JPS61227524A - Prazosin preparation and production thereof - Google Patents

Abstract

PURPOSE:To obtain a prazosin preparation useful as an antihypertensive, having prazosin dispersed in an amorphous state in a compounding base, by dissolving prazosin and a specific compounding base in an organic solvent and removing the solvent. CONSTITUTION:Prazosin and one or more compounding bases selected from PVP, PEG, propylene glycol, water-soluble gel high polymer (e.g., hydroxypropyl cellulose, MC, etc.), base soluble in the stomach (e.g., polyvinylacetal diethylaminoacetate, etc.), enteric base (e.g., hydroxypropylmethyl cellulose phthalate, etc.) is dissolved in an organic solvent and the solvent is removed, to give the titled preparation. A blending ratio of prazosin to the compounding base is preferably 1:10 (weight ratio). Prazosin is dispersed and dissolved in an amorphous state in the base and the preparation has more improved solubility and absorption properties than alpha form of prazosin hydrochloride.

Description

[Detailed description of the invention] The present invention relates to a prazosin formulation and a method for producing the same.

Prazosin is a drug that is poorly soluble in water [more than 10 A of water is required to dissolve 1 g of prazosin hydrochloride crystals (at 20°C)].
It is used to treat hypertension because it has an effect on the circulatory system, dilating peripheral blood vessels, decreasing peripheral resistance, and lowering blood pressure. The therapeutic effects of drugs that act on the circulatory system are closely related to blood concentrations, but the half-life of prazosin from the blood is short, about 2 hours, and it is necessary to take it several times a day. Japanese Patent Publication No. 30-4188 describes the crystal forms of prazosin hydrochloride as α-form, β-form, r-form and anhydrous form with a water content of about 1.5% or less, and hydrates with a water content of 4% or more. and prazosine metalate hydrochloride have been shown to exist. Furthermore, among these various crystal forms, the use of only the relatively highly soluble α-form is indicated for regular tablets and injections, since other crystal forms have problems with solubility and the like. However, the α-form absorbs moisture over time and converts into a stable polyhydrate with low solubility, which poses a problem in maintaining a preparation with good solubility. It is known that pharmaceuticals with insufficient solubility generally have problems with absorption, resulting in decreased bioavailability. The present inventors conducted research to increase the solubility of prazosin and develop a formulation with improved bioavailability. As a result, surprisingly, by combining prazosin with a specific base, hydrochloric acid Prazosin α
The inventors completed the present invention by discovering that a preparation with better solubility than that in the human body could be obtained.

The present invention provides substantially amorphous prazosin and one or two selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, propylene glycol, water-soluble gel polymer, gastric soluble base and/or enteric base. This is a prazosin formulation that is a compound with more than one component (compounding base).

The present invention further provides a method for producing a prazosin preparation, which comprises dissolving prazosin and a blending base in an organic solvent and then removing the organic solvent.

Note that a preparation containing substantially amorphous prazosin can also be produced by adding prazosin to a blended base, heating and dissolving it, and then cooling it, without using an organic solvent.

The most distinctive feature of the prazosin preparation of the present invention is that prazosin is dispersed and/or dissolved in the compounding base in a substantially non-crystalline state, and in this state, prazosin is easily dissolved in water and Absorption from the bloodstream is also improved, and the AUC (Area Under the Blood Concentration One-Hour Curve) is increased and the bioavailability is improved.

Prazosin is preferably a hydrochloride, but it may also be a salt of an inorganic acid such as hydrobromic acid or hydriodic acid, or a free base. When prazosin hydrochloride is used, it may be in a crystal form such as an α-form, a β-form, a γ-form, or a mixture of two or more of these crystal forms.

Among the compounding bases used in the present invention, polyvinylpyrrolidone has an average molecular weight of 10,000 to 1,200,000, preferably 10,000 to 200,000, particularly 10,000 to 50,000.

As polyethylene glycol, the average molecular weight is 200~
20,000, preferably 4,000 or more to produce a solid preparation at room temperature. Propylene glycol is preferably propylene glycol listed in the Japanese Pharmacopoeia.

The water-soluble gel polymer is a substance that easily dissolves in water and forms a film when the solution is dried, and cellulose derivatives such as hydroquinepropylcellulose, hydroxypropylmethylcellulose, and methylcellulosenato are preferable, and mixtures thereof may also be used. can.

The gastrosoluble base is a substance that is insoluble in water but dissolves in an acidic region, such as polyvinyl acetal diethylaminoacetate, dimethylaminoether methacrylate-methyl methacrylate copolymer, etc., and mixtures thereof may also be used. can.

The enteric base is a substance that dissolves at a pH of 5.0 or higher, such as hydroxypropyl methyl cellulose hetatalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, and methacrylic acid methyl methacrylate copolymer. , mixtures thereof can also be used.

The compounding ratio of prazosin to the compounding base is 2 to 30 by weight.
, preferably 1:10. If the blending ratio of the blending base is lower than this, the interaction with prazosin will be weak, and the increase in solubility and bioavailability will not be sufficient. Further, even if the blending ratio is higher than this, no particular effect can be obtained and the amount of solvent used increases, which is economically disadvantageous.

When producing the formulation of the present invention, prazosin and the above-mentioned combination base are first dissolved in an organic solvent. At this time, the solubility of the drug can be further increased by using a surfactant as an additive. A coloring agent, a flavoring agent, a flavoring agent, an anti-adhesive agent, a filler, a disintegrant, a plasticizer, etc. may be added to the dissolved liquid mixture as necessary. In addition, when prazosin is dissolved in the compounding base, the mixture of prazosin and the compounding base may be heated to melt and then cooled, without using an organic solvent.

The organic solvent is then removed from this mixture to obtain a formulation in which prazosin is dispersed and/or dissolved in a substantially non-crystalline form in the formulation base. To remove organic solvents, use a concentration method under reduced pressure or normal pressure or a spray drying method, or use a fluidized bed granulator to granulate pharmaceutical additives (powder, fine granules, granules, or two or more excipients). A method in which the mixture is poured into the mixture (core particles obtained by For example, a method may be used in which a mixed solution is sprayed onto the core particles using a centrifugal fluid granulation coating device, the core particles are coated, and then dried.

Any organic solvent may be used as long as it can dissolve prazosin and the compounding base, and methanol, ethanol, impropatol, acetone, chloroform, methylene chloride, benzyl alcohol, and mixtures thereof are usually used. The organic solvent is used in an amount necessary to dissolve at least each component.

As surfactants, polyoxyethylene alkyl ether, polyoxyethylene sorbitan monooleate,
Polyoxyethylene hydrogenated castor oil, polyoxyl stearate, glycerin fatty acid ester, etc. are used.

Examples of pharmaceutical additives include lactose, sucrose, glucose,
Those commonly used as excipients for pharmaceuticals, such as crystalline cellulose and starch, are preferred.

j Also, a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, polyvinylpyrrolidone, and more preferably a surfactant such as alkyl sulfate or dialkyl sulfosuccinate is blended with these excipients, and the mixture is processed according to a conventional method. Granulated products are available.

Additives such as excipients, disintegrants, lubricants, binders, etc. are mixed with the powders, granules, etc. thus obtained, and then processed into fine granules, granules, hard capsules, tablets, and external preparations. , suppositories, etc.

When preparing an external preparation, it can also be prepared by pouring it into a solution dissolved in an organic solvent and kneading it.

In addition, in this case, a powder or granules containing prazosin with an enteric base and a powder or granules containing prazosin with a base other than the enteric base may be mixed in an appropriate ratio to form a formulation. good.

The preparation of the present invention has a rapid rise in blood concentration.

AUG becomes large and bioavailability can be significantly improved.

Example 1 Lactose 450.0% was added to a fluidized bed granulator. ! 9 and crystalline cellulose 30
g, and 50 g of ethanol, 5 I of prazosin hydrochloride (anhydrous) and 15 g of hydroxypropyl cellulose.
The solution was sprayed and dried to obtain granules. The granules were sieved through a 32-mesh sieve and then filled into No. 2 capsules in an amount of about 200 rng to form hard capsules containing prazosin hydrochloride 2rn9 in each capsule.

Example 2 In the same manner as in Example 1, 475 g of lactose, 5 g of prazosin hydrochloride (anhydrous), 7 of polyvinylpyrrolid, and 2 of 30
Granules were obtained using 0 g and 500 ml of ethanol-k.

Example 6 Granules were obtained in the same manner as in Example 1 using 475I lactose, 5 g of prazosin hydrochloride (polyhydrate), 2910020 g of hydroxyglobil methylcellulose, and 500 ml of ethanol.

Example 4 Prazosin hydrochloride (anhydrous) 5 g and Eudragid E (
20g of ROHM Pharma product) and 500% of ethanol
ml of the solution, the organic solvent was distilled off by spray drying to obtain a powdery substance.

Example 5 490 g of Nonbarrel-101 (product of Freund Sangyo Co., Ltd.: granules of refined white sugar coated with cornstarch) was placed in a centrifugal fluid granulation coating device, and prazosin hydrochloride (anhydrous) was added.
A solution prepared by dissolving 5 g of hydroxypropyl methylcellulose phthalate 200731 5I and Tween 80 in 500 ml of ethanol was sprayed and dried to obtain coated spherical granules, without adding Merck if necessary to prevent the granules from adhering to each other. Ta.

Example 6 After melting white petrolatum 84.9 and glycerin monostearate 5I at about 80°C, a solution of 1 g of 7' lazosine hydrochloride dissolved in 5 g of benzyl alcohol and propylene glycol 5II was added and kneaded with stirring. and got the ointment.

Example 7 Prazosin hydrochloride (anhydrous) 1.5.9 and 1000p of polyethylene glycol 4000 were mixed.

The mixture was heated to 65° C. to dissolve, cooled, and then ground to obtain granules.

Example 8 Polyethylene glycol 3000 590.9 at 65°C
Heat to melt. Add to this prazosin hydrochloride (anhydrous)
Add 5 g, 10 p of 1-menthol and 400 g of propylene glycol*, stir at 500 rpm for 30 minutes to form a viscous mixture.

This is filled into warm hard gelatin capsules and then cooled.
Hard capsules were obtained.

Comparative Example: 5 g of prazosin hydrochloride (anhydrous), 450 I of lactose, 209 I of crystalline cellulose, and 11 carboxymethy A/-1! A/
200 ml of a 5% hydroxypropyl cellulose aqueous solution was added to the mixed powder of CI-S159 and extruded using a screwdriver to obtain granules. The granules were sieved through a 62-mesh sieve and then filled into No. 2 capsules of approximately 200 square centimeters to obtain hard capsules containing prazosin hydrochloride 2rn9 in each capsule.

Test Example 1 A dissolution test was conducted on the formulations A and B of the present invention obtained in Examples 1 and 2, the comparative formulation P obtained in the comparative example, and prazosin hydrochloride crystals (α form). The test is based on the diurnal cycle 10 “Dissolution test method/Second
method (rotating paddle method). Japanese Bureau No. 1 in the container
Add 2 aaml of the solution and a sample equivalent to 20 rv of prazosin hydrochloride, and stir at 200 ml using a stirring blade while keeping the temperature at 37°C.
Stirred at rpm. UV
It was determined by absorbance method. The results are shown in Table 1. The elution from the preparations A and B of the present invention was more rapid than that from the comparison preparation P and the crystals, and the elution amount was also larger.

Table 1 Test Example 2 Preparation A of the present invention and comparative preparation P were orally administered to pegle dogs weighing around 10 ky in an amount equivalent to 2rn9 as prazosin hydrochloride per dog, and the plasma concentration (n, 9/me ) was measured by high performance liquid chromatography. Required by law. The results are shown in Table 2. From this, it is known that the plasma concentration of prazosin when the preparation A of the present invention is administered rises more quickly and is significantly higher than that of the comparative preparation P.

Table 2

Claims (1)

[Scope of Claims] 1. One member selected from the group consisting of substantially amorphous prazosin, polyvinylpyrrolidone, polyethylene glycol, propylene glycol, water-soluble gel polymer, gastric soluble base, and enteric base. Or a prazosin preparation that is a combination with two or more components. 2. Prazosin and 1 selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, propylene glycol, water-soluble gel polymer, gastric soluble base, and enteric coated base
The blending ratio with seeds or two or more ingredients is 1:0.2-30
(weight ratio). 3. The water-soluble gel polymer is hydroxypropyl cellulose, hydroxypropyl methyl cellulose and/or methyl cellulose, the gastric soluble base is polyvinyl acetal diethylamino acetate and/or dimethylaminoethyl methacrylate/methyl methacrylate copolymer, and the enteric group is The formulation according to claim 1, wherein the agent is hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose and/or methacrylic acid/methyl methacrylate copolymer. 4. 1 selected from the group consisting of prazosin and polyvinylpyrrolidone, polyethylene glycol, propylene glycol, water-soluble gel polymer, gastric soluble base and enteric coated base
A method for producing a prazosin preparation, which comprises dissolving a species or two or more components in an organic solvent and then removing the organic solvent.