KR20110026311A - Novel salts of entecavir - Google Patents

Abstract

PURPOSE: A novel salt of entecavir is provided to ensure biological and pharmaceutical activity and high solubility in the water. CONSTITUTION: A novel salt of entecavir contains (+)-(1S)-champhor-10-sulfonate salt of entecavir or hydrate thereof, or p-toluenesulfonate salt or hydrate thereof. A method for preparing the novel salt of entecavir comprises: a step of dissolving entecavir in an organic solvent; a step of adding (1)-(1S)-champhor-10-sulfonate or p-toluene sulfonic acid to the solution and stirring; and a step of evaporating the solvent and adding acetone to form crystal. The organic solvent is methanol. A composition for preventing or treating chronic hepatitis B contains the novel salt as an active ingredient.

Description

Novel salts of entecavir

The present invention relates to novel salts of entecavir.

In general, in order for a drug to be absorbed from the digestive tract and exhibit high pharmacological activity in vivo, the drug must be rapidly eluted from the digestive tract. The dissolution rate of the drug determines the absorption rate of the digestive tract and is an important phenomenon that determines drug concentration in the blood. It depends on the solubility.

Entecavir is [1S- (1α, 3α, 4β)]-2-amino-1,9-dihydro-9- [4-hydroxy-3- (hydroxymethyl) -2- of Formula 1 Methylenecyclopentyl] -6H-purin-6-one and having antiviral activity in animals and humans are well known as therapeutic agents for chronic hepatitis B.

Conventional technology for the entecavir US Pat. No. 5,024,024 discloses the compound represented by the formula (1) and its antiviral activity, in particular, to prevent chronic hepatitis B virus infection, Chinese Patent No. 1310969 Discloses a pharmaceutical composition comprising a low dosage of a compound of Formula 1 above.

The solubility of entecavir is less than 2.5 mg / ml in aqueous and / or neutral physiological buffer solutions at room temperature, which belongs to insoluble compounds. Low solubility typically increases the difficulty of preparing a pharmaceutical formulation, hinders the rapid release of the active ingredient from the formulation, and is used in the manufacture of other formulations or in preparations for parenteral administration, eg in the preparation of solid oral formulations. Affect. Thus, increasing the solubility of insoluble drugs is important to increase the effectiveness and broaden the range of formulations of insoluble drugs, which can also contribute to reducing manufacturing costs.

Salt formation provides a means of changing the physicochemical and biological properties of a drug without modifying the drug's chemical structure. The form of the salt can greatly affect the properties of the drug. The selection of suitable salts is determined in part by the proportion and amount of crystalline structure obtained. In addition, hygroscopicity, stability, solubility and process profile of the drug in salt form are important considerations, in particular the solubility of the drug in salt form is an important property that can affect its suitability for use as a drug.

Thus, in order to increase the solubility of the entecavir, a study on salts has been conducted by the drug molecular design experiment method until now, the charge density of the nitrogen atom of the 2-amino group of the purine ring due to the nature of the chemical structure of entecavir ) Was found to be 0.53 and pKb was found to be only 4.31. This meant that entecavir could not form acid salts with any acid anions.

Korean Patent Publication No. 2008-0033186 discloses the entecavir and hydrobromic acid (pKa = -9), hydrochloric acid (pKa = -7), sulfuric acid (pKa = -7), nitric acid (pKa = -1.64), phosphoric acid (pKa = 2.12 ), Acid salts of some inorganic acids, including carbonic acid (pKa = 3.88), have been studied, of which double reactions with hydrobromic acid, hydrochloric acid, sulfuric acid and nitric acid can form stable salts. It was disclosed that it was not stable and did not react with carbonic acid. Also, entercavir and methanesulfonic acid (pKa = 0.5), maleic acid (pKa = 1.92), tartaric acid (pKa = 2.98), fumaric acid (pKa = 3.02), citric acid (pKa = 3.13), malic acid (pKa = 3.4), lactic acid ( Acid salts with some organic acids, including pKa = 3.86) and acetic acid (pKa = 4.75), have been studied, of which double can be reacted with methanesulfonic acid, maleic acid, tartaric acid, fumaric acid and citric acid to form stable salts. It has been disclosed that salts formed by reaction with, malic acid, lactic acid and acetic acid are not stable.

Accordingly, the present inventors, while searching for a new salt to improve the solubility while maintaining the activity of the conventional entecavir, found a salt substituted with various substituents of entecavir, the compound has a high solubility in water, the activity of the conventional entecavir The present invention was confirmed to be equivalent to or higher than that of the present invention.

It is an object of the present invention to provide a novel salt of entecavir with improved solubility.

In order to achieve the above object, the present invention provides a novel salt of entecavir including (+)-(1S) -camphor-10-sulfonate or p-toluenesulfonate of entecavir.

The novel salts of entecavir according to the present invention exhibit activity equivalent to the biological and pharmaceutical activities of entecavir known in the art, and are particularly chronic because of its excellent solubility in water compared to the crystalline forms of entecavir and salts thereof. It can be usefully used as a therapeutic agent for hepatitis.

The present invention provides novel salts of entecavir.

Specific examples of the novel salts of entecavir according to the present invention are as follows:

(1) (+)-(1S) -camphor-10-sulfonate of entecavir; And

(2) p-toluenesulfonate of entecavir.

In the present invention, the novel salts of entecavir also include their suitable pharmaceutically acceptable solvates and / or hydrates.

In addition, the novel salt according to the present invention

Dissolving entecavir in an organic solvent (step 1);

Adding (1)-(1S) -camphor-10-sulfonic acid or p-toluenesulfonic acid to the entecavir solution prepared in step 1 and stirring (step 2); And

The solution prepared in step 2 may be prepared by a method comprising the step of evaporating the solvent under reduced pressure and adding acetone to form crystals to prepare a new salt of entecavir (step 3).

First, step 1 is a step of dissolving entecavir in an organic solvent.

In this step, the entercavir may be prepared by the method of the prior art or commercially available.

In this step, methanol may be used as the organic solvent, but is not limited thereto.

Next, step 2 is a step of adding and stirring (1)-(1S) -camphor-10-sulfonic acid or p-toluenesulfonic acid to the entecavir solution prepared in step 1 above.

The step may be performed by a method commonly used in the art.

Next, step 3 is a step of preparing a new salt of entecavir by evaporating the solvent under reduced pressure in the solution prepared in step 2 and adding acetone to form crystals.

Through this step, entecavir new salt crystals are spontaneously formed by evaporating the solvent under reduced pressure and adding acetone, and the crystals formed can be obtained through filtration and vacuum drying.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating chronic hepatitis B, which contains the novel salt of entecavir as an active ingredient.

The composition containing the novel salt according to the present invention as an active ingredient shows an activity equivalent to the biological and pharmaceutical activity of the free base of entecavir known in the art, and in particular, because it has better solubility in water than the conventional crystalline entecavir, It can be usefully used for the prevention or treatment of chronic hepatitis B.

The composition containing the novel salt according to the present invention as an active ingredient may be used in the form of a general pharmaceutical preparation.

That is, the novel salts according to the invention can be administered in various formulations, oral and parenteral, in actual clinical administration. In addition, when formulated, in addition to the active ingredient, it may be prepared by including one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added.

Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like, which may comprise at least one excipient in the compound, for example starch, calcium carbonate, sucrose (Sucrose) or lactose (Lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

In addition, liquid preparations for oral administration include suspending agents, liquid solutions, emulsions, and syrups, and various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. This may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Furthermore, the pharmaceutical compositions of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection. To formulate into parenteral dosage forms, the compounds are mixed in water with stabilizers or buffers to prepare solutions or suspensions, which are formulated in unit dosage forms of ampoules or vials.

The novel salt according to the present invention is preferably included in 0.1 to 50% by weight relative to the total weight of the composition. However, the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient, the type of disease, and the degree of progression.

The preferred dosage of the novel salt according to the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and can be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer from 0.1 mg / kg to 10 g / kg, preferably from 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.

< Example  1> Antecavir  (+)-(1S)- Camper -10- Sulfonate  Produce

15 ml of methanol was added to 300 mg (0.001 mol) of entecavir to dissolve the solids, and then 0.24 g of (+)-(1S) -camphor-10-sulfonic acid was slowly added dropwise. The mixture was stirred until uniform and the solution was evaporated under reduced pressure to remove most of the methanol. Then 15 ml of acetone were added to the residue. While the crystals were formed, the solution was left, the crystals were filtered off, washed with a small amount of acetone and dried at 40 ° C. in vacuo to yield 0.3 g (80.1%) of the title compound.

< Example  2> Antecavir  p- Of toluenesulfonate  Produce

300 mg (0.001 mole) of entecavir was added dropwise to 15 ml of methanol to dissolve the solid, and then 0.17 g of p-toluenesulfonic acid was slowly added dropwise. The mixture was stirred until uniform and the solution was evaporated under reduced pressure to remove most of the methanol. Then 15 ml of acetone were added to the residue. While the crystals were formed, the solution was left, the crystals were filtered off, washed with a small amount of acetone and dried at 40 ° C. in vacuo to yield 0.34 g (90%) of the title compound.

< Formulation example  1> Preparation of Pharmaceutical Formulations

<1-1> Powder  Produce

2 g of new salt of entecavir

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of new salt of entecavir

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<1-3> Preparation of Capsule

100 mg of new salt of entecavir

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml of new salt of entecavir

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

The new salt of entecavir was dissolved in an appropriate volume of sodium chloride BP for injection, and the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection and mixed well. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

Claims (4)

Novel salts of entecavir comprising (+)-(1S) -camphor-10-sulfonate of entecavir or hydrates thereof, or p-toluenesulfonate or hydrates of etecavir. Dissolving entecavir in an organic solvent (step 1); Adding (1)-(1S) -camphor-10-sulfonic acid or p-toluenesulfonic acid to the entecavir solution prepared in step 1 and stirring (step 2); And The method of claim 1, wherein the solution prepared in step 2 is evaporated under reduced pressure, and acetone is added to form crystals to prepare a new salt of entecavir (step 3). 3. The process for producing novel salts of entecavir according to claim 2, wherein the organic solvent is methanol. Chronic hepatitis B prophylaxis or treatment composition containing the novel salt of entecavir of claim 1 as an active ingredient.