a dispersion solvent;
(b) mixing the high molecular compound, olanzapine and a water-insoluble organic solvent to form a dispersed phase;
(c) O / W (oil-in-water), O / O (oil-in-oil) by mixing the dispersed phase of step (b) with the dispersion solvent mixed with the water-insoluble organic solvent of step (a) Preparing a) -type or water-in-oil-in-water (W / O / W) type emulsion, and maintaining the temperature of the emulsion at 0 ° C to 10 ° C;
(d) removing the water-insoluble organic solvent from the emulsion by adding a base or an acid while maintaining the emulsion prepared in step (c) at 0 ° C to 10 ° C; And
(e) obtaining the polymer microspheres from which the water-insoluble organic solvent prepared in step (d) is removed and redispersing in a warmed dispersion solvent
Schizophrenia and related psychoses, bipolar mania, bipolar disorders, seizures, obsessive / compulsive disorders, including For the treatment or prevention of symptoms selected from the group consisting of generalized anxiety disorder, post traumatic distress syndrome, extreme shyness, diabetic nerve pain and depression Pharmaceutical compositions.
The method of claim 1 or 2, wherein the polymer compound is polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide (PLGA), polyphosphazine, polyiminocarbonate, poly Phosphoesters, polyanhydrides, polyorthoesters, copolymers of lactic acid and caprolactone, polycaprolactones, polyhydroxyvalates, polyhydroxybutyrates, polyamino acids, copolymers of lactic acid and amino acids, and mixtures thereof Compositions selected from the group consisting of.
The composition of claim 1 or 2, wherein the high molecular compound is polylactide-co-glycolide (PLGA).
The composition of claim 1 or 2, wherein the water-insoluble organic solvent of step (b) is the same as the water-insoluble organic solvent of step (a).
The composition of claim 1 or 2, wherein the step (c) comprises a ratio of 1: 3 to 100 of the dispersion solvent in which the dispersed phase of step (b) and the water-insoluble organic solvent of step (a) are mixed. .
According to claim 1 or 2, wherein the step (c) is a composition characterized in that the ratio of the dispersed solvent of the dispersed phase of step (b) and the water-insoluble organic solvent of step (a) is 1: 4-20. .
The composition of claim 2, wherein the temperature of the heated redispersion solvent of step (e) is in the range of 20 ° C to 80 ° C.
The composition of claim 2, wherein the temperature of the heated redispersion solvent of step (e) is 30 ° C to 50 ° C.
The method of claim 1 or 2, wherein the water-insoluble organic solvent is an acid halogen, anhydride, phosphoric anhydride, ester, carboxylic ester a water-insoluble organic solvent having any one structure selected from the group consisting of esters, phosphoric esters, sulfuric acid esters, nitric acid esters, boric acid esters, amides and carboxylic amides. Composition.
According to claim 1 or 2, wherein the water-insoluble organic solvent is methyl acetate, ethyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate ), Methyl formate, ethyl formate, isopropyl formate, propyl formate, butyl formate, methyl dichloroacetate ), Methyl chloroacetate, ethyl chloroacetate, ethyl dichloroacetate, methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate (ethyl fluoroacetate), ethyl difluoroacetate, maleic anhydride (m aleic anhydride, acetic anhydride, propionic anhydride, phosphoric anhydride, acetamide, propionamide, butylamide And carboxyl amide (carboxyl amide) characterized in that the composition selected from the group consisting of.
The method of claim 1 or 2, wherein the dispersion solvent is an aqueous polyvinyl alcohol solution, a polysorbate-based aqueous solution or an aqueous dispersion solvent thereof, or glycerin esters of fatty acids, lecithin and A composition characterized in that the non-aqueous dispersion solvent selected from the group consisting of silicone oil, vegetable oil, toluene and xylene containing the same emulsifier.
The method of claim 1, wherein the base is sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium hydroxide (KOH), ammonium hydroxide (NH ₄ OH), copper hydroxide (Cu (OH) ₂ ), and Iron hydroxide (Fe (OH) ₃ ) The composition characterized in that it is selected from the group consisting of.
The method of claim 1, wherein the acid is hydrochloric acid (HCl), nitric acid (HNO ₃ ), sulfuric acid (H ₂ SO ₄ ), acetic acid (CH ₃ COOH), boric acid (H ₃ BO ₃ ), and carbonic acid (H _2). CO ₃ ) is selected from the group consisting of.
A pharmaceutical formulation comprising the pharmaceutical composition of claim 1.
The formulation of claim 15, wherein the pharmaceutical formulation is an injection.
The formulation of claim 16, wherein the injection is an intravenous, subcutaneous or intramuscular injection.

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