A bioabsorbable release-sustaining pharmaceutical formulation using a biodegradable release-sustaining base material which can prevent an effective component drug from being released too rapidly just after administration of the formulation and then allow continued release of the drug for at least one month at a defined rate, is provided. For the biodegradable release-sustaining base material, a lactic acid-glycolic acid copolymer (PLGA) with an adjusted distribution in molecular weight is used.

Description of the Invention

SUMMARY OF THE INVENTION

(Disclosure of the Invention)

(The Problems to be Solved by the Invention)

An object of the present invention is to provide a bioabsorbable pharmaceutical formulation which prevents an effective component drug from being released rapidly just after the administration of the formulation, thereby allowing continued release of the drug for at least a month at a defined rate.

[Means for Solving the Problem]

The present inventors made a detailed study to solve the above problem, and, as a result, have found that a lactic acid-glycolic acid copolymer with an adjusted distribution in molecular weight can be used as a biodegradable release-sustaining base material to solve the problem, and thus completed the present invention.

Therefore, various embodiments of the present invention are as follows:

1. A bioabsorbable pharmaceutical formulation comprising a lactic acid-glycolic acid copolymer and a drug, wherein the lactic acid-glycolic acid copolymer has the following fraction contents in percent of the total weight for their respective molecular weights determined by gel-permeation chromatography:

a fraction content of 0% to 5% for a molecular weight of 40,000 or more,

a fraction content of 0.1% to 20% for a molecular weight of 16,000 or more and less than 40,000,

a fraction content of 45% to 95% or more for a molecular weight of 5,000 or more and less than 16,000,

a fraction content of 1% to 10%, preferably 5% to 10% for a molecular weight of 2,000 or more and less than 4,000, and

a fraction content of 5% to 55%, preferably 5% to 10% for a molecular weight of 500 or more and less than 1,500.

2. The bioabsorbable pharmaceutical formulation according to claim 1, wherein the drug is a luteinizing hormone-releasing hormone (LH-RH) or a derivative thereof.

(Effects of the Invention)

The lactic acid-glycolic acid copolymer having the above fractions in molecular weight can be used to provide a bioabsorbable pharmaceutical formulation which prevents an effective component drug from being released rapidly just after the administration of the formulation, thereby allowing continued release of the drug from 1 month to 3 months at a defined rate. The formulation allows a drug to exist at an optimal therapeutic blood level in order to be effective in the body, within a range that is between the side effect expressing level and the minimum effective level, thereby resulting in a high effect based on a small dose (or frequency) of the pharmaceutical formulation that is administered.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(Best Mode for Carrying Out the Invention)

The lactic acid-glycolic acid copolymer (hereinafter, sometimes referred to as "PLGA") of the present invention means a polymer which can have the following fraction contents for their respective molecular weights determined by gel-permeation chromatography (hereinafter, sometimes referred to as "GPC"): a fraction content of less than 5% for a molecular weight of 40,000 or more, a fraction content of less than 20% for a molecular weight of 16,000 or more and less than 40,000, a fraction content of 45% or more for a molecular weight of 5,000 or more and less than 16,000, a fraction content of less than 10% for a molecular weight of 2,000 or more and less than 4,000, and a fraction content of 5% or more for a molecular weight of 500 or more and less than 1,500. More preferably, the copolymer can have the following fraction contents: a fraction content of 0% or more and less than 5% for a molecular weight of 40,000 or more, a fraction content of less than 20% for a molecular weight of 16,000 or more and less than 40,000, a fraction content of 45% or more and less than 95% for a molecular weight of 5,000 or more and less than 16,000, a fraction content of less than 10% for a molecular weight of 2,000 or more and less than 4,000, and a fraction content of 5% or more and less than 20% for a molecular weight of 500 or more and less than 1,500.

The molecular weight described herein means a molecular weight in terms of polystyrene determined by GPC. Specifically, it means a molecular weight which is determined in terms of the molecular weights of polystyrenes used as reference materials: 6.77.times.10.sup.6, 1.80.times.10.sup.6, 9.0.times.10.sup.5, 6.0.times.10.sup.5, 2.33.times.10.sup.5, 1.0.times.10.sup.5, 5.0.times.10.sup.4, 1.75.times.10.sup.4, 9.0.times.10.sup.3, 4.0.times.10.sup.3, 2.0.times.10.sup.3, 8.0.times.10.sup.2, and 4.18.times.10.sup.2, using GPC columns of TSLgel G6000HXL, G5000HXL, G4000HXL, G2500HXL, G1000HXL (7.8 mm I.D..times.30 cm L) or TSK guard column HXL-H (all supplied by Tosoh Corporation) and a measurement device of HLC-8120 (supplied by Tosoh Corporation).

The lactic acid-glycolic acid copolymer described herein can include the lactic acid-glycolic acid copolymer or a salt thereof. As the salt, for example, a salt or a complex salt of the copolymer with an inorganic base including an alkali metal, such as sodium or potassium, and an alkaline earth metal such as calcium or magnesium, an organic base including an organic amine such as triethylamine and basic amines such as arginine, or a transition metal such as zinc, iron, or copper can be used. The lactic acid-glycolic acid copolymer can have preferably a compositional molar ratio of 90:10-40:60, and more preferably 70:30-80:20 of lactic acid to glycolic acid. The copolymer which has a glycolic acid content of 10 mole % or less is hydrolyzed too slowly to release a defined amount of a drug even one month after administration of the pharmaceutical formulation. In addition, the copolymer which has a glycolic acid content of beyond 60 mole % is low in solubility in an organic solvent that is generally used for a formulation, thereby creating an unfavorable effect brought about in the process for manufacturing the pharmaceutical formulation.

The lactic acid-glycolic acid copolymer of the present invention can be manufactured, but not limited to, by well known methods. For example, the method can include dehydration polycondensation from lactic acid and glycolic acid as cited in Polymeric Processing, 30(5), 208, (1981), or ring-opening polymerization from lactide and glycolide using a Lewis acid, a metal salt, an organometal and the like as a polymerization catalyst. A higher alcohol, a fatty acid and the like can also be used as an initiator.

Further, the lactic acid-glycolic acid copolymer characterized by fraction contents for the molecular weights according to the present invention can be obtained more efficiently by "two step polymerization" wherein a monomer such as lactic acid and glycolic acid, or an oligomer comprising lactic acid and glycolic acid is added in the course of polymerization to continue further polymerization. Alternatively, the polymer obtained by a well known method as described above including "two step polymerization" may be supplied to mix with at least two or more kinds of lactic acid-glycolic acid copolymers which are different in molecular weight and composition.

Further, the lactic acid-glycolic acid copolymer can be purified by well known methods, for example, by using an organic solvent. The organic solvent can be, for example, acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, hexane, methanol or combinations thereof. In particular, the combinations of methylene chloride, chloroform, methanol, hexane and the like are preferably used.

As a method for removing organic solvents, well known methods or modifications thereof can be used. The methods include a method wherein organic solvents are evaporated under a normal pressure or a gradually reduced pressure while stirring with a propeller stirrer, a magnetic stirrer or an ultrasonic generator, a method wherein organic solvents are evaporated under a controlled vacuum with a rotary evaporator and the like, a method wherein organic solvents are removed by heating under a reduced pressure using a vacuum dryer and the like, and a method wherein organic solvents are removed using a dialysis membrane.

Further, the lactic acid-glycolic acid copolymer having a distribution in molecular weight of the present invention can also be prepared by mixing at least two or more kinds of lactic acid-glycolic acid copolymers obtained by purification described above.

The bioabsorbable pharmaceutical formulation of the present invention means a release sustaining composition having an action which prevents an effective component drug from being released too rapidly just after the administration of the formulation, thereby allowing continued release of the drug for at least a month at a defined rate, thereby controlling the release of the drug with the sustained pharmacological effect. The formulation is not limited to an oral, injection, or transdermal formulation or the like, as long as it can sustain releasing a drug. The oral or injection formulation is preferred. The bioabsorbable pharmaceutical formulation can comprise well known pharmaceutically acceptable additives.

Releasing a drug at a defined rate described herein means that a bioabsorbable pharmaceutical formulation applied to a body continues releasing the effective component drug for at least one month. Specifically, the formulation can release the drug to give a residual rate of 90 to 100% on day 1, 65 to 85% on day 7, 50 to 70% on day 14, 40 to 60% on day 21, and 30 to 50% on day 28. The residual rate of a drug described herein can be determined as follows.

As a method for determining the residual rate of a drug in the present invention, a variety of well known methods can be used. For example, a high performance liquid chromatography can be used in accordance with a method for determining the residual rate of a drug, which is described in Journal of Controlled Release 28 (1994) 121-129, Chem. Pharm. Bull., 36, 1095 (1988), European Pharmacopoeia 4, and the like. For example, drug-supporting microspheres are suspended in 10 mL of 1/30 M phosphate buffer, pH 7.0 with 0.05% surfactant (Tween 80) contained, followed by rotating the suspension by a rotator at 25 cycle/min and filtering the microspheres by a Millipore filter having a pore size of 1 .mu.m, and then the amount of a remaining drug is determined by a high performance liquid chromatography. The residual rate can be defined as a proportional percent of the amount of a remaining drug in the microspheres to an initial value, wherein the initial value is a drug content at an initial stage.

The drug comprised in a bioabsorbable pharmaceutical formulation of the present invention includes, but not limited to, a luteinizing hormone releasing hormone (LH-LR), analogs thereof, a thyroid hormone releasing hormone and salts and derivatives thereof. LH-RH or derivatives thereof can be used.

As an LH-RH derivative, an agonist or an antagonist of LH-RH may be used.

As an LH-RH antagonist, for example, biologically active peptides represented by the general formula (I) below or the salts thereof and the like can be used. General Formula (I): X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-DAlaNH.sub.2 [wherein X represents N(4H.sub.2-furoyl)Gly or NAc, A represents a residue selected from NMeTyr, Tyr, Aph(Atz), and NMeAph(Atz), B represents a residue selected from DLys (Nic), DCit, DLys(AzaglyNic), DLys(AzaglyFur), DhArg(Et2), DAph(Atz) and DhCi, and C represents Lys(Nisp), Arg or hArg(Et2)].

As an LH-RH agonist, for example, biologically active peptides represented by general formula (II) or salts thereof and the like can be used. General Formula (II): 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [wherein Y represents a residue selected from DLeu, DAla, DTrp, DSer(tBu), D2Nal and DHis(ImBzl), Z represents NH--C.sub.2H.sub.5 or Gly-NH.sub.2]. In particular, a peptide wherein Y represents DLeu, and Z represents NH--C.sub.2H.sub.5 (namely, a peptide represented by 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH--C.sub.2H.sub.5) or salts thereof (for example, acetates) can be used. More particularly, leuprorelin acetate can be used.

These peptides can be manufactured by methods, for example, shown in Patent Document No. 4.

The bioabsorbable pharmaceutical formulation of the present invention can be prepared by containing the above described drug in a biodegradable release sustaining base material of the present invention to microencapsulate. The microcapsule can be prepared by well known methods, for example, a W/O/W method described in Patent Document No. 4, a phase separation method, and a spray-drying method.

The drug is preferably contained in a biodegradable release sustaining base material at about 3-20 w/w %, and more preferably about 5-15 w/w %.
 

Claim 1 of 9 Claims

1. A bioabsorbable pharmaceutical formulation comprising a lactic acid-glycolic acid copolymer and a drug, wherein the lactic acid-glycolic acid copolymer has the following fraction contents for their respective molecular weights determined by gel-permeation chromatography: a fraction content of 0% to less than 5% for a molecular weight of 40,000 or more, a fraction content of 0.1% to less than 20% for a molecular weight of 16,000 or more and less than 40,000, a fraction content of 45% or more for a molecular weight of 5,000 or more and less than 16,000, a fraction content of 1% to less than 10% for a molecular weight of 2,000 or more and less than 4,000, and a fraction content of 5% or more for a molecular weight of 500 or more and less than 1,500.

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