KR100497256B1 - Process to make a sustained release formulation - Google Patents

Abstract

The present invention is a sustained release type compound (I) containing a compound (A) having a structural formula (A) and a copolymer containing poly- (1) -lactic-glycolic-tartaric acid (P (1) LGT). Regarding the process for preparing the complex, wherein the amino group of compound (A) is ionically bound to the carboxyl group of P (1) LGT.

Description

  Process to make a sustained release formulation

           The present invention has a compound (A) having the following structural formula

And a compound (I) containing a copolymer containing poly- (1) -lactic-glycolic-tartaric acid (P (1) LGT), wherein the compound (A ) Amino group is ionically bound to the carboxyl group of P (1) LGT.

Many drug delivery systems have been developed, tested, and used to control in vivo release of pharmaceutical compositions. For example, polyesters such as poly (DL-lactic acid), poly (glycolic acid), poly (ε-caprolactone) and various other copolymers have been used to release physiologically active substances such as progesterone, They have been used in the form of microcapsules, films, rods (published by M. Chaesin and R. Langer, Biodegradable Polymers as Drug Delivery Systems, Decker, New York, 1990). By dosage form of the polymer / therapeutic composition, eg, subcutaneously or intramuscularly, the therapeutic agent is released over a certain time interval. Such biocompatible biodegradable polymer systems are designed such that captured therapeutic agents can diffuse out of the polymer matrix. By release of the therapeutic agent, the polymer degrades in vivo to avoid surgical removal of the implant. Although the factors contributing to polymer degradation are not well understood, the degradation of these polyesters is shown to be controlled by the proximity of the ester bonds to the non-enzymatic autocatalytic hydrolysis of the polymer component.

A few EPO publications and U.S. The patent discloses a polymer matrix design and its role in controlling the release ratio and extent of therapeutic agents in vivo.

For example, Deluca (EPO Publication No. 0 467 389 A2) describes the physical interaction between a biodegradable hydrophobic polymer and a protein or polypeptide. The composition formed is a mixture of hydrophobic polymer and therapeutic agent that, after being administered to a subject, delays its diffuse release from the matrix.

Hutchinson (U.S. Patent No. 4,767,628) regulated the release of a therapeutic agent by constant dispersion in a polymer device. This is because the agent has two phases: first, diffusion dependent on the dissolution of the drug from the surface of the agent; And secondly, sustained release controlled by the overlap of release by water soluble channels due to degradation of the polymer.

PCT publication WO 93/24150 discloses a sustained release formulation containing a peptide having a basic group and a carboxy terminated polyester.

U.S. Patent 5,612,052 describes cation exchange microparticles of typically carboxyl containing polyester chains in which a basic bioactive agent is immobilized to provide a controlled release system in an adsorptive gel-forming liquid polyester.

Compound (A) is U.S. Patents 5,552,520 are described and claimed.

Applicant's PCT Publication No. WO 97/40085 discloses a biodegradable polyester containing a lactic acid unit, a glycolic acid unit and a hydroxy-polycarboxylic acid unit such as tartaric acid or pamo acid and a process for preparing the polyester. Describe. More specifically, poly-lactide-glycolide-tartaric acid polymers are described whose ratios are each 65/33/2.

Applicant's PCT publication WO 94/15587 discloses an ionic conjugate of a bioactive peptide having at least one effective ionogenic amine and a polyester having free COOH groups. More specifically, polymers made from polycarboxylic acids are disclosed by reacting a copolymer with malic acid or citric acid. U.S. Patent 5,672,659 is a US national stage continuing application of WO 94/15587. U.S. Patent 5,863, 985 discloses U.S. Pat. Patent Application No. 5,672,659. Pending U.S. Application 09 / 237,405 discloses U.S. Pat. CIP of Patent No. 5,863,985, which preferably comprises a citric acid, ε-caprolactone and glycolide; A composition containing the polyester and polypeptide just mentioned; Polyesters which necessarily include citric acid in its absence; A composition containing the polyester and polypeptide just mentioned; And the aforementioned compositions in the form of rods selectively applied with biodegradable polymers.

Applicant's PCT publication WO 97/39738 describes a process for the preparation of microparticles of sustained release ionic conjugates as described in WO 94/15587.

The contents of the foregoing patents, applications and publications are fully incorporated herein.

The present invention relates to a preferred process for preparing a preferred embodiment of a sustained release ionic conjugate of a polymer and compound (A) characterized by a surprising and not easy result of completely releasing compound (A) from the conjugate. It is. Another advantage of the process of the present invention is that the solvent used has no side effects and can be utilized at a lower cost than conventionally known processes.

Brief description of the drawings

1 shows the in vivo release form of compound (A) from a sample of compound (I) in a dog, wherein the sample of compound (I) consists of about 11.25% of compound (A) and the polymer is 1- Lactide: glycolide: tartaric acid (72: 27: 1), and compound (I) is administered intramuscularly as microparticles. Spun sample refers to a sample of γ-ray spun compound (I) from a cobalt source.

    The present invention relates to a method for preparing compound (I), which is compound (A),

                                  (A) and a polymer, wherein the polymer comprises lactide units, glycolide units, and tartaric acid units, and the molar ratio of lactide units in the polymer comprises 71% to 73%; The molar ratio of glycolide units comprises 26% to 28%; The molar ratio of tartaric acid units comprises 1% to 3%; The amino group of compound (A) is ionically bound to the carboxyl group of the acid unit of the polymer; The preparation process is carried out in a mixture of acetonitrile and water, in which the weight ratio of acetonitrile to water is about 3 to 1, at a temperature of 0 ° C. to 5 ° C., respectively, until compound (I) is substantially produced. Reacting an aqueous solution of with a polymer or salts thereof.

Preferred production method of the above-mentioned production method is the temperature of the reaction mixture is 2.5 ℃; The preparation method additionally comprises the step of separating compound (I).

In another aspect, the present invention includes a process for preparing microparticles of compound (I) as described above, wherein the process comprises (I) in isopropyl alcohol to obtain microparticle dispersion of compound (I). Spraying an ethyl acetate solution of wherein the concentration of compound (I) in the ethyl acetate solution is from about 8% to about 12% (W / W); The dispersion ratio of the solution of compound (I) from the nebulizer with isopropyl alcohol is from about 4.9 ml to about 5.1 ml per minute; The setting cycle of the nebulizer is such that the nebulizer does not spit an ethyl acetate solution of compound (I); The volume of isopropyl alcohol is about 20 to about 30 times greater than the volume of ethyl acetate; The temperature of the isopropyl alcohol is from about -60 ° C to about -78 ° C; Warming the isopropyl alcohol from about 0 ° C. to about 22 ° C .; And separating the microparticles from isopropyl alcohol.

A more preferred process of the foregoing process is that the dispersion ratio is about 5 ml per minute and the volume of isopropyl alcohol is greater than about 20 compared to ethyl acetate.

More preferred processes of the foregoing process are those wherein the polymer comprises about 72% lactide units, about 27% glycolide units, and about 1% tartaric acid units.

A more preferred process of the foregoing process is that the microparticles have a size of about 10 micrometers to about 100 micrometers.

A more preferred process of the foregoing process is that the microparticles have a size of about 40 micrometers to about 70 micrometers.

The term "about" as used herein with respect to displacement or amount means that the displacement or amount is within ± 5% of the described displacement or amount.

The term "microparticle" as used herein refers to micrometer sized particles of an ionic conjugate containing compound (A) and a poly-lactic-co-glycolic-co-L-(+)-tartaric acid polymer. It is desirable to be spherical.

The present application relates to standard three letter abbreviations known in the art, such as Phe = phenylalanine; Abu = α-aminobutyl acid is used to represent amino acids.

General course:

      Copolymer Formation: Copolymers consisting of L-lactide, glycolide and L (+)-tartaric acid can be prepared according to methods well known to those skilled in the art, as can be done here. Thus, monomers of steinus 2-ethyl hexanoate and glycolide, L-lactide and L (+)-tartaric acid are added dropwise to the reactor in toluene solution. Preferably the molar ratio of each L-lactide, glycolide and L (+)-tartaric acid is 72/27/1.

L (+)-tartaric acid is preferably dried for about 10 minutes on silica gel in an Abderhalden drying apparatus. The reactor is then stirred under vacuum to remove toluene. The reactor is then heated under an atmosphere of oxygen-free nitrogen, preferably immersed in an oil bath at a temperature = about 180 ° C. to 190 ° C., and the agitation increased to about 125 rpm. Prior to immersion, a heating tape (eg thermoin type 45500, input control setting = 4) is placed in the reactor lid. The time it takes for the reactor contents to dissolve completely can be seen, typically about 15 minutes for about 300 g of load at about 180 ° C. Samples are taken every hour during the synthesis and analyzed by GPC to determine the proportion of residual monomers and to obtain average molecular weight values by number (Mn) and weight (Mw) dispersion. Typical reaction time is about 9-15 hours. The final polymer is also analyzed by titration to determine the acid value in meq / g and the remaining unreacted monomer content by GC. Furthermore, the analysis includes IR (detection of characteristic C═O peaks); NMR (determination of lactide and glycoide content in the polymer) and residual tin (determination of residual tin due to the use of stanus 2-ethyl hexanoate as catalyst) ).

Refining / Sodium Salt Formation of the Copolymer: Residual monomer (typically less than 5% (W / W)) is removed in one step and the copolymer is converted to the form of sodium salt (to promote ionic salt formation) Poly-L-lactic-co-glycolic-co-L-(+)-tartaric acid copolymer (PLGTA) is dissolved in acetone by ultrasound in a sonication bath to a concentration in the range of 19-21% PLGTA by weight. Obtain a solution with

To this solution is added a weak solution of an inorganic base such as NaOH or Na ₂ CO ₃ , preferably 0.2 M sodium carbonate-the concentration of sodium obtained when Na ₂ CO ₃ is used is 1 to 2 times greater than that of the copolymer carboxyl groups. Preferably, more than 1.2 moles. The solution is stirred at room temperature for 15 to 60 minutes, preferably 30 minutes, to aid in sodium salt formation. Then it is fed at about 50-300 ml / min, preferably about 100 ml / min, to a jacketed reactor containing deionized water cooled to about 1 to 4 ° C., preferably 2.5 ° C., using a circulating bath; The amount of water is in excess of about 20 to 30 times the volume of acetone, preferably in excess of 20: 1 volume. A paddle connected to the stir motor is used to stir this water in sufficient proportion to allow surface alternating current to prevent polymer clumping between settlings.

When the precipitation is complete, the dispersion is stirred for 30 to 60 minutes to help remove the monomer before turning into a centrifuge. The supernatant is discarded and the cake is again suspended in more deionized water, turned again and dried, preferably frozen.

Preparation of Compound (A) Polymeric Ionic Conjugate: This synthesis comprises acetonitrile in a medium in which both are available, preferably 3; 1 (W / W); Compound (A) is bound to the copolymer sodium salt in water and the precipitate obtained in deionized water and the water insoluble precipitate formed are recovered.

12,000 MW in acetonitrile added so that the acetate salt solution of compound (A) in deionized water is a weak base, preferably 0.5 M Na ₂ CO ₃ , more than about 1.05 molar Na of the acetate content of the compound (A) acetate salt. / 28/1 to 73/26/1 was added to a solution consisting of a washed Na salt of PLGTA and stirred for about 5 minutes to bring the alkaline environment, preferably pH 8, to neutralize the acetate groups of compound (A) . The approximate weight ratio of acetonitrile: water is 3: 1. Based on the desired target loading (typically about 8% to about 12%), the amount of compound (A) required is determined. From this the volume of aqueous sodium carbonate required to neutralize the acetate of compound (A) is determined, and finally the desired final acetonitrile: water (added sodium carbonate) having a volume of water for dissolution of compound (A) of about 3: 1. In the volume ratio).

The compound (A) -copolymer solution is stirred at about 0 to 5 ° C., preferably at 2.5 ° C. for about 10 to 15 minutes to promote ionic bonds and inhibit covalent bonds (by use of low temperatures) between the two components. This solution is then fed to a solution of about 20-30 to more than 1 volume of 50-300 ml / min relative to the volume of acetonitrile: water acetonitrile of 3: 1 described above, providing surface agitation to provide agglomeration Stir at a sufficient rate to prevent and cool to about 1-4 ° C., preferably 1.7 ° C., in a jacketed reactor connected to a circulation bath.

When the precipitation is complete, the dispersion is further stirred for 30 to 60 minutes before being put into the centrifuge for about 15 minutes at 5000 rpm to obtain a low level of PLGTA, which is undesirable because the oligomer is water soluble. Molecular weight fraction). The centrifugal cake obtained is resuspended in deionized water and turned again. They are then frozen and dried by lyophilization for 2 days to recover compound (I) (compound (A) ionically bound to PLGTA). The dropwise addition is determined by HPLC and nitrogen analysis of the supernatant for unbound compound (A) (compound (A) nitrogen content is known and the polymer does not contain nitrogen in any case). Extraction of compound (A) from compound (I) following HPLC analysis also allows determination of the dropping.

Spray of Compound (I): Dissolve Compound (I) in ethyl acetate to provide the most suitable formulation for infusion into the patient and dissolve the solution of ethanol, isopropanol or hexane and isopropanol at about -60 ° C to -78 ° C. The mixture, preferably isopropanol, is sprayed and microspherically formulated using ultrasonic spray (aka spray) to formulate compound (I) into microspheres in contact with cold isopropanol and compound (I). Compound (I) / ethyl acetate solution can be sterilized by passing through a 0.2 μm filter.

Compound (I) is preferably dissolved in ethyl acetate by sonication / stirring to drop the polymer molecular weight and compound (I), both of which can change the solution viscosity, depending on the range of about 8% to about 12% ( Weight / weight) to obtain a solution. This solution is an industrial nebulizer (power-about 70%, amplification-about 80%, frequency-about 34-35 kHz; typically the nebulizer is a concentration of about 8% to a concentration of compound (I) / ethyl acetate solution to form a solid microsphere. At a concentration of about 12% (W / W), it must be strong enough to generate a frequency that can be sprayed (without a constant dose) and the frequency should be 40 to 20 so that it can be easily injected through a 21-gauge or 19-gauge needle. 70 micrometers should be obtained so that an average particle size can be obtained from about 4.90 mL / min to 5.10 mL / min, preferably 5.00 mL / min, and sprayed in a volume of isopropanol (IPA) and isopropanol Silver 20 to 30 times, preferably 20 times greater than the volume of ethyl acetate, and cooled to about -60 to -78 ° C, the cooling (e.g. addition of reactor jacket, addition of dry ice or insertion of cooling coils) through Can be achieved), (at least 200 rpm) to avoid microsphere coagulation. Deionized water at a temperature of about 6 [deg.] C. is preferably fed to the nebulizer at 1.5 L / min to remove local heating effects that may cause contamination of the nebulizer tip due to evaporation of ethyl acetate. The solution is sprayed uniformly to show that a grayish white particulate dispersion is formed in the IPA. It is thawed at about 0 ° C. to 22 ° C. over about 30 minutes to 2 hours (to remove large non-injectable agglomerates / particles), passed through a 125 μm sieve and vacuum filtered on Whatman First filter paper. The filter cake is further washed with IPA and then vacuum dried.

The invention is illustrated in detail by the following examples, but is not limited to these details.

Example 1

Step A: 300 g of P (1) LG / tartaric acid copolymer (1-lactide: glycolide: tartaric acid = 72: 27: 1)

Of glycolid (Purac Biochem, Netherlands, 68.71 g), lactide (Purac Biochem, Netherlands, 227.53 g) and L (+)-tartar acid (Ridel-De Han, Siltz, Germany, Article No. 33801, 3075 g) Toluene (Ridel-De Han, Siltz, Germany) solution (0.0982M, 4.47 mL) of monomer and steinus 2-ethyl hexanoate (Sigma, St. Louis, Mizouri, USA, Article No. S-3252) was reactor Drop on This corresponds to 71.81%; 26.82%; and 1.36% mole fraction of L-lactide, glycolide, and L (+)-tartaric acid, respectively.

L (+)-tartaric acid is pre-dried on silica gel (Ridel-De Han, Siltz, Germany) for 10 hours in an Abderhalden dryer. The reactor (connected to the pump via a liquid nitrogen trap) is then placed under vacuum (0.04 mbar) with stirring for about 50 minutes to remove toluene. The reactor is then immersed in an oil bath (temperature = -180 ° C.) under an acid-free nitrogen atmosphere (BOC gas, Dublin, Ireland, moisture content of 8 VPM) and the agitation is increased to 125 rpm. Prior to dipping, a heating tape (thermoline tea leaf 45500, input control setting = 4) is placed on the reactor lid. The time it takes for the reactor contents to dissolve completely can be seen, typically about 15 minutes for about 300 g of load at about 180 ° C. Samples are taken every hour during the synthesis and analyzed by GPC to determine the proportion of residual monomers and to obtain average molecular weight values by number (Mn) and weight (Mw) dispersion. Typical reaction time is about 15 hours. The final polymer is also analyzed by titration to determine the acid value in meq / g and the remaining unreacted monomer content by GC. Furthermore, the analysis includes IR (detection of characteristic C═O peaks); NMR (determination of lactide and glycolide content in the polymer) and residual tin (determination of residual tin due to the use of staininos 2-ethyl hexanoate as catalyst) ).

Step B: Purification / Sodium Salt Formation with the Copolymer

In one step, the residual monomer (typically less than 5% (w / w)) is removed and the copolymer is converted to the form of sodium salt (to enhance the ionic salt formulation). 81.05 g of 12,000 g / mol 72/27/1 poly-L-lactic-co-glycolic-co-L-(+)-tartaric acid copolymer (acid value with titration = 0.223 meq / g) In a bath (Branson, Danbury, Connecticut, USA) by sonication in 324.24 g acetone (Liedel-De Han, Siltz, Germany) to obtain a solution having a concentration of 20.00% PLGTA by weight.

To this solution was added 56.17 mL of 0.2 M NaOH (Aldrich, Gillingham, Dorsett, UK) and this gave 1.2 times more molar sodium than the copolymer carboxyl group. The solution is stirred at room temperature for 30 minutes to aid in sodium salt formation. It is then fed at -100 ml / min to a 10 L jacketed reactor containing 8.2 L of deionized water (approximately 20: 1 volume greater than acetone cooled to about 2.5 ° C). A paddle connected to the stir motor is used to stir this water in sufficient proportion to allow surface alternating current to prevent polymer clumping between settlings.

Once the precipitation is complete, the dispersion is stirred for an additional 30 minutes prior to running at 5000 rpm for about 15 minutes in a centrifuge pail (Dupont Soval, Wilmington, Delaware, USA) to aid in monomer removal. Discard the supernatant and resuspend the cake in more deionized water, run it again, freeze overnight in the freezer (-13 ° C.) and dry the next day in a small freeze dryer (Edward, Crowlay, West Success, UK). This lyophilizer does not include a cooling system. After 5 days lyophilized 65.37 g of the washed copolymer was recovered in a yield of 80.65%.

Step C: Preparation of Compound (I)

Acetate salt of 1.27 g of compound (A) in 5.87 g of deionized water (Batch No. 97K-5801 from Kinnerton, Ireland, titer = 85.8% (titer is free base peptide present in peptide acetate salt) Acetate = 10.87%) solution was added 24.84 g of acetonitrile to which 2.41 ml of 0.5 M Na ₂ CO ₃ (which is about 1.05 mole of Na above the acetate content of Compound (A) -acetate salt) was added. (Liedel de Hane) (24.38% (W / W)) was added to a solution consisting of 8.01 g of washed Na salt of 12,000 MW 71/28/1 to 73/26/1 PLGTA in solution, and acetate of compound (A) Stir for about 5 minutes to the alkaline environment (pH 8) to neutralize the group. The approximate weight ratio of acetonitrile: water is 3: 1. Based on the required target loading, the amount of compound (A) required is determined. From this the volume of aqueous sodium carbonate required to neutralize the acetate of compound (A) is determined, and finally the desired final acetonitrile: water (added sodium carbonate) having a volume of water for dissolution of compound (A) of about 3: 1. In the volume ratio).

Compound (A) -copolymer solution is stirred at about 2.5 ° C. for about 15 minutes to promote ionic bonding and inhibit covalent bonding between the two components. The solution is then added to ˜100 ml / min in 630 ml (more than about 20: 1 volume compared to acetonitrile) stirred at 350 rpm (to provide surface agitation to prevent compound (A) -copolymer agglomeration). Feed and cool to about 1.7 ° C. in a 6L jacketed reactor connected to a circulation bath.

When the precipitation is complete, the dispersion is stirred for 30 minutes before being run in a centrifuge pail for about 15 minutes at 5000 rpm in a fired centrifuge (Dupont Sobal, Wilmington, Delaware, USA). It is further stirred for 30 to 60 minutes before turning into a centrifuge for about 15 minutes at 5000 rpm to help remove the water-soluble compound (A) -oligomeric compound. The centrifugal cake obtained is resuspended in deionized water and turned again. They are then frozen and dried by lyophilization for 2 days. 8.30 g of the title product was recovered in 91.3% yield. The dropwise addition is determined by HPLC and nitrogen analysis of the supernatant for unbound compound (A) (compound (A) nitrogen content is known and the polymer does not contain nitrogen in any case). Extraction of compound (A) from compound (I) following HPLC analysis also allows the determination of dropping, which is 11.25% in this example.

Step D: Spraying Compound (I)

From step C 8.27 g of compound (I) is obtained in 12.00% (W / W) solution by sonication / stirring (room temperature) in 60.77 g of ethyl acetate. The solution was supplied at 5 ml / min to an industrial sprayer (Martin Walter Powersonic Model MW400GSIP, available from Sodeva, France) with power = 70%, amplification = 80%, frequency = 34.50 kHz, and in a jacketed reactor Sprayed to 1.35 L of isopropanol (IPA) (more than 20 times volume relative to ethyl acetate volume) cooled to about-74 ± 4 ° C. (cooling achieved through reactor jacket) and stirred at 200 rpm (to avoid microsphere coagulation) do. Deionized water is supplied to the sprayer jacket at 1.5 ° C. at a temperature of 6 ° C. to remove the local heating effect that ethyl acetate can cause contamination of the sprayer tip due to evaporation. The solution is sprayed uniformly to show that a grayish white particulate dispersion is formed in the IPA. It is thawed at about 0 ° C.-4 ° C. over about 30 minutes to 2 hours (to remove large non-injectable agglomerates / particles) through a 125 μm sieve and vacuum filtered on Whatman First filter paper. The filter cake is further washed with IPA and then vacuum dried. 6.88 g of injectable material are obtained with a yield of 83.19%. The microparticles of compound (I) have an average particle size of about 54 micrometers.

In vivo release of compound (A) from microparticles of compound (I) is possible and tested according to the following detailed description. To evaluate the in vivo release properties of compound (A) following intramuscular administration of microparticles of compound (I) to male beagle dogs, an in vivo study was designed by the nature of the pharmacokinetics of compound (A) following the administration. do.

 Pharmacological preparations of microparticles of compound (I) are administered intramuscularly into the hindlimb muscles. Single intramuscular administration of a pharmacological form prepared by radiation or non-radiation containing microparticles of compound (I) (compound (A) dropped to compound (I) is equivalent to 5 mg of compound (A) based on 11.23%) The amount of microparticles to be injected) is administered to each of six groups per pharmacological form, and then the amount of compound (A) and the pharmacokinetic analysis in the serum sample is performed as follows.

Blood collection from dogs was administered before injection (time 0) and 5, 15 and 30 minutes; 1, 2, 4, 8 and 12 hours; 1, 2, 3 and 4 days; And twice per week in the first month; And finally, once a week from the second month until the experiment is complete, ie, compound (A) is no longer detected at the serum level. However, the actual time of blood collection is recorded and used for drug analysis. A blood sample (5 ml) at time 0 (prior to intramuscular administration) and 7, 21, 35, 56 and 84 after intramuscular administration and a blood sample (4 ml) at the remaining sampling time were jugular or two Collect via vein.

Place the sample into two fractions: one to each of aprotinin solution of 50 and 80㎕ about 2.5㎖ 3.5㎖ or sampled over a period of time (Trad frozen silole ^ⓡ 500000KJU of the re-dissolved in dry 10㎖ number of ppi 2㎖ Place in a tube containing dehydrated) and place the other in about 1.5 ml.

      After erythrocytes are tangled, the tubes are centrifuged at + 4 ° C. 30000 r.p.m. for 20 minutes. Serum with aprotinin is removed and stored in two fractions at −20 ° C. until the sample is analyzed for compound (A).

      The concentration of compound (A) in the serum sample is analyzed by radioimmunoassay method. A standard curve is prepared daily with a blank dog plasma and compound (A) standard solution. In this method the limit of quantitation for Compound (A) in dog serum samples is about 0.050 nanograms (ng) / ml. The area under the curve (AUC) and the maximum serum concentration (Cmax) are normalized by the dose supplied (dose expressed in μg / kg administered to each animal). The index of absorption (Cmax / AUC) is also calculated.

The result of the experiment mentioned above is shown in FIG.

Compound (A) or a pharmaceutically acceptable salt thereof, Compound (I) or microparticles of Compound (I) may be oral, parenteral (eg, intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant ), Nasal, intravaginal, rectal, sublingual or topical routes of administration and may be formulated in a pharmaceutically acceptable carrier to provide the appropriate dosage form for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms the active compound may be mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms also typically include additional substrates in addition to inert diluents such as, for example, lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Tablets and rings can additionally be made with an enteric coating.

Liquid dosage forms for oral administration include elixirs containing inert diluents commonly used in the art, such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups, water. In addition to these inert diluents, the compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and flavoring agents.

Formulations for parenteral administration include sterile water or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or carriers are injectable organic esters such as vegetable oils such as propylene glycol, polyethylene glycol, olive oil and corn oil, gelatin, and ethyl oleate. Such dosage forms may also include adjuvants such as preservation, wetting, emulsifying, and dispersing agents. They can be sterilized by filtration through a bacteria-containing filter, by administration of a sterilant to the composition, by spinning the composition, or by heating the composition. They may also be prepared in sterile solid compositions that can be dissolved in sterile water, or other sterile injectable medium immediately before use.

Compositions for administration to the rectum or vaginal are preferably suppositories which may include excipients such as coca butter or suppository waxes in addition to the active substrate.

Compositions for administration into the nose or sublingual are also prepared with standard excipients well known in the art.

The fine particles of compound (I) are preferably administered through parenteral administration or oral administration.

The effective dosage of the microparticles of compound (I) administered to the patient can be determined by the attending physician or a specialist and the calculated appropriate dosage for compound (A) and the dropping of compound (A) in compound (I) Depends on the quantity. Such dosages are well known to those of ordinary skill in the art and may be determined. Preferably the dosage should be at a level of compound (A) of at least 200 picograms / ml to the patient.

Claims (7)

In the method for producing a sustained release complex containing a peptide and a polymer represented by the formula Wherein the polymer comprises lactide units, glycolide units and tartaric acid units and the molar ratio of lactide units in the polymer comprises 71% to 73%; The molar ratio of glycolide units comprises 26% to 28%; The molar ratio of tartaric acid units comprises 1% to 3%; The amino group of the peptide is ionically bound to the carboxyl group of the acid unit of the polymer; The preparation method is carried out in a mixture of acetonitrile and water in which the weight ratio of acetonitrile to water is about 3 to 1, at a temperature of 0 ° C. to 5 ° C., respectively, until the production of the sustained release complex is substantially completed. A method for producing a sustained release composite, comprising reacting an aqueous solution with a salt of the polymer. The method of claim 1, wherein the temperature is about 2.5 ° C .; The method for producing a sustained-release complex, characterized in that additionally comprises the step of separating the sustained-release complex. In the method of producing a sustained release complex containing a peptide and a polymer represented by the formula Wherein the polymer comprises lactide units, glycolide units and tartaric acid units and the molar ratio of lactide units in the polymer comprises 71% to 73%; The molar ratio of glycolide units comprises 26% to 28%; The molar ratio of tartaric acid units comprises 1% to 3%; The amino group of the peptide is ionically bound to the carboxyl group of the acid unit of the polymer; The process comprises spraying an ethyl acetate solution of the sustained release complex in isopropyl alcohol to obtain microparticle dispersion of the sustained release complex, wherein the concentration of the sustained release complex in the ethyl acetate solution is at about 8%. About 12% (W / W); The dispersion ratio of the solution of the sustained release complex from the nebulizer to isopropyl alcohol is from about 4.9 ml to about 5.1 ml per minute; The setting cycle of the nebulizer is such that the nebulizer does not spit out the ethyl acetate solution of the sustained release complex; The volume of isopropyl alcohol is about 20 to about 30 times greater than the volume of ethyl acetate; The temperature of the isopropyl alcohol is from about -60 ° C to about -78 ° C; Warming the isopropyl alcohol from about 0 ° C. to about 22 ° C .; And Method for producing a sustained release composite, characterized in that it comprises the step of separating the fine particles from isopropyl alcohol. 4. The method of claim 3, wherein the dispersion ratio is about 5 ml per minute and the volume of isopropyl alcohol is about 20 times greater than that of ethyl acetate. 5. The method of claim 4, wherein the polymer comprises about 72% lactide units, about 27% glycolide units, and about 1% tartaric acid units in molar ratio. 6. The method of claim 5, wherein the microparticles have a size of about 10 micrometers to about 100 micrometers. 7. The method of claim 6, wherein the microparticles have a size of about 40 micrometers to about 70 micrometers.