The compositions of estramustine with improved pharmaceutical properties

 

(57) Abstract:

The invention relates to pharmaceutical compositions containing the derivative estramustine and cyclodextrin, in particular, to obtain drugs suitable for oral administration derived estramustine patient suffering from a tumor. The tool has higher bioavailability. 2 C. and 10 C. p. F.-ly, 23 PL.

The invention relates to pharmaceutical compositions containing the derivative estramustine and cyclodextrin.

Cyclodextrins [here and below the Central Depository (CD)] is a well - known oligosaccharides composed of D-glucose residues having a structure with a cylindrical void that can include a variety of guest molecules. In fact, one of the most interesting properties of the CD lies in their ability to form inclusion or complexes. This interaction is strongly dependent on the hydrophobicity of the guest molecules, spatial difficulties between the medicinal product and the AC and the size of the CD cavity. Anyway, this type of complexation gives new physico-chemical properties of drugs, and its intensive use in the pharmaceutical field to improve the solubility Andas a consequence, their dissolution characteristics and bioavailability.

More generally, the complexing the drug - CD is used to improve the bioavailability of the active molecules, which have very low solubility in water, but a good rate of absorption (suction) through biological membranes [D. Duchene et al. STP Pharma, 323 (1985)] . These inclusion complexes are usually obtained in a liquid medium, and then after drying get them in powder form.

Suitable various methods of obtaining solid compounds include, such as a mixture of [K. Uekama et al. Int. J. Pharm. , 10, 1 (1982)] , the coprecipitation [K. Uekama et al. Int. J. Pharm. , 16, 327 (1983)] , the spray drying [H. P. R. Bootsma et al. , Int. J. Pharm. , 51, 213 (1989)] , drying by freezing [P. Chiesi et al. , U.S. patent 4603123, July 29 (1986)] .

In some cases, the formation of the complex in the solid phase is thermodynamically spontaneous and inclusion can usually be achieved by rubbing [C. Torricelli et al. Int. J. Pharm. , 71, 19 (1991)] .

We unexpectedly found that the characteristics of the bioavailability of certain drugs can be further enhanced through the CSD also for molecules with high solubility in water, which theoretically does not require any particular approach, in particular p is th form.

This invention relates to a pharmaceutical composition containing the derivative estramustine and cyclodextrin.

Derivatives estramustine in accordance with the invention are, for example, the compounds of formula (I)

< / BR>
where R stands for

< / BR>
where R1represents C1-C4alkyl and n = 0, 1, or 2,

and pharmaceutically acceptable salts.

Especially preferred derivatives of estramustine are the compounds of formula (I), where R denotes

< / BR>
i.e. Estramustin-17-phosphate, and its sodium salt, i.e., Estramustin-17-disodium phosphate; or where R denotes

< / BR>
i.e. Estramustin-17-L-alaninate, or methansulfonate salt, i.e., Estramustin-17-L-alaninate methanesulfonate.

Estramustin-17-phosphate disodium salt (Patent UK 1016959) is a drug used in prostate tumors, most commonly in the treatment of patients, which cannot be further treated with hormones, and patients with a poor prognosis. The drug is applied for all patients whose disease has spread through metastatic tumors. As the swelling decreases, the pain caused by the tumor, is also weakening. Although n is the disodium salt has strong limitations when administered orally due to its interaction with food and drink; you must enter the drug on an empty stomach in order to avoid re-deposition of the drug, which is called cations, in particular calcium ions [P. O. Gunnarsson et al. , Europ. J. Clin. Pharm. , 38, 189 (1990)] .

This fact significantly reduces the bioavailability of drugs and cause side effects in the gastrointestinal tract.

Estramustin-17-L-alaninate (patent application EP 351561) has the same therapeutic indications that Estramustin-17-phosphate disodium salt, and inherent in it is the same drawback associated with presidenial, but called anions, such as chloride ions.

This invention primarily relates to the use of any CD, natural (-CD, -CD and-CD), synthetic or semi-synthetic (as, for example, hydroxypropyl--CD or dimethyl--CD) or digidratirovannogo [A. Martini et al. , U.S. patent 5126333, June 30, (1992)] .

In particular, the preferred cyclodextrins are-cyclodextrin, hydroxypropyl--cyclodextrin and cyclodextrin.

The authors unexpectedly been found that, when the cyclodextrin is mixed with Estramustine-17-phosphate disodium salt, the solubility of the drug itself ions, very little, because cyclodextrins are able to block the site of interaction of Estramustine-17-phosphate with calcium or other cations.

The formation of the complex in solution between the medicinal product and the corresponding cyclodextrin can prevent re-deposition of free drug or the salt of the drug in physiological conditions.

This phenomenon can have a big advantage with the introduction of drugs, making its bioavailability is higher irrespective of the conditions for empty/non-empty stomach.

Cyclodextrins were suddenly able not only to prevent re-deposition of Estramustine-17-phosphate in the presence of cations, but also allow you to enroll in a solution of a medicinal product, for example, when calcium ions are present in the environment, dissolution, and re-dissolve already excited sediment Estramustin-17-phosphate with calcium.

It is shown that cyclodextrins interact with Estramustine-17-L-alaninato, preventing re-deposition of various kinds of anions.

In addition, you must pay attention to the fact that for this application there is no necessary is to introduce a simple physical mixture of the two chemical components.

The ratio between the drug and the cyclodextrin may vary, for example from 1: 0.5 to 1: 10 (molar ratio). The preferred molar ratio is from 1: 1 to 1: 4. A suitable range is from 1: 1 to 1: 2.

Pharmaceutical composition containing composition of the invention, the drug - cyclodextrin, which is included in the scope of the invention, can be obtained the following well-known and usual ways. The proposed system drug - cyclodextrin can be used to obtain a solid, semi-solid or liquid compositions for oral dosage forms such as tablets, hard or soft gelatin capsules, sachets, and so on , with or without adding one or more fillers commonly used for pharmaceutical formulations. Can be present in pharmaceutically acceptable carriers or diluents.

The dose depends on age, weight, conditions of the patient and route of administration. For example, the dose intended for oral administration to humans ranges from 50 to 1500 mg daily.

This invention relates also to pharmaceutical compositions mentioned above for use in the method l is tion also relates to the use of cyclodextrin in obtaining a medicinal product, suitable for oral administration derived estramustine the patient, and the specified drug contains a derivative of estramustine and cyclodextrin and cyclodextrin upon receipt of a medicinal product for the treatment of the tumor, the drug contains a derivative of estramustine and cyclodextrin.

The composition according to the present invention can be used in the treatment or prevention of a tumor, which includes an introduction to a subject suffering from or Prednisolonum thereto an effective amount of the composition.

The following examples are provided only to better illustrate this invention, but they should not be construed as limiting the scope of invention.

Example 1. To a solution of HCl/KCl buffer (I = 0,1) with a pH of 3.1, containing 640 g/ml Estramustin-17-phosphate disodium salt (EFS, EPS), add the appropriate amount of calcium chloride to achieve a molar ratio of drug: salt in the range from 1: 0 to 1: 1. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are shown in Table 1.eve salt (EFS, EPS) and different amounts of cyclodextrins: -cyclodextrin (-CD), 2-hydroxypropyl--cyclodextrin (SE--CD) or-cyclodextrin (-CD), add the appropriate amount of calcium chloride so that the molar ratio of drug: salt was 1: 1. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are presented in Tables 2a, 2b and 2c.

Example 3. To a solution of HCl/KCl buffer (I = 0,1) with a pH of 3.1, containing about 1 mg/ml Estramustin-17-phosphate disodium salt (EFS, EPS) and different amounts of cyclodextrins: -cyclodextrin (-CD), 2-hydroxypropyl--cyclodextrin (SE--CD) or-cyclodextrin (-CD), add the appropriate amount of calcium chloride in order to obtain the molar ratio of drug: salt 1: 2. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are presented in Tables 3a, 3b, and 3c.

Example 4. To a solution of HCl/KCl buffer (I = 0,1) with a pH of 3.1, containing about 1 mg/ml Estramustin-17-phosphate disodium salt (EFS, EPS) different amounts of cyclodextrins: -cyclodextrin (-CD) or 2-hydroxypropyl--citobi to obtain the molar ratio of drug: salt 1: 4. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are presented in Tables 4a, 4b and 4c.

Example 5. To a solution of HCl/KCl buffer (I = 0,1) with a pH of 3.1, containing about 1 mg/ml Estramustin-17-phosphate disodium salt (EFS, EPS) and 1 mol of calcium chloride per mole EFS add different amounts of cyclodextrins: -cyclodextrin (-CD), 2-hydroxypropyl--cyclodextrin (SE--CD) or-cyclodextrin (-CD), in order to obtain a molar ratio of drug: salt is from 1: 0 to 1: 4, to assess solubilizing properties of cyclodextrins in the dissolution of pre-formed precipitate EFS with calcium. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are presented in Tables 5a, 5b and 5c.

Example 6. To a solution of HCl/KCl buffer (I = 0,1) with a pH of 3.1, containing about 1 mg/ml Estramustin-17-phosphate disodium salt (EFS, EPS) and 2 mol of calcium chloride per mole EFS add different amounts of cyclodextrins: -cyclodextrin (-CD), 2-hydroxypropyl--cyclodextrin (SE--CD) or-cyclodextrin (-CD), so that molar ratio of drug ilen obtained precipitate EFS with calcium. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are presented in Tables 6a, 6 and 6c.

Example 7. To a solution of HCl/KCl buffer (I = 0,1) with a pH of 3.1, containing about 1 mg/ml Estramustin-17-phosphate disodium salt (EFS, EPS) and 4 mol of calcium chloride per mole EFS add different amounts of cyclodextrins: -cyclodextrin (-CD), 2-hydroxypropyl--cyclodextrin (SE--CD) or-cyclodextrin (-CD), so that molar ratio of drug: salt was from 1: 0 to 1: 4, to assess solubilizing properties of cyclodextrins in the dissolution of pre-formed precipitate EFS with calcium. The filtered samples and the number of Estramustine-17-phosphate disodium salt in the solution analyzed by UV-spectroscopy.

The results are presented in Tables 7a, 7b and 7c.

Example 8. Test the rate of dissolution is carried out by comparing the characteristics already sold, free of cyclodextrin composition Estramustin-17-phosphate disodium salt, and the composition containing Estramustine-17-phosphate disodium salt: hydroxypropyl--cyclodextrin (EFS/SE--CD) in a molar ratio of 1: 2. Conditions corresponded to the test soon mol of calcium chloride in the environment dissolved per mole of the drug.

The results are shown in Table 8.

Example 9. Test the rate of dissolution is carried out by comparing the characteristics of different formulations of Estramustine-17-phosphate disodium salt (EFS) containing various cyclodextrins: -cyclodextrin (-CD), 2-hydroxypropyl--cyclodextrin (SE--CD), -cyclodextrin (-CD) or digidrirovanny-cyclodextrin (de-CD) in a molar ratio of 1: 2 with the drug. Conditions corresponded to the test on the rate of dissolution USP XII N 1 (method baskets) in submerged conditions, 37oC, 100 rpm. /min, HCl/KCl buffer pH of 3.1 (I = 0,1) with 1 mol of calcium chloride in the environment dissolved per mole of the drug.

The results are shown in Table 9.

Example 10. Test the rate of dissolution is carried out by comparing the characteristics of different formulations of Estramustine-17-phosphate disodium salt (EFS) containing various cyclodextrins: -cyclodextrin (-CD) or 2-hydroxypropyl--cyclodextrin (SE--CD) in 1: 2 molar ratio with the drug. Conditions corresponded to the test on the rate of dissolution USP XII N 1 (method baskets) in submerged conditions, 37oC, 100 rpm. /min, HCl/KCl buffer pH 6,8 (I = 0,1) with 1 mol of calcium chloride in the environment dissolved per mole of the drug.

The results are shown in Table 11.

1. Pharmaceutical composition for oral administration containing an effective amount of estramustine and cyclodextrin with pharmaceutically acceptable carriers or diluents, in which the derived estramustine and cyclodextrin are present as a physical mixture or pre-prepared complex.

2. The pharmaceutical composition under item 1, where the derivative of estramustine is Estramustin-17-phosphate or Estramustine-17-phosphate disodium salt.

3. The pharmaceutical composition under item 1, where the derivative of estramustine is Estramustin-17-L-alaninate or Estramustin-17-L-alaninate methansulfonate salt.

4. The pharmaceutical composition according to any one of paragraphs. 1-3, where the cyclodextrin is a cyclodextrin, -cyclodextrin, -zicheskaya composition p. 4, where the cyclodextrin is a cyclodextrin.

6. The pharmaceutical composition according to p. 4, wherein the cyclodextrin is hydroxypropyl--cyclodextrin.

7. The pharmaceutical composition according to p. 4, wherein the cyclodextrin is a cyclodextrin.

8. The pharmaceutical composition according to p. 4, where the cyclodextrin is digidrirovanny cyclodextrin.

9. The pharmaceutical composition according to any one of paragraphs. 1-8, where the molar ratio derived estramustine to cyclodextrin is from 1: 0.5 to 1: 10.

10. The pharmaceutical composition according to any one of paragraphs. 1-9, characterized in that it is designed to treat tumors.

11. The use of cyclodextrin as an inhibitor deposition derived estramustine in the gastrointestinal tract upon receipt of a medicinal product containing the derived estramustine intended for oral administration to a patient, in which the cyclodextrin and a derivative of estramustine are in the form of a complex or a physical mixture.

12. The use of cyclodextrin on p. 12, where the specified drug is used to treat tumors.

 

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