Composition and microsphere with controlled exendin release and method of obtaining microsphere

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmacy and represents microsphere with controlled release, which has covering layer and contains core, which contains exendin as active ingredient and biodegradable polymer, and covering layer, which covers core with covering material, exendin being exendin-4 (SEQ ID NO:2), biodegradable polymer represents polymer, selected from group, consisting of polylactide (PLA), polyglycolide (PGA), lactide and glycolide copolymer (PLGA), polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and polyalkylcarbonate; copolymer or simple mixture of two or more polymers, selected from said group of polymers; copolymer of said polymer and polyethylene glycol (PEG); or polymer-sugar complex, in which sugar is bound with said polymer or said copolymer, covering material is selected from group, consisting of essential amino acids, polypeptides and organic nitrogenous compounds, essential amino acid being one or more, selected from group, consisting of arginine, lysine and histidine; polypeptide represents L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and organic nitrogenous compound is selected from group, consisting of creatine, creatinine and urea, content of covering layer constitutes from 0.01 to 5 wt fractions in terms per 100 wt fractions of microsphere.

EFFECT: invention ensures increase of bioaccessability and reduction of initial peak of exendin for prevention of such side effects as vomiting, nausea, headache.

10 cl, 7 ex, 5 tbl, 7 dwg

 

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the preferential right of priority to Korean patent application No. 10-2007-0029586 filed March 27, 2007, which is hereby incorporated by reference for all purposes as though it were fully set forth in the present description.

BACKGROUND of the INVENTION

(a) the technical Field to which the invention relates.

The present invention relates to compositions with controlled release and the microsphere controlled release containing Asendin as the active ingredient, as well as the way they are received.

(b) Description analogs

Essendine are agonists of like peptide-1 (GLP-1), acting as GLP-1 in the body, and Asendin-4 has a 53%homology sequences with the amino acid sequence of GLP-1(7-36)NH2(Goke, et al., J. Biol. Chem., 268: 19650-19655, 1993).

GLP-1, typical incrediby hormone is a peptide selected from L-cells of the intestine, secreted by ingestion of food in the digestive tract and reduces blood sugar levels by stimulating insulin secretion from the beta cells of the pancreas (Orskov, et al., Diabetes, 42:658-661, 1993). In addition, GLP-1 inhibits the release of glucagon from the alpha cells of the pancreas (D'alessio, et al., J. Clin. Invest., 97:133-138, 1996) and increases the release of gastro-Kish the con tract, which leads to the inhibition of the absorption of food (Schira et al., J. Clin. Invest., 97:92-103, 1996). Functions of GLP-1 are not only in stimulating insulin secretion from the beta cells of the pancreas, but also to increase the rate of proliferation and survival of beta-cells (Buteau et al., Diabetologia, 42:856-864, 1999). However, GLP-1 loses the ability to perform their function with cleavage of its N-terminal section through dipeptidylpeptidase-4 (DPP-4) and has a very short half-life of approximately 2 minutes (Pridal, et al., Eur. J. Drug. Metab. Pharmacokinet., 21:51-59, 1996; Deacon, et al., Diabetes, 47:764-769, 1998).

Essendine known ability to increase insulin secretion depending on the level of blood sugar in the body, inhibiting the release of glucagon after meals, as well as reduce the rate of release of the gastrointestinal tract, which leads to inhibition of absorption of food. In addition, essendine have the advantage of longer half-life compared to GLP-1, because Asendin, unlike GLP-1 is cleaved at the N-terminal region by DPP-4, and therefore essendine can exert its action in the body for longer periods of time than GLP-1 (Thum et al., Exp. Clin. Endocrinol. Diabetes., 110:113-118, 2002). Essendine found in the secretions of the salivary glands of lizards Gila (Gila monster and Mexican adotube (Mexican Beaded Lizard), and copies ndin-3 was detected in mexicanago of adotube, Heloderma horridum, Asendin-4 found in lizards Gila, Heloderma suspectum (Eng, J., et al., J. Biol. Chem., 265:20259-62, 1990; Eng., J., et al., J. Biol. Chem., 267:7402-05, 1992).

By intraperitoneal injection of essendine-4 mice with diabetes, obesity (ob/ob-mice) once a day, it was confirmed that Asendin-4 has a prolonged effect of reducing the level of sugar in the blood (Greig et al., Diabetologia 42:45-50, 1999). Recently worked out a solution for essendine-4 as agent injection that is injected subcutaneously twice per day dose, component 5 mcg or 10 mcg. Although Asendin exhibits stability against enzyme DPP-4, is also known for its ability to cause side effects such as vomiting, nausea, headaches and the like, in a subcutaneous human dose of 0.2 mcg/kg or more (Drug Development Research, 53:260-267, 2001). With the introduction of Akindinov limit dose because of the side effects associated with the initial peak and the initial high concentration in the blood, is the greatest obstacle for the development of agent controlled release of essendine.

In the General case, the agent controlled release of water of a drug shows a very high release rate in the initial stage after the introduction, and have conducted various studies to reduce excessive initial peak. the particular when developing agent controlled release of Akindinov important reduction of the initial peak to prevent such side effects as vomiting, nausea, headaches and the like caused by excessive initial peak.

To reduce the initial peak of the microspheres with controlled-release, containing octreotide (octreotide), has a therapeutic effect against acromegaly and similar diseases, a study was conducted to obtain microspheres by obtaining the primary emulsion of a medicinal product, together with glucose, and subsequent implementation of the method of double emulsification. In the course of this study it was found that the initial peak can be reduced through the introduction of a drug simultaneously with glucose. However, in terms of preparation, in which the initial peak from the microspheres is approximately 5%, the addition of glucose may not lead to an increase in the input number, and rather increases the initial peak (J. Wang et al., Biomaterials, 25:1919-1927, 2004).

Therefore, the technology disclosed in the above document, very difficult to use in order to obtain a composition with controlled release of essendine whereby the initial peak should be 5% or below to reduce the side effects caused by the initial peak.

Patent school is No. 7164005 and US2005/0271702 disclose a method of obtaining extendedstay microspheres by phase separation method using a copolymer of lactide and glycolide (PLGA)), in which the ratio of lactide and glycolide is 50:50. In the above-mentioned documents of the polymer used is a polymer 3A (IV=of 0.38 DL/g (IV - redundant. from the Inherent Viscosity is a characteristic viscosity - note. the translation), the polymer 4A (IV=at 0.42 DL/g) and the like, in particular, the polymer 4A, provided by the company Alkermes Inc. In the above documents microspheres prepared by mixing the peptide drug with Vasiliauskas components, for example, ammonium sulfate, and sugars, such as sucrose and mannitol, to obtain a primary emulsion to improve the bioavailability of microspheres composed of essendine and polymer 3A or 4A, as well as the stability of the peptide drug. That is, these documents are designed to improve bioavailability by adding additives, such as sugars, ammonium sulfate, and the like, which provides sufficient release of essendine from the polymer matrix. As a result, the bioavailability can be improved to some extent, however, the maximum concentration (Cmax) remains high, which causes the problem of side effects caused by the high initial peak. That is, when the bioavailability of the initial peak becomes excessive, while at lower initial peak bioavailability is reduced.

As describe what about the above, the existing technology of production of microspheres with controlled-release is limited to that obtained microsphere has an excessively high initial peak and poor bioavailability for use in obtaining extendedstay microspheres of controlled release, which require minimize side effects caused by the high initial peak, along with improved bioavailability.

Therefore to resolve the above problems, it is necessary to develop biodegradable extendedstay composition exhibiting low initial peak and improved bioavailability.

SUMMARY of the INVENTION

To meet the above needs, the present invention is the provision of agent controlled-release with high bioavailability, containing Asendin as an active ingredient and a biodegradable polymer as a carrier, which reduced the excessive initial peak, which is one of the problems of existing agents, controlled release, and how to obtain it.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 is a graph showing changes in the concentration of drug in the blood of rats depending on the presence of a coating layer attendancebased part of RG502H.

2 p is ecstasy a graph showing changes in the concentration of drug in the blood of rats depending on the presence of a coating layer attendancebased part of RG503H.

Figure 3 is a graph showing changes in the concentration of drug in the blood of rats depending on the presence of a coating layer and the type of covering material in extendedstay mixture compositions RG502H:RG503H=1:1.

Figa represents the image of microspheres under an electron microscope, obtained from a conventional method of double emulsification.

Fig.4b represents the image of microspheres under an electron microscope, coated with a special covering materials using a double emulsion in accordance with the present invention.

Figs represents the image of microspheres under an electron microscope, obtained by the method of double emulsification with covering materials in the primary aqueous phase.

Fig.4d represents the image of microspheres under an electron microscope, obtained by the method of double emulsification with covering materials with polymers dissolved oil phase.

A DETAILED DESCRIPTION of the PREFERRED embodiments

A more complete evaluation of the invention and many of its inherent advantages will be apparent as it is better understood through the your reference to the following detailed description.

The present invention relates to compositions with assindysemiemia microspheres with controlled-release with high bioavailability and minimized the initial peak of the drug when injected into the body.

Korean patent No. 140209 discloses a method of producing microspheres by dissolving in water a medicinal product with a specific basic organic materials to obtain a primary emulsion and subsequent implementation of the double emulsification for the inhibition of the initial peak water drug. The above stated document reveals the efficiency of saturation of the drug in the inhibition of the excessively high level of initial peak through the formation of a solid layer by the interaction between the acidic residues biodegradable polymers and basic residues of the drug. As disclosed in the above document, the above method can be used to obtain compositions with controlled release, containing basic or neutral polypeptide, such as gonadotropin-releasing hormone (LHRH), thyrotropin-releasing hormone (TRH) and their derivatives. However, this method cannot be used due to the characteristics of injected drugs, cha is in the surrounding area, when obtaining compositions with controlled release containing acidic drug with a relatively high molecular weight compared to LHRH and TRH, such as Asendin and the like. In addition, in the above method, the addition of basic materials causing increased porosity of the surface of the obtained microspheres, and therefore, this method is not suitable for obtaining the composition of controlled release, containing Asendin, which shows various side effects caused by the initial peak.

The authors of the present invention have confirmed that the microspheres having high bioavailability and no side effects due to excessive initial peak, can be performed by coating covering specific materials during or after receiving extendedstay microspheres using biodegradable polymers as carriers, to make the present invention.

First, the present invention provides the composition with controlled release containing Asendin as the active ingredient, biodegradable polymer with a specific viscosity and covering materials with a high bioavailability and a prolonged release of the active ingredient in an effective concentration within ODA is divided periods of time without excessive initial peak of the active ingredient.

In another aspect the present invention provides a microsphere controlled release, containing the core, including Asendin as an active ingredient and a biodegradable polymer; and a coating layer covering the core.

Further, the present invention is described more specifically.

In the present invention Asendin may be one or more selected from the group consisting of essendine-3 (SEQ ID NO:1), essendine-4 (SEQ ID NO:2), their fragments and derivatives and their pharmaceutically acceptable salts.

Derivatives of essendine can be a compound represented by the following chemical formula I, or its pharmaceutically acceptable salt.

(Chemical formula I)

Xaa1 Haa Haa Haa Haa Haa Haa Haa Haa Xaa10 Xaa11 Xaa12 Haa Haa Haa Haa Haa Ala Xaa19 Haa Haa Haa Haa Haa Haa Xaa26 Xaa27 Xaa28-Z1

where:

Xaa1 represents His, Arg, Tyr, Ala, Norval, Val, Norleu, or 4-imidazolidinyl;

Haa represents Ser, Gly, Ala or Thr;

Haa represents Ala, Asp or Glu;

Haa represents Ala, Norval, Val, Norleu, or Gly;

Haa represents Ala or Thr;

Haa represents Ala, Phe, Tyr or nafcillin;

Haa represents Thr or Ser;

Haa represents Ala, Ser or Thr;

Haa represents Ala, Norval, Val, Norleu, Asp or Glu;

Xaa10 is an Ala, Leu, Ile, Val, pencillin or Met;

Xaa11 is with the battle Ala or Ser;

Xaal2 represents Ala or Lys;

Haa represents Ala or Gln;

Haa represents Ala, Leu, Ile, pencillin, Val or Met;

Haa represents Ala or Glu;

Haa represents Ala or Glu;

Haa represents Ala or Glu;

Xaa19 represents Ala or Val;

Haa represents Ala or Arg;

Haa represents Ala, Leu, or Lys-NHε-R where R is Lys, Arg or a linear or branched alkanoyl with 1-10 carbon atoms);

Haa represents Ala, Phe, Tyr or nafcillin;

Haa represents Ile, Val, Leu, papillitis, tert-butylglycol or Met;

Haa represents Ala, Glu or Asp;

Haa represents Ala, Trp, Phe, Tyr or nafcillin;

Haa represents Ala or Leu;

Haa represents Ala or Lys;

Haa represents Ala or Asn; and

Z1 represents-HE,

-NH2,

Gly-Z2,

Gly Gly-Z2,

Gly Gly Xaa31-Z2,

Gly Gly Xaa31 Ser-Z2,

Gly Gly Xaa31 Ser Ser-Z2,

Gly Gly Xaa31 Ser Ser Gly-Z2,

Gly Gly Xaa31 Ser Ser GlyAla-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala Xaa36-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37 Xaa38-Z2 or

Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37 Xaa38 Xaa39-Z2,

(where Xaa31, Haa, Xaa37 and Xaa38 are independently Pro, homopolymer, or, nor, thioproline, N-allylglycine, N-alkylpolyglycoside or N-alkylamino, Haa represents Ser or Tyr, more preferably Ser, and Z2 is with the fight-HE or-NH 2),

provided that not more than three of Xaa3, Haa, Haa, Haa, Haa, Haa, Xaa10, Xaa11, Xaa12, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa and Hoa are Ala, and if Xaa1 represents His, Arg or Tyr at least one of Xaa3, Haa, and Ha represents Ala.

The preferred N-alkyl groups for N-allylglycine, N-alkylpolyglycoside and N-alkylamine may include lower alkyl groups, preferably from 1 to about 6 carbon atoms, more preferably from 1 to 4 carbon atoms. The compound represented by chemical formula I, may include compounds identified in examples 1-89 (Compound 1-89, respectively), and the compounds identified in examples 104 and 105 of the PCT application serial number PCT/US98/24273, filed November 13, 1998, entitled "New connections agonist of essendine" ("Novel Exendin Agonist Compounds"), which are hereby incorporated by reference.

Preferred derivatives of essendine chemical formula I can include those in which Xaa1 represents His, Ala, Norval or 4-imidazolidinyl, more preferably, Xaa1 represents His, Ala or 4-imidazolidinyl, and even more preferably, Xaa1 represents His or 4-imidazolidinyl).

Preferred derivatives of essendine chemical formula I can be those in which HEA pre who is a Gly.

Preferred derivatives of essendine chemical formula I can be those in which Haa represents Ala.

Preferred derivatives of essendine chemical formula I can be those in which Haa represents Ala.

Preferred derivatives of essendine chemical formula I can be those in which Haa represents Ala.

Preferred derivatives of essendine chemical formula I can be those in which Xaa14 represents Leu, pencillin or Met.

Preferred derivatives of essendine chemical formula I can be those in which Haa represents Lys-NHε-R where R is Lys, Arg or a linear or branched alkanoyl with 1-10 carbon atoms).

Preferred derivatives of essendine chemical formula I can be those in which Haa represents Trp or Phe.

Preferred derivatives of essendine chemical formula I can be those in which Haa represents Ala, Phe or nafcillin, Haa represents Phe or nafcillin, and Ha represents Ile or Val. In addition, the preferred derivatives of essendine chemical formula I can be those in which Haa, Haa, Haa and Hoa independently selected from the group consisting of Pro, homatropine, thioproline and N-alkylamine, and more preferably, Z1 represents-NH2, a Z2 represents-NH2.

In another aspect of the preferred derivatives of essendine chemical formula I can be those in which Xaa1 represents Ala, His or Tyr, more preferably Ala or His; Xaa2 represents Ala or Gly; Ha represents Phe or nafcillin; Xaa14 is an Ala, Leu, pencillin or Met; Xaa22 represents Phe or nafcillin; Ha represents Ile or Val; Hua, Hua, Hua and Hua independently selected from the group consisting of Pro, homatropine, thioproline and N-alkylamine; Ha represents Ser or Tyr and more preferably Ser; and preferably, Z1 represents-NH2.

In accordance with a particularly preferred aspect, especially preferred derivatives of essendine chemical formula I can be those in which Xaa1 represents His or Ala; Xaa2 represents Gly or Ala; Ha represents Ala, Asp or Glu; Xaa4 represents Ala or Gly; Ha represents Ala or Thr; Ha represents Phe or nafcillin; Ha represents Thr or Ser; Ha represents Ala, Ser or Thr; Ha represents Ala, Asp or Glu; Ha represents Ala, Leu or pencillin; Xaa11 is a Ala or Ser; Ha represents Ala or Lys; Xaal3 represents Ala or Gln; Xaa14 is an Ala, Leu, Met or pencillin; Xaa15 is an Ala or Glu; Xaa16 is predstavljaet an Ala or Glu; Xaa17 is an Ala or Glu; Xaa19 represents Ala or Val; Ha represents Ala or Arg; Xaa21 is an Ala or Leu; Xaa22 represents Phe or nafcillin; Ha represents Ile, Val or t-butylglycol; Ha represents Ala, Glu or Asp; Xaa25 is an Ala, Trp or Phe; Ha represents Ala or Leu; Ha represents Ala or Lys; Ha represents Ala or Asn; Z1 represents-OH, -NH2, Gly-Z2, Gly Gly-Z2, Gly Gly Xaa31-Z2, Gly Gly Xaa31 Ser-Z2, Gly Gly Xaa31 Ser Ser-Z2, Gly Gly Xaa31 Ser Ser Gly-Z2, Gly Gly Xaa31 Ser Ser Gly Ala-Z2, Gly Gly Xaa31 Ser Ser Gly Ala Xaa36-Z2, Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37-Z2, Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37 Xaa38-Z2 or Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37 Xaa38 Xaa39-Z2; Xaa31, Haa, Xaa37 and Xaa38 independently represent a Pro, gemopolis, thioproline or N-methylalanine; Ha represents Ser or Tyr, more preferably Ser; and Z2 represents-IT or-NH2, provided that not more than three of Haa, Haa, Haa, Haa, Xaa10, Xaa11, Xaa12, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa and Hoa are Ala, and if Xaa1 represents His, Arg or Tyr, at least one of Haa, Haa and Hoa can be Ala.

Especially preferred compounds of chemical Formula I can include those that have the amino acid sequence from SEQ ID NO:5 to SEQ ID NO:93, described in PCT application serial number PCT/US98/25728, or those set out in the preliminary application With The And 60/066029, included in this description by reference.

In accordance with a particularly preferred aspect are provided compounds in which Xaa14 represents Leu, Ile, Val or pentillion, and more preferably Leu or pencillin; and Haa represents Ala, Phe, Tyr or nafcillin, and more preferably Phe or nafcillin. These compounds are less sensitive to oxidative degradation, both in vitro and in vivo, as well as during the synthesis of the compounds.

In another aspect, the derivatives of essendine can also include compounds represented by the chemical Formula II, or their pharmaceutically acceptable salts.

(Chemical formula (II)

Xaa1 Haa Haa Haa Haa Haa Haa Haa Haa Xaa10 Xaa11 Xaa12 Haa Haa Haa Haa Haa Ala Ha Ha Ha Ha Ha Ha Ha Ha X1-Z1

where

Xaa1 represents His, Arg, Tyr, Ala, Norval, Val, Norleu, or 4-imidazolidinyl;

Xaa2 represents Ser, Gly, Ala or Thr;

Haa represents Ala, Asp or Glu;

Xaa4 represents Ala, Norval, Val, Norleu, or Gly;

Xaa5 is an Ala or Thr;

Haa represents Ala, Phe, Tyr or nafcillin;

Haa represents Thr or Ser;

Haa represents Ala, Ser or Thr;

Haa represents Ala, Norval, Val, Norleu, Asp or Glu;

Xaa10 is an Ala, Leu, Ile, Val, pentylphenol (pentylglycine or Met;

Xaa11 represents the t a Ala or Ser;

Xaa12 is an Ala or Lys;

Xaa13 is an Ala or Gln;

Xaa14 is an Ala, Leu, Ile, pencillin, Val or Met;

Xaa15 is an Ala or Glu;

Xaa16 is an Ala or Glu;

Xaa17 is an Ala or Glu;

Haa represents Ala or Val;

Haa represents Ala or Arg;

Haa represents Ala, Leu or Lys-NHε-R where R is Lys, Arg, linear or branched alkanoyl with 1-10 carbon atoms or cyclic allyl-alkanoyl);

Haa represents Phe, Tyr or nafcillin;

Haa represents Ile, Val, Leu, pencillin, tert-butylglycol or Met;

Haa represents Ala, Glu or Asp;

Haa represents Ala, Trp, Phe, Tyr or nafcillin;

Haa represents Ala or Leu;

X1 represents Lys Asn, Asn Lys, Lys-NHε-R Asn, Asn Lys-NHε-R, Lys-NHε-R Ala Ala Lys-NHε-R where R is Lys, Arg, linear or branched alkanoyl with 1-10 carbon atoms or cycloalkylcarbonyl);

Z1 represents-HE,

-NH2,

Gly-Z2,

Gly Gly-Z2,

Gly Gly Xaa31-Z2,

Gly Gly Xaa31 Ser-Z2,

Gly Gly Xaa31 Ser Ser-Z2,

Gly Gly Xaa31 Ser Ser Gly-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala Xaa36-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37-Z2,

Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37 Xaa38-Z2 or

Gly Gly Xaa31 Ser Ser Gly Ala Ha Xaa37 Xaa38 Xaa39-Z2,

(where Xaa31, Haa, Xaa37 and Xaa38 are independently selected from the group consisting of Pro, homatropine, or, nor, tipr is Lina, N-allylglycine, N-alkylpolyglycoside and N-alkylamino, Xaa39 is a Ser or Tyr, and Z2 represents-IT or-NH2),

provided that not more than three of Xaa3, Haa, Haa, Haa, Haa, Haa, Xaa10, Xaa11, Xaa12, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa, Haa and Hoa are Ala, and if Xaa1 represents His, Arg, Tyr or 4-imidazolidinyl at least one of Xaa3, Haa and Hoa represents Ala.

Preferred derivatives of essendine chemical formula II may be those in which Xaa1 represents His, Ala, Norval or 4-imidazolidinyl, preferably His, 4-imidazolidinyl or Ala, and more preferably His or 4-imidazolidinyl.

Preferred derivatives of essendine chemical formula II may include those elements in which Ha is a Gly.

Preferred derivatives of essendine by Chemical Formula II may be those in which Haa represents Ala.

Preferred derivatives of essendine chemical formula II may be those in which Haa represents Ala.

Preferred derivatives of essendine chemical formula II may be those in which Haa represents Leu, pencillin or Met.

Preferred derivatives of essendine chemical formula II may be those in which Haa represents Trp or Phe.

Predpochtite the global derivatives of essendine chemical formula II can be those in which Haa represents Ala, Phe or nafcillin, Haa represents Phe or nafcillin, and Ha represents Ile or Val.

Preferred derivatives of essendine by Chemical Formula II may include those elements in which Z1 represents-NH2.

Preferred derivatives of essendine chemical formula II may be those in which Haa, Haa, Haa and Hoa independently selected from the group consisting of Pro, homatropine, thioproline and N-alkylamine.

Preferred derivatives of essendine chemical formula II may be those in which Haa represents Ser or Tyr, preferably Ser.

Preferred derivatives of essendine chemical formula II may be those in which Z2 represents-NH2.

Preferred derivatives of essendine chemical formula II may be those in which Z1 represents-NH2.

Preferred derivatives of essendine chemical formula II may be those in which Haa represents Lys-NHε-R where R is Lys, Arg or a linear or branched alkanoyl with 1-10 carbon atoms).

Preferred derivatives of essendine chemical formula II may be those in which X1 represents Lys Asn, Lys-NHε-R Asn, or Lys-NHε-R Ala where R is Lys, Arg or a linear or branched alkanoyl with 1-10 carbon atoms)

Preferred derivatives of essendine chemical formula II include compounds having the amino acid sequence identified as SEQ ID NO:95 - SEQ ID NO:110, represented in WO99/025728. Derivatives of essendine chemical formula II include compounds having the amino acid sequence identified as SEQ ID NO:5 - SEQ ID NO:93, as described in PCT application PCT/US98/24210, filed November 13, 1998, entitled "New connections agonist of essendine" ("Novel Exendin Agonist Compounds"). In another aspect, the derivatives of essendine chemical formula II include compounds having the amino acid sequence identified as SEQ ID NO:37 to SEQ ID NO:40, described in WO99/007404. The above documents are included in the present description as a reference.

Abbreviations used in chemical formulas I and II have the following meanings.

"ACN" and "CH3CN" means acetonitrile.

"Howl", "tBoc" and "Tboc" means tert-butoxycarbonyl.

"DCC" means N,N'-dicyclohexylcarbodiimide.

"Fmoc" refers to foranimation.

"HBTU" refers to 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexaflurophosphate.

"HOBt" refers to 1-hydroxybenzotriazole monohydrate.

"homoP and hPro" means gamopolis.

"MeAla" and "Nme" means N-methylalanine.

"naph" means nafcillin.

"pG" and "pGly" means pentillion.

"tBuG" about the means tertiary butylglycol.

"ThioP" and "tPro" means tiopronin.

"Nur" means 3-hydroxyproline.

"Nur" means 4-hydroxyproline.

"NAG" means N-allylglycine.

"NAPG" means N-ALKYLPHENOLS.

"Norval" means Norvaline.

In the preferred embodiment, fragments or derivatives of essendine may have With the ending, substituted or not substituted amide group, and can be selected from the group consisting of essendine-4 (1-28) (SEQ ID NO:3), essendine-4(1-28) amide, essendine-4(1-30) (SEQ ID NO:4), essendine-4(1-30) amide, essendine-4 (1-31) (SEQ ID NO:5), essendine-4(1-31) amide,14Leu25Phe of essendine-4(S ID NO:6),14Leu25Phe of essendine-4 amide and its pharmaceutically acceptable salts.

According to a preferred embodiment, the composition or microspheres with controlled-release may contain Asendin as an active ingredient in an amount of from 0.1 to 10 mass. parts, and more preferably from 0.8 to 6 mass. parts, per 100 wt. parts of the song or microspheres containing Asendin, biorazlagaemykh polymers and covering materials. If the number of essendine contained in the composition or microspheres in accordance with the present invention, below the above range, the efficiency of essendine cannot be obtained, and if the number of essendine higher than the above range, the initial peak eksen the ina increases, thereby causing adverse effects due to excessive initial peak, and thus, it is preferable that the number of essendine was within the specified range.

Biodegradable polymer refers to all polymers which do not harm the human body, as when it is injected into the body it can slowly be degraded and excreted. The biodegradable polymer can include one or more polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), a copolymer of lactide and glycolide (PLGA), complex polyarteritis, polyanhydride, polyhydroxyalkanoic acid, polycaprolactone and polyalkylacrylate, as well as copolymers of one or more polymer and polyethylene glycol (PEG), with one or more polymer can be in the form of a copolymer or a simple mixture.

For example, the biodegradable polymer may be one or more polymer selected from the group consisting of copolymers of lactide and glycolide (PLGA), consisting of RG502H (IV=0,16...of 0.24 DL/g), RG503H (IV=0,32...of 0.44 DL/g) and RG504H (IV=0,45...to 0.60 DL/g)having the ratio of lactide and glycolide equal to 1:1, and RG752H (IV=0,14...is 0.22 DL/g)having the ratio of lactide and glycolide equal to 75:25, polylactide (PLA), R202H (IV=0,16...of 0.24 DL/g) and R203H (IV=0,25...to 0.35 DL/g), provided by Boehringer-Ingelheim company, Germany; copolymers of lactide and glycolide), 5050DL 2A (IV=0,15...of 0.25 DL/g), 5050DL 3A (IV=0,25...0,43 d is/d), and 5050DL 4A (IV=0,38...of 0.48 DL/g), which are copolymers provided Lakeshore Biomaterials Company (previously Alkermes Company), USA, with the ratio of lactide and glycolide equal to 1:1; and the like.

In another aspect, the biodegradable polymer may be a polymer-sugar complex in which a sugar is bound to the polymer, selected from the group consisting of polylactide (PLA), polyglycolides (PGA), copolymers of lactide and glycolide (PLGA), complex polyarteritis, polyanhydrides, polyhydroxyalkanoic acids, polycaprolactones and polyalkylbenzenes,

a copolymer of at least two polymers of this group of polymers or

copolymer of polyethylene glycol (PEG) and one polymer of this group of polymers.

In the exemplary embodiment of the present invention, polymer-sugar complex may relate to the complex, in which the polymer substituted gidroksilnami group sugar. Sugar may include monosaccharides and polysaccharides, which include from 1 to 8 sharidny units, each sahariana unit includes from 3 to 6 hydroxyl groups, and a linear sugar alcohol comprising from 3 to 6 hydroxyl groups and having a molecular weight of 20,000 or less. Sugar alcohols may include mannitol, pentaerythritol, sorbitol, ribitol and xylitol. The polymer binds with sugar in three or more hydroxyl group is, present in the Sahara.

In accordance with the foregoing embodiment, the polymer-sugar complex in vivo has properties similar to the properties of the polymer associated with sugar, has a different degradation rate depending on the type of polymer and the body is decomposed to harmless polymer and sugar, and therefore, it can be suitable biodegradable polymer. In the preferred embodiment, the polymer-sugar complex can be PLA-glucose complex, PGA-glucose complex or PLGA-glucose complex, with PLGA-glucose complex may be a complex having the following structure:

In the microsphere controlled release according to the present invention, the covering layer is performed on its surface, helps to ensure effective control of the initial peak of essendine, thereby preventing the side effects caused by excessive initial peak. The biodegradable polymer can be used without any limitation of viscosity.

In the composition of the controlled release according to the present invention biodegradable polymer serves as a matrix for the active ingredient, essendine, which has poor low viscosity polymer not p is positioned effectively to save the active ingredient, that, as a consequence, increases the initial peak, and the excessively high viscosity of the polymer causes a decrease in the total released amount of the active ingredient, which, consequently, reduces its bioavailability. In the present invention is not only biodegradable polymer, but also covers the material contained in the composition, perform the role of controlling release of the drug, and thus, can be used biodegradable polymer having a relatively low viscosity. Therefore, to effectively control the initial peak of the drug and to increase bioavailability, characteristic viscosity (IV) biorazlagaemykh polymer, measured for biorazlagaemykh polymer dissolved in chloroform at a concentration of 1% (weight/volume) at 25±0.1°C using a viscometer of Ubbelohde, may preferably be from 0.1 to 0.6 DL/g, more preferably from 0.15 to 0.31 DL/g and even more preferably from 0.16 to 0.24 DL/g

In the composition or in the microspheres of the present invention biodegradable polymer serves as a matrix for the active ingredient in the process of release and to control the speed of release, while its content in the composition or in the microspheres preferably can be from 85 to 99.89 wt. parts, and more prepact the positive - from 91 to 99 wt. parts per 100 wt. parts of the song or microspheres containing Asendin, biodegradable polymer(s) and covering material(s).

The covering material is used to prevent excessive release and increase the bioavailability of the active ingredient, and the microspheres of the present invention it may be in the form of a coating layer on their surface. The covering material may be one material or more selected from basic amino acids, polypeptides and organic nitrogen compounds. The basic amino acid may include arginine, lysine, histidine and derivatives thereof. The polypeptide can include from 2 to 10 amino acids, and more preferably from 2 to 5 amino acids, including one or more amino acid selected from arginine, lysine and histidine. The polypeptide can include more essential amino acids than acidic amino acids, thereby exhibiting the properties of a base. For example, the polypeptide may be L-Ala-L-His-L-Lys, L-Arg-L-Phe, Gly-L-His, Gly-L-His-Gly, Gly-L-His-L-Lys, L-His-Gly, L-His,-Leu, L-Lys-L-Tyr-L-Lys, L-His-L-Val, L-Lys-L-Lys L-Lys-L-Lys-L-Lys L-Lys-L-Thr-L-Thr-L-Lys-L-Ser, etc. in Addition, the organic nitrogen compound may be creatine, creatinine, urea, etc.

The amount of coating material contained in the composition according to the present invention or deposited on the microspheres, may preferably the composition is better from 0.01 to 5 wt. parts, and more preferably between 0.015 to 3 wt. parts per 100 wt. parts of the song or microspheres containing Asendin, biodegradable polymer(s) and covering material(s). Effective control release of the drug can not be achieved if the content of the covering material below the specified range, at the same time, the effect of controlling the initial peak of the addition does not increase, even if the content of the covering material increases beyond the above range. Thus, the above range of content covering material may be preferred.

In accordance with the present invention, each microsphere controlled release has a smooth surface covered with a covering material, and the average size of from 1 to 50 μm, and preferably from 5 to 30 µm (see Figure 4-b). This smooth surface of the microspheres allows to achieve effective control of the initial peak and the best bioavailability.

Unlike conventional forms of microsphere controlled release or microsphere obtained from compositions in accordance with the present invention, is covered with a covering material, providing a warning of excessive initial peak and the increase of bioavailability, which cannot be achieved in conventional extendedstayamerica.com. In particular, excessive initial peak essendine causes various side effects such as vomiting, nausea, headache and the like, and therefore, decrease the value of the initial peak to 5% or lower is very important. Microsphere controlled release or microsphere obtained from compositions in accordance with the present invention allows to reduce the released amount in the first 24 hours up to 5% or below. With the aim of reducing side effects associated with the introduction of extendedstay microspheres with controlled-release, the value of the initial peak in the first hour may be preferably 5% or lower, and more preferably 1% or lower as measured by a test release in vitro, as described here.

Several attempts were made to reduce the side effects caused by the initial peak extendedstay microspheres obtained in the usual way. However, most of such attempts, which was achieved successfully prevent excessive initial peak, have some problems in that the total release decreases as the initial peak, resulting in significantly reduced bioavailability of the drug. However, the microspheres of the present invention contain a coating layer of a covering material on apowersoft, which allows to effectively control the initial peak to avoid side effects due to excessive initial peak, and receive continuous and sufficient release of the drug to achieve the best bioavailability.

In the exemplary embodiment of the present invention composition or microspheres can additionally contain fillers, such as protective colloids and/or stabilizers.

Composition or microspheres can optionally contain one protective colloid or more selected from polyvinyl alcohols, albumin, polyvinylpyrrolidone, gelatino etc. spite, the fact that the protective colloid has no special property of preventing an excessive initial peak of essendine contained in the microspheres, it has the role to prevent aggregation between the microspheres and to improve dispersibility. Given this role, the content of protective colloid preferably may be on the mass fraction of from 0.02% to 1.0% calculated on the total weight of the composition or microspheres containing Asendin, biodegradable polymer(s) and covering material(s).

In addition, to improve the stability of the microspheres in the process of freeze-drying the composition or microspheres of the present invention may additionally contain fillers, selected from mannitol is La, trehalose, sucrose, sodium carboxymethylcellulose and the like, in a mass fraction of 5% to 30%, and more preferably in a mass fraction of 10% to 20% calculated on the total weight of the composition or microspheres containing Asendin, biodegradable polymer(s) and covering material(s).

Also the composition or microspheres of the present invention may optionally contain any additives and fillers commonly used in the composition of medicines, the type and content of which can be easily determined by a specialist in its respective field.

In another aspect the present invention provides a method of obtaining extendedstay microspheres with controlled-release described above. In accordance with the present invention, extendedstudies microspheres with controlled release can be obtained in various ways, for example by covering the surface of the microspheres by suspending the microspheres in a solution of coating material during or after receipt of the microspheres to obtain microspheres with controlled release. A method of producing microspheres in accordance with the present invention can be implemented using a double emulsion (water-oil-water), by the method of single emulsion (oil-water), a phase separation method, a method of raspylitelnoj etc.

Specifically, the method of obtaining extendedstay microspheres with controlled-release may include the following operations:

mixing of essendine and biorazlagaemykh polymer(s) to obtain an emulsion of the type water-in-oil" or homogeneous mixture; and

emulsification by adding an emulsion or a homogeneous mixture in an aqueous solution of coating material for surface layer formation.

More specifically, in the case of the double emulsion, the method according to the present invention may include the operation of emulsification by mixing an aqueous solution of essendine and biorazlagaemykh polymer dissolved in an organic solvent, to form a primary emulsions (type water in oil); suspending emulsion in an aqueous solution of coating material for the formation of emulsions of the type water-in-oil-water; heating the emulsion-type water-oil-water to remove solvent and solidification of the obtained microspheres; collecting and washing the hardened microspheres; and freeze-drying of the microspheres. The organic solvent may be any organic solvent which is capable of forming an emulsion by dissolving biorazlagaemykh polymer and then mixed with an aqueous solution, and, for example, it can be one or more solution selected from the group consisting of chloroform, e is racette, of methylene chloride and methyl ethyl ketone, and more preferably methylene chloride. In this case, the covering material is contained in the secondary aqueous phase (external aqueous phase of the emulsion water-oil-water)for surface layer formation on the outside of the microspheres containing Asendin and biodegradable polymer, when the organic solvent is removed.

In another case, when using the single emulsion, the method according to the present invention may include dissolving operation of essendine and biorazlagaemykh polymer in an organic solvent for the formation of a homogeneous mixture; adding an aqueous solution containing a coating material to the mixture to form an emulsion; heating the emulsion for solvent removal and curing of the obtained microspheres; collecting and washing the hardened microspheres; and freeze-drying of the microspheres. The organic solvent may be any organic solvent capable of fully mix Asendin and biodegradable polymer for the formation of a homogeneous mixture, and mixed with the aqueous solution for formation of the emulsion. For example, an organic solvent may be a mixed solvent, in which is mixed in one or more solvent selected from the group consisting of alcohols having from 1 to 5 carbon atoms, glacial acetic is islote, formic acid, dimethyl sulfoxide and N-methylpyrrolidone, and one or more solvent selected from the group consisting of chloroform, ethyl acetate, methyl ethyl ketone and methylene chloride, and preferably in which a mixture of methanol and methylene chloride. In this case, the surface of the finally obtained microspheres has a coating layer on it due to the emulsification of a homogeneous mixture biorazlagaemykh polymer and essendine and add a covering material to aqueous solution to remove the organic solvent.

In another aspect, a method of obtaining extendedstay microspheres with controlled-release of the present invention may include the operation:

mixing of essendine and biorazlagaemykh polymer to form a homogeneous emulsion or mixture;

curing the resulting emulsion or a homogeneous mixture, to obtain primary microspheres; and

suspending the resulting primary microspheres in an aqueous solution of coating material for surface layer formation on each microsphere.

The method of curing is not limited and may be any method of curing, commonly used in the relevant field, for example, by the method of phase separation or by spray drying method.

More specifically, in the case of applying the method of separation of phases in operation Oteri is recommended reading method of the present invention may include the operation:

mixing an aqueous solution of essendine and biorazlagaemykh polymer dissolved in an organic solvent, to form emulsions or mixing of essendine and biorazlagaemykh polymer in the mixed solvent to form a solution of a homogeneous mixture;

add oil, such as silicone oil, to the resulting emulsion or solution to obtain the primary microspheres;

add precipitator for biorazlagaemykh polymer, for example a mixed solvent of an alcohol having from 1 to 5 carbon atoms, and alkane having from 1 to 12 carbon atoms, preferably a mixed solvent of ethanol and heptane, to remove the organic solvent from the microspheres and hardening of the microspheres;

suspending the obtained microspheres in an aqueous solution of coating material for surface layer formation on each microsphere; and

collection, washing and freeze-drying of the microspheres with the formed coating layer.

The organic solvent may be one or more solvent selected from the group consisting of chloroform, ethyl acetate, methylene chloride and methyl ethyl ketone, and preferably it can be methylene chloride. The mixed solvent may be such that mixes one or more solvent selected from the group consisting of an alcohol having from 1 to 5 atoms angle of the ode, glacial acetic acid, formic acid, dimethyl sulfoxide and N-methylpyrrolidone, and one or more solvent selected from the group consisting of chloroform, ethyl acetate, methyl ethyl ketone and methylene chloride, and preferably it can be mixed solvent of methanol and methylene chloride.

In another case, if you are using the spray drying method, the method according to the present invention may include the operation:

mixing an aqueous solution of essendine and biorazlagaemykh polymer dissolved in an organic solvent, to form emulsions or mixing of essendine and biorazlagaemykh polymer in a single solvent or mixed solvent to form a solution of a homogeneous mixture;

spray drying the resulting emulsion or solution to obtain the primary microspheres;

suspending the resulting primary microspheres in an aqueous solution of coating material for surface layer formation on each microsphere; and

leaching and freeze-drying of microspheres with an educated coating layer.

The organic solvent may be one or more solvent selected from the group consisting of chloroform, ethyl acetate, methylene chloride and methyl ethyl ketone, and preferably it can be methylene chloride. A single solvent may be one will dissolve the LEM or more, selected from the group consisting of glacial acetic acid and formic acid, and a mixed solvent may be such that mixes one or more solvent selected from the group consisting of an alcohol having from 1 to 5 carbon atoms, glacial acetic acid, formic acid, dimethyl sulfoxide and N-methylpyrrolidone, and one or more solvent selected from the group consisting of chloroform, ethyl acetate, methyl ethyl ketone and methylene chloride, mixed, and preferably it is a mixed solvent of methanol and methylene chloride.

In accordance with the present invention, the method may further include the operation of adding a protective colloid material in any conventional manner, and preferably protective colloidal material can be added to the operation of the coating of the microspheres covering material.

The preferred concentration of coating material dissolved in the aqueous phase or in the aqueous solution may be from 0.01 M to 1 M, and preferably from 0.1 M to 0.5 M lower concentration of coating material than the above range, it is not possible to completely cover the surface of the microspheres covering material, while a higher concentration of coating material than the above range leads to oversaturation of the solution covering the of material, that may not lead to an increased effect on controlling the initial peak, and thus, the concentration of coating material preferably may be in the above range.

In the method according to the present invention, the types and content of essendine, biodegradable polymers and coating materials are described above.

Extendedstay composition of the present invention may be oral or parenteral routes, and preferably parenterally, for example intravenously, subcutaneously, intramuscularly, intraperitoneally, etc. Therefore, in the preferred embodiment of the present invention extendedstay the composition can be used as a solution for injection in the form of a dispersed solution. An effective amount of the composition may be appropriately selected depending on the age of the subject, type and severity of the disease and condition of the subject, and the dosage of the active ingredient in the composition may range from 0.01 to 100 μg/kg/day, and more preferably, from 0.1 to 10 µg/kg/day, the dose can be entered at once or divided into several times.

Further, the present invention is explained in more detail with reference to the following examples. These examples, however, should not be construed as limiting the marijuana scope of the present invention in any way.

EXAMPLE 1

<Example 1> Obtaining microspheres containing Asendin a 4-way spray drying

4,850 g biorazlagaemykh polymer, RG502H (lot No. 1009848, IV=0,19 DL/g), and 0.150 g of essendine-4 (Polypeptide Laboratories, USA) were dissolved until smooth in 97 ml of glacial acetic acid. To obtain microspheres prepared solution was placed in a spray dryer (SODEVA, France)equipped with an ultrasonic nozzle (Sono-tek, 120 kHz) with a flow rate of 1.5 ml/min using a piston pump at a flow of dry air at a temperature of 180°C. the Obtained microspheres were suspensibility in 0.5 M aqueous solution of lysine (part 1-1), in 0.01 M aqueous solution of lysine (part 1-2), 0.1 M aqueous solution of histidine (part 1-3) and 0.5 M aqueous solution of arginine (part 1-4), respectively, in which the solutions contains 1% (weight/volume) of polyvinyl alcohol (trademark of polyvinyl alcohol Gohsenol, EG-50) as a protective colloid; stirred for three hours, were collected, washed with distilled water and then subjected to freeze-drying. For comparison, we performed the same operations suspending, mixing, washing and freeze-drying except for using 1% aqueous solution of polyvinyl alcohol (weight/volume) without covering materials (part 1).

<Example 2> Effects kompozitsiiu based on polymer

Microspheres containing Asendin-4 were obtained in the same manner as in example 1 except for the use of RG503H (lot No. 1006370, IV=of 0.38 DL/g, the compounds 2, 2-1 and 2-2), the mixture in the same amount of RG502H and RG503H (lot No. 1009848: lot number 1006370=1:1, IV=0,29 DL/g, the compounds 3 and 3-1), RG504H (lot No. 1016605, IV or=0.51 DL/g, compounds 4 and 4-1), 5050DL 2A (lot No LP-207, IV=of 0.18 DL/g, compounds 5 and 5-1), and 5050DL 4A (lot # LP-206, IV=0,46 DL/g, compounds 6 and 6-1), as biorazlagaemykh polymer.

<Experimental example 1-1> Test effects of coating of the microspheres

The content of essendine in the microspheres obtained in examples 1 and 2 was quantified in the following way. Asendin-4 (Polypeptide Laboratories, USA) was dissolved in DMSO (dimethyl sulfoxide)was diluted with DMSO to concentrations of 2, 5, and 10 μg/ml, respectively, which were used as standard solutions, and subjected to fluorescence measurement method for excitation of the Ex 280 nm and Em radiation of 350 nm using a fluorescence spectrometer (Cary Eclipse, Varian, USA) to obtain the measurement scale. The obtained microspheres were dissolved in DMSO to a concentration of 150 μg/ml, and then the fluorescence measured at him, extrapolated to the scale of measurement, thereby determining the content of essendine in the microspheres.

To determine the content of coating materials used in the composition of the present invention, and the company and, lysine, arginine, histidine, etc. contained in the surface of the microspheres, the method was used for quantitative analysis fluorescamine. The solution, in which the obtained microspheres were dissolved in DMSO to a concentration of 150 μg/ml, was mixed with 0.01 percent acetone solution fluorescamine (weight/volume) and 0.5m solution of sodium borate (pH 9,5), maintained at room temperature for 20 minutes and subjected to fluorescence measurement method for excitation of the Ex 392 nm and Em radiation 480 nm using a fluorescence spectrometer (Saga Eclipse, Varian, USA). Applying the same method used covering materials were dissolved in DMSO and diluted by DMSO to concentrations of 2, 5, and 10 μg/ml, respectively, for the standard solutions. After this, the measured fluorescence method to obtain a measurement scale, thereby fulfilling the quantitative analysis covering materials from the surface of the microspheres.

To confirm the inhibitory effect of the initial peak due to the microspheres were measured in vitro released quantities of microspheres covered with a covering material, and existing uncoated microspheres. 10 mg of each type of microspheres were suspended in 1 ml of control solution on the release (10 mm HEPES (biological buffer that represents the sodium salt of N-(2-g is proxetil)piperazine-N'-2-econsultancy acid note. the translations.), pH 7.5, 100 mm NaCl), and incubated at 37°C with constant rotation 5 revolutions per minute. After 1 and 24 hours, each sample was collected and subjected to centrifugation. Released a number of essendine in the supernatant was determined by measuring by the method of fluorescence at excitation Ex 280 nm and Em radiation of 350 nm.

The content and the initial peak in vitro microspheres obtained in this example were analyzed in accordance with the foregoing description, and the results were summarized in the following Table 1. Table 1 shows the decrease in the initial peak in vitro depending on the types of coating materials and biodegradable polymers.

Table 1
Part No.PolymerSuspensionNama
Chan
Naya load (%)
The actual content of drug (%)The main content of organic materials in surface(%)Release after 1 hour (%)Visvobodi
tion after 24 hours (%)
1N1% on Ivanilova alcohol 3was 2.76-4,509,90
1-1N1% polyvinyl alcohol + 0,5M lysine32,730,2490,793,84
1-2N1% polyvinyl alcohol + 0,01M lysine32,720,0993,765,66
1-3N1% polyvinyl alcohol + 0,1M histidine32,710,0151,533,51
1-4N1% polyvinyl alcohol + 0.5m arginine32,560,1561,464,60
2N 1% polyvinyl alcohol32,88-1,401,50
2-1N1% polyvinyl alcohol + 0,5M lysine32,960,0570,000,29
2-2N1% polyvinyl alcohol + 0,1M histidine32,850,1320,000,58
3N:N1% polyvinyl alcohol32,75-2,804,0
3-1N:N1% polyvinyl alcohol + 0,5M lysine32,910,0560,000,75
4N 1% polyvinyl alcohol32,46-1,232,25
4-1N1% polyvinyl alcohol + 0,5M lysine32,470,0180,810,84
55050DL 2A1% polyvinyl alcohol32,53-1,311,95
5-15050DL 2A1% polyvinyl alcohol + 0,5M lysine32,540,0341,021,66
65050DL 4A1% polyvinyl alcohol32,40-1,212,03
6-1 5050DL 4A1% polyvinyl alcohol + 0,5M lysine3of 2.510,0180,790,82

As shown in Table 1, revealed that the released amount of the compositions covered with the covering material in accordance with the present invention, in the first hour and after 24 hours are reduced compared to compounds 1, 2, 3, 4, 5 and 6, which only suspensions in a protective colloid, solution of polyvinyl alcohol and then spray drying. Such effects are obtained regardless of the viscosity range of the polymer and are important in preventing side effects caused by the sharp increase in the initial concentration in blood immediately after injection extendedstay microspheres with controlled release.

<Experimental example 1-2> Decrease of drug concentration in the blood at the initial stage after the introduction in accordance with the viscosity of polymers and coating materials

Because side effects of Akindinov caused by a sharp increase in the concentration of the drug in the blood at the initial stage after the introduction, it is very important to prevent the increase in the concentration of the drug in the blood due to the initial high is obozrenie drug immediately after its introduction. It was found that when using the compositions in accordance with the present invention the concentration of drug in the blood reaches a peak within one hour after injection and then decreased. To determine the bioavailability and maximum initial concentration in the blood (conc. after 1 hour) after administration of the compositions obtained in examples 1 and 2, these compounds were introduced to male rats S. D. (genetic lines Sprague-Dawley - note. translation.) (350±20 g). Extendedstudies microspheres obtained as described above were suspended in culture medium (0,5% (mass fraction) sodium carboxylmethylcellulose, 5% (mass fraction) of mannitol and 0.1% (mass fraction) tween 80 (Polysorbate 80 - note. translation.) and then introduced via subcutaneous injection in a dose of 0.6 mg (essendine)/kg after anesthesia with ether. Blood was taken from tail vein at time 0 and at the end of the first hour, and in the 1st, 2nd, 4th, 7th, 14th, 21st and 28th day after administration, and made centrifugation at 12000 rpm at 4°C for 10 minutes. He then assembled obtained from this serum and placed it in storage at -20°C. Asendin in serum was quantified using a kit enzyme immunoassay (EC-070-94, Phoenix Pharmaceuticals, Inc., USA), and the relative bioavailability compared with the area under the curve obtained for g is the Afik "concentration in the blood - time."

The obtained graphs of the concentration in the blood is shown in Fig.1-3, and the results obtained are summarized in Table 2. Table 2 shows the results of reducing the concentration of drug in the blood at the initial stage after the introduction and comparison of area under the curve in accordance with the viscosity of coating materials and polymers.

Table 2
SOS
Tav No.
PolymerSuspensionThe actual content of the medicinal product (wt.%)Concentration in 1 hourThe area under the curve (PG·day/ml)
1N1% polyvinyl alcoholwas 2.7610969 (1 hour)24169
1-1N1% polyvinyl alcohol + 0,5M lysine2,73900 (1 hour)of 26,681
2N1% polyvinyl alcohol 2,883561 (1 hour)5401
2-1N1% polyvinyl alcohol + 0,5M lysine2,96159 (1 hour)5569
3N:N1% polyvinyl alcohol2,756363 (1 hour)8030
3-1N:N1% polyvinyl alcohol + 0,5M lysine2,91320 (1 hour)10909

As shown in Figure 1-3 and in Table 2, revealed that uncovered the compositions exhibit higher peak concentrations in the blood at the initial stage after the introduction than covered wagons. In addition, it also revealed that the polymer RG502H, with very low viscosity, showed the highest value of the area under the curve, i.e. the highest bioavailability, and that the floor covering materials improves the bioavailability of both compounds with polymers having high molecular weight and compositions with polymers having low molecular weight. In conclusion, despite the fact bioavailability depends on the viscosity of the polymer used, effective inhibition of the initial peak, which cannot be achieved using existing structures obtained by conventional means, is achieved by coating covering materials in accordance with the present invention.

<Example 3> Obtain microspheres with different drug loading

Biodegradable polymer RG502H and Asendin-4 were mixed so as to ensure the maintenance of essendine-4 with a mass fraction of 1% (formulations 7 and 7-1) and mass fractions of 7% (compounds 8 and 8-1, respectively, and the mixtures were dissolved in glacial acetic acid. The resulting solution was subjected to spray drying in the same manner as in example 1 to obtain microspheres. The obtained microspheres were suspensively in 1% aqueous solution of polyvinyl alcohol (compounds 7 and 8), and an aqueous solution of 1% polyvinyl alcohol and 0.5 M lysine (compounds 7-1 and 8-1, respectively, for three hours, and then collected, washed with distilled water and subjected to lyophilization.

<Experimental example 2> Reduced initial peak depending on various drug load

Quantitative analysis of the initial peak of the microspheres obtained in Example 3 was produced by the same method as in experimental example 1-1, and the results obtained are summarized in Table 3. Table 3 shows the effect of coating covering m is materials depending on the content of the medicinal product.

Table 3
Part No.Scheduled load (%)The actual content of drug (%)The main content of organic materials in surface(%)Release after 1 hour (%)Release after 24 hours(%)
710,85-3,06a 3.87
7-110,810,2952,633,68
13was 2.76-4,509,90
1-132,730,2490,793,84
875,79- 8,0011,34
8-175,851,6362,045,47

As shown in Table 3, compounds 1, 7 and 8, which are not covered with the covering materials have an increased initial peak in accordance with the increase in the number of essendine entered in biodegradable polymer, while the compounds 1-1, 7-1 and 8-1, which is covered with a covering material, demonstrate significantly reduced the initial peak, despite the number of essendine entered in the biodegradable polymer.

<4> Obtaining microspheres containing Asendin-4, using a double emulsion

970 mg RG502H dissolved in 3,23 ml dichloromethane (Junsei Chem.). 30 mg of essendine-4 dissolved in 0.3 ml of distilled water was added to the obtained solution RG502H and dispersively ultrasound to obtain a primary emulsion of the type water-in-oil". The obtained emulsion was injectively in 270 ml of 0.5% (weight/volume) aqueous solution of polyvinyl alcohol with stirring with a speed of 5000 rpm to obtain an emulsion of the type water-in-oil-water. The emulsion was suspensively at 4000 rpm at 40°C for one hour, thereby removing dichloromethane and hardening p is limera, and then the obtained microspheres were collected. The collected microspheres were washed twice with distilled water and subjected to lyophilization to obtain microspheres. In the process of obtaining compositions in the same way as described above, suspension for injection box primary emulsion was suspensively in 1% polyvinyl alcohol (composition 9), 0.5 M aqueous solution of lysine + 1% polyvinyl alcohol (9-1), 0.5 M aqueous solution of Tris (tris(hydroxymethyl)aminomethane - note. translation.) + 1% polyvinyl alcohol (9-2), 0.5 M aqueous solution of urea + 1% polyvinyl alcohol (9-3), 0.05 M aqueous solution of creatinine + 1% polyvinyl alcohol (9-4), 0.5 M aqueous solution of creatinine + 1% polyvinyl alcohol (9-5), respectively, for one hour and was collected, washed with distilled water and subjected to lyophilization.

Image obtained microspheres under an electron microscope, as described above, is shown in Figa and 4b. Figa shows the structure 9, which is not covered with the covering material, and Fig.4b 9-1 shows the composition, which is covered with a covering material. As shown in Fig.4b reveals that the composition of the present invention has a smooth surface.

<Experimental example 3> Reduced initial peak, depending on the type of covering material

Quantitative analysis of release of the drug from the micro is fer, obtained in example 4, within the first 24 hours after administration was carried out by the same method as in experimental example 1-1, and the results obtained are summarized in Table 4. Table 4 shows the reduced initial peak, depending on the covering material.

Table 4
Part No.SuspensionRelease after 1 hour (%)Release after 24 hours (%)
91% polyvinyl alcohol7,4513,88
9-11% polyvinyl alcohol + 0,5M lysine0,871,87
9-21% polyvinyl alcohol + 0,5M tris5,79to 9.91
9-31% polyvinyl alcohol + 0,5M urea2,235,04
9-41% polyvinyl alcohol + 0,05M creatinine2,20 3,06
9-51% polyvinyl alcohol + 0,5M creatine0,891,23

As shown in Table 4, despite the fact that reduced the value of the initial peak varies slightly depending on the type of covering material microspheres formulations 9-1 9-5...covered with a covering material, demonstrate significantly reduced the initial peak in comparison with microspheres composition 9, not covered with the covering material.

<Comparative example> Obtaining microspheres loaded with accendino-4 and covering materials, and the measurement of the initial peak

970 mg RG502H dissolved in 3,23 ml dichloromethane (Junsei Chem.). 30 mg of essendine-4 and 6.68 mg lysine was dissolved in 0.3 ml of distilled water and added to the resulting solution RG502H to obtain a primary emulsion of the type water-in-oil". The obtained emulsion was suspensively in aqueous solution of 1% polyvinyl alcohol, and microspheres composition 10 was obtained in the same manner as in example 4. In addition, 970 mg RG502H and 6.68 mg lysine was dissolved in 3,23 ml dichloromethane (Junsei Chem.). To the resulting solution was added 30 mg of essendine-4 dissolved in 0.3 ml of distilled water to obtain a primary emulsion of the type water-in-oil". The emulsion was suspensively in aqueous solution of 1% polyvinyl the CSOs alcohol to obtain microspheres of part 11.

Image obtained above compounds 10 and 11 under the electron microscope, as described above, is shown in Figs and 4d. As shown in Figs obtained in the comparative example, the microspheres have a lot of pores on their surfaces.

The released amount of the microspheres obtained in the comparative example, in the first 1 hour and 24 hours were appropriately measured by the same method as in experimental example 1-1, and the results obtained are summarized in Table 5. Table 5 shows the change in the value of the initial peak, depending on the ways in which added covering materials in the manufacture of microspheres.

Table 5
SOS
Tav No.
The primary emulsionSuspensionRelease after 1 hour (%)Release after 24 hours (%)
9N, Asendin-41% polyvinyl alcohol7,4513,88
9-1N, Asendin-41% polyvinyl alcohol + 0,5M lysine 0,871,87
10N, Asendin-4 + lysine (aqueous phase)1% polyvinyl alcohol65,6371,64
11N + lysine (oil phase), Asendin-41% polyvinyl alcohol80,3187,00

As shown in Table 5, when the covering material is simply put together with accendino without forming a coating layer or are simply mixed with polymers, there is excessive initial peak, which is a critical defect, not allowing accendino take the form of controlled release.

As shown in Figs and 4d, the addition of coating materials in the oil phase or the aqueous phase of the primary emulsion increases the porosity of the surface of the microspheres. In conclusion, the addition of covering materials inside the microspheres increases the porosity of the surface, which, ultimately, leads to excessive initial peak of the drug contained within them. Conversely, microspheres covered with a covering material, in accordance with the present invention, no increase Pori the openness of the surface and show a lower initial peak, the structure 9 having a smooth surface, but not covered with the covering material.

In conclusion, existing extendedstudies compositions obtained by conventional means, for example, disclosed in Korea patent No. 140209, do not allow to achieve the desired reduction of the initial peak, and therefore, they do not have the advantage of using an effective extendedstay compositions because of side effects due to excessive initial peak. Conversely, the composition of the present invention is very useful in the development extendedstay microspheres of controlled release, to meet the requirements vysokokontrastnoe initial release. In addition, the present invention can achieve high bioavailability attendancebased composition, which cannot be achieved by conventional technology for controlling an initial peak attendancebased composition.

<Example 5> Obtaining microspheres containing Asendin-3 way spray drying

4,850 g biorazlagaemykh polymer, RG502H (lot No. 1009848, IV=0,19 DL/g), and 0.150 g of essendine-3 (Peptron Inc., South Korea), melted to a homogeneous state in 97 ml of glacial acetic acid. To obtain microspheres obtained solution was fed to the spray dryer (SODEVA, France)equipped with an ultrasonic nozzle (Sono-tk, 120 kHz), using a piston pump at a flow rate of 1.5 ml/min and the flow of dry air with a temperature of 180°C. the Obtained microspheres were suspensively 0.5 aqueous solution of lysine with added 1% (mass/vol) polyvinyl alcohol (polyvinyl alcohol Gohsenol, EG-50) as a protective colloid, was stirred for three hours, was collected, washed with distilled water and then subjected to lyophilization.

<Example 6> Obtaining microspheres containing Asendin-4(1-28)amide, the method of spray drying

4,850 g biorazlagaemykh polymer, RG502H (lot No. 1009848, IV=0,19 DL/g), and 0.150 g of essendine-4(1-28)amide (Peptron Inc., South Korea), melted to a homogeneous state in 97 ml of glacial acetic acid. To obtain microspheres prepared solution was fed to the spray dryer (SODEVA, France)equipped with an ultrasonic nozzle (Sono-tek, 120 kHz), using a piston pump at a flow rate of 1.5 ml/min and the flow of dry air with a temperature of 180°C. the Obtained microspheres were suspensively in 0.5 M aqueous solution of L-Lys-L-Thr-L-Thr-L-Lys-L-Ser with added 1% (mass/vol) polyvinyl alcohol (polyvinyl alcohol Gohsenol, EG-50) as a protective colloid, was stirred for three hours, was collected, washed with distilled water, was suspensively in 10 ml of 10% aqueous solution of D-mannitol (mass fraction) and then subjected is ifilesize.

<Example 7> Obtaining microspheres containing Asendin-4, method of separation of phases.

To obtain a primary emulsion 0.1 g of essendine-4 (Polypeptide Laboratories, USA) was dissolved in of 1.86 ml of distilled water was slowly injectively in the solution in which was dissolved 1.86 g RG502H (lot No. 1009848, IV=0,19 DL/g) in 23,32 ml of dichloromethane, and was dispersively ultrasound. The resulting emulsion is homogenized by the addition thereto of 58.8 g of silicone oil for the formation of the embryonic microspheres. A mixture of 400 g of heptane and 50 g of ethanol was slowly added to formed the embryonic microspheres under stirring at a speed of 500 revolutions per minute and maintaining the temperature of 3°C for curing the embryonic microspheres. After stirring for about one hour the solvent was removed by decantation. Then to the resulting additional added 200 g of heptane and stirred for one hour to remove silicone oil and dichloromethane from embryonic microspheres. The obtained microspheres were filtered, collected, washed with heptane at 4°C and dried in vacuum to prepare the microspheres. The prepared microspheres were suspensively 0.5% (weight/volume) of polyvinyl alcohol and 0.5 M aqueous solution of lysine for one hour, collected, washed with distilled water and made the lyophilization for the manufacture of composition.

As pokazanev the above examples, the present invention provides a new composition with assindysemiemia microspheres with controlled-release, having reduced side effects and improved bioavailability by covering the surface of the microspheres covering materials, which reduces the excessive release of drug at the initial stage after injection.

1. Microsphere controlled release, having a coating layer containing
the core containing Asendin as an active ingredient and a biodegradable polymer, and
the covering layer that covers the core covering material, and attendin is accendino-4 (SEQ ID NO:2), biodegradable polymer is a polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), a copolymer of lactide and glycolide (PLGA), complex polyarteritis, polyanhydride, polyhydroxyalkanoic acid, polycaprolactone and polyalkylacrylate; copolymer or a simple mixture of two or more polymers selected from the specified group of the polymer; a copolymer of a specified polymer and polyethylene glycol (PEG); or polymer-sugar complex in which sugar is associated with said polymer or specified copolymer,
coating material selected from the group consisting of basic amino acids, polypeptides and organic nitrogen compounds, pricemoney amino acid is one or more, selected from the group consisting of arginine, lysine and histidine; the polypeptide is a L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and an organic nitrogen compound selected from the group consisting of creatine, creatinine and urea, and the content of the overcoat layer is from 0.01 to 5 parts by weight per 100 parts by weight of the microspheres.

2. Microsphere controlled release according to claim 1, in which the biodegradable polymer has a characteristic viscosity of from 0.1 to 0.6 DL/g

3. Microsphere controlled release according to claim 1, in which the biodegradable polymer has a characteristic viscosity of from 0.15 to 0.31 DL/g

4. Microsphere controlled release according to claim 1, in which the content of essendine is from 0.1 to 10 parts by weight per 100 parts by weight of the microspheres.

5. Microsphere controlled release according to any one of claims 1 to 4, optionally containing one ingredient or more selected from the group consisting of pharmaceutically acceptable protective colloids, fillers, and additives.

6. The method of obtaining extendedstay microspheres with controlled-release, having a coating layer according to claim 1, containing the following:
mixing of essendine and biorazlagaemykh polymer to obtain emulsions of the type water-in-oil" or homogeneous mixture; and
emulsification by adding an emulsion or a homogeneous mixture in water, R is the target of coating material for surface layer formation,
this Asendin is accendino-4 (SEQ ID NO:2), biodegradable polymer is a polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), a copolymer of lactide and glycolide (PLGA), complex polyarteritis, polyanhydride, polyhydroxyalkanoic acid, polycaprolactone and polyalkylacrylate; copolymer or a simple mixture of two or more polymers selected from the specified group of the polymer; a copolymer of a specified polymer and polyethylene glycol (PEG); or polymer-sugar complex in which the sugar is linked to said polymer or specified copolymer, and
coating material selected from the group consisting of basic amino acids, polypeptides and organic nitrogen compounds, and essential amino acid is one or more selected from the group consisting of arginine, lysine and histidine; the polypeptide is a L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and an organic nitrogen compound selected from the group consisting of creatine, creatinine and urea, and the content of the overcoat layer is from 0.01 to 5 parts by weight per 100 parts by weight of the microspheres.

7. The method according to claim 6, in which the concentration of an aqueous solution of coating material is from 0.01 M to 1 M.

8. The method of obtaining extendedstay microspheres with controlled-release, having a coating layer according to claim 1, containing from ewusie operations:
mixing of essendine and biorazlagaemykh polymer to form a homogeneous emulsion or mixture;
curing the resulting emulsion or a homogeneous mixture for the production of primary microspheres; and
the suspending of the initial microspheres in an aqueous solution of coating material for surface layer formation on each microsphere,
this Asendin is accendino-4 (SEQ ID NO:2) biodegradable polymer is a polymer selected from the group consisting of polylactide (PLA), polyglycolide (PGA), a copolymer of lactide and glycolide (PLGA), complex polyarteritis, polyanhydride, polyhydroxyalkanoic acid, polycaprolactone and polyalkylacrylate; copolymer or a simple mixture of two or more polymers selected from the specified group of the polymer; a copolymer of a specified polymer and polyethylene glycol (PEG); or polymer-sugar complex in which the sugar is linked to said polymer or specified copolymer, and
coating material selected from the group consisting of basic amino acids, polypeptides and organic nitrogen compounds, and essential amino acid is one or more selected from the group consisting of arginine, lysine and histidine; the polypeptide is a L-Lys-L-Thr-L-Thr-L-Lys-L-Ser; and an organic nitrogen compound selected from the group consisting of creatine, creatine the and and urea, moreover, the content of a coating layer is from 0.01 to 5 parts by weight per 100 parts by weight of the microspheres.

9. The method of claim 8 in which the curing operation is performed by the method of phase separation or by spray drying method.

10. The method according to claim 8, in which the concentration of an aqueous solution of coating material is from 0.01 M to 1 M.



 

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28 cl, 54 ex, 4 tbl

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30 cl, 15 dwg, 4 tbl

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39 cl, 1 tbl, 10 ex, 9 dwg

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23 cl, 10 ex, 2 tbl

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13 cl, 15 ex, 7 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

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34 cl, 9 tbl, 2 dwg, 6 ex

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22 cl, 3 tbl, 1 ex

FIELD: chemistry.

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EFFECT: obtaining a purified peptide product.

11 cl, 4 tbl, 18 ex

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