HU190082B - Process for producing compozitions well and quickly soluble in water from slowly and wrong soluble active agents containing basic nitrogen atom - Google Patents

Abstract

Easily and quickly water soluble pharmaceutical prepns. are obtd. from pharmaceutical cpds. contg. a basic nitrogen atom, which by themselves dissolve only slowly and with difficulty in water, by preparing an acidified aq. soln. of the basic cpds. with an excess of an easily soluble adjuvant and a pharmaceutically acceptable acid at a pH of 1-2, spray drying the acid soln. and converting the resulting mixt. of the acid addition salt and the easily soluble adjuvant into solid pharmaceutical prods.. Most of the active ingredient in the prods. dissolves in water within 2-5 minutes.

Description

BACKGROUND OF THE INVENTION The present invention relates to a novel process for the preparation of water-soluble and fast-dissolving pharmaceutical compositions containing poorly and slowly soluble basic nitrogen.

As is known, the prerequisite for the efficacy of orally administered drugs is that the active ingredient is dissolved in the gastrointestinal tract of the gastrointestinal tract and is thus ready for absorption. In the case of solids that are poorly soluble in water, the rate of dissolution may be of great importance, since increasing the dissolution rate may improve the bioavailability of the drug (cf. Kedvessy, Gy., Pharmaceutical Technology, V Edition, Medicina, Budapest, 1981; , Wiss, Verlagsges. MbH., Stuttgart, 1973).

Several technological advances are known to increase the dissolution rate.

A frequently used method is to increase the specific surface area of a solid drug substance by fine-comminuting it, for example by air-milling it (for example, István Bayer et al., Drugs and Pharmaceuticals, Technical Publishing House, Budapest, 1976; Kósa, L .: Pharmacy 8, 389 1964). The increase in the dissolution rate in this way is limited by the fact that micronization cannot reduce the particle size of solids to less than about 1 micrometer.

Another known solution is the so-called. preparing a solid solution or solid dispersion. The essence of this is that the poorly water-soluble drug substance is dispersed in a water-soluble, usually high-molecular-weight, excipient.

Appropriate choice of excipient properties, amount, and process employed will allow the drug substance to be present in the resulting product in a molecular distribution, thereby significantly increasing its dissolution rate [Sekiguchi, K. and Obi, N., Chem. Pharm. Bull. 9, 866 (1961); Frank, S.G .: J. Pharm. Sci. 64, 1585 (1975); Fremming, K.H .: Pharm. In Unserer Zeit 2, 109 (1973)].

One method of preparing solid dispersions is to blend the drug and excipient blend, homogenize the melt, and freeze the substance upon cooling. e.g., Goldberg, A.H. et al., J. Pharm. Sci. 54, 1145 (1965); Kreuschner, K., et al., Pharm. Ind. 42, 843 (1980)]. The melting process is not applicable to heat sensitive materials.

Alternatively, the poorly water-soluble drug substance and the water-soluble excipient may both be dissolved in a well-soluble organic solvent and then evaporated from the homogeneous solution [Gidwanl, R.N .: Can. J. Pharm. Sci., 11, 117 (1976); El-Banna, 11.4. et al., J. Pharm.

Sci., 67, 1112 (1978)]. The disadvantage of this method is the use of organic solvents which are often flammable or harmful to health.

In recent years, some drug active ingredients have also been formulated into nebulized - essentially solid solutions [cf. e.g., Nuremberg, E., et al., Pharm. Ind. 38, 74, 907 (1976); Junginger, H .: Acta Pharm. Technol. 23, 225, 239 (1977); Nürnberg, E .: Acta Pharm. Technol. 26, 39 (1980), using urea as an excipient (Fremming, K.H. et al., Acta Pharm. Techrol. 26, 69 (1980)]. However, for poorly soluble drug substances, this method alone does not produce satisfactory results.

A composition is known to increase the solubility of eburane backbone compounds by containing the parent compound as a single additional component in admixture with ascorbic acid (German Patent Publication No. 2,326,301), but a composition having the desired good solubility properties is not obtained. It is also known to formulate a non-toxic solid acid such as salicylic acid, fumaric acid, malic acid, succinic acid, or an acidic inorganic salt such as sodium or potassium as a single component to enhance the solubility properties of cinnarizine. dihydrogenphosphate or an amino acid such as tryptophan or isoleucine (Japanese Patent Publication No. 58135333). However, in addition to increasing the solubility of a basic compound with an acid in a known manner, this measure does not result in an increase in solubility of the desired size.

Further efforts to promote or enhance solubility have been made, for example, in the case of cinrarlzine, wherein the formulation contains polyvinylpyrrolidone, polyethylene, dextrose, or other mono- or polysaccharide as the only component, together with a surfactant [Farmatsiya Sofia 1981, 31 Nos. 6), 25-30 and 1,456,618. United Kingdom Patent No. 1]. However, even in these cases, the desired strong solubility improvement for such formulations is below expectations.

Solubility-reducing efforts are also known, for example, to include formulations containing a tablet disintegrant, namely polyvinylpyrrolidone (German Patent Publication No. 2,549,740), as well as formulations containing a medium to increase the absorption German Patent Publication No. 433, Jiel Publication) or formulations containing polyethylene glycol for purposes of absorption in the gjonorni juice (U.S. Patent No. 4,151,273), and dispersions having a component of a cellulose derivative or a starch derivative (3 013). German Patent Publication No. 839) and preparations specifically containing dipyrldamol which contain acid and other usual additives and which granulated together with a cellulose derivative such as hydroxyethyl cellulose (U.S. Pat. No. 2,101,484). British Patent Specification).

In summary, it is readily apparent that numerous literature have already dealt with the solubility of pharmacologically active compounds which are difficult to dissolve in water or in digestive juices. A variety of methods have become known for this purpose, including the use of nebulized embedding or various excipients, such as various pharmaceutically acceptable acids or polyethylene glycols in the case of pure basic substances, but also in the case of basic nitrogen containing pharmacones. neither the process nor the use of various excipients led to the desired dissolution increase.

The aim of our research was to develop a novel process which, in addition to eliminating the drawbacks and disadvantages of the previously described processes, provides a simple and easy-to-use process for the preparation of water-soluble, poorly and slowly soluble . In our experiments, it has been surprisingly found that water-soluble formulations of these poorly and / or slowly-soluble basic pharmaceutical ingredients are obtained when the basic active ingredient is a non-toxic, water-soluble solid excipient, preferably urea, by adding an excess of a solid polyhydric alcohol, carbohydrate, or polymer, such as polyethylene glycol or a highly soluble cellulose derivative and a pharmaceutically acceptable acid, to an acidified aqueous solution of pH 1 to 2 and spraying the acidic solution with the forming a soluble excipient mixture into a particulate solid formulation.

The process according to the invention provides a highly soluble and rapidly soluble product of any organic basic drug which is poorly and / or slowly soluble in water; in particular, the process for converting vincamine derivatives such as vinpocetine (ethyl apovincamine acid) and cinnarizine (1-cinnamyl-4-benzhydrylpiperazine) into highly soluble pharmaceutical compositions is particularly useful.

The acid addition salts of water-soluble addition salts of the organic base used as the active ingredient of the pharmaceutical active ingredient which are non-toxic and free of adverse side effects, such as hydrochloric acid, caranoic acid, and mono- or polybasic acids, in particular citric acid or tartaric acid. . Such acids are used in an excess of 30-50%, preferably 40%, relative to the stoichiometric amount needed to form the acid addition salt, such that the pH of the aqueous solution to be spray-dried is preferably between 1 and 2.

Water-soluble excipients for the incorporation of the active ingredient in a solid formulation obtained by spray drying include, for example, lactose, sorbitol, mannitol, 4X10, 6000 or 20,000 average molecular weight polyethylene glycol, urea, polyvinylpyrrolidone, cellulose hydroxypropyl cellulose, hydroxyethyl , hydroxypropylmethylcellulose, and mixtures thereof. The amount of these embedding excipients will depend on the quality of the excipient used; the most preferred amount can be determined experimentally for each embedding material or mixture of materials. It has been found to be 80-90% by weight, based on the total dry solids content of the solution to be sprayed, for urea, and 3 to 10% by weight for hydroxyethylcellulose or other soluble callulose derivatives.

Spray drying of the acidic aqueous solution of the active ingredient prepared as described above is conveniently carried out in a spray disk machine with a flow of air of 100 ° C to 115 ° C, preferably 110 ° C, at a speed of 20,000-30,000 atomizer discs per minute. Under these conditions, the process of the present invention provides a finely divided, uniformly sprayed dry product having a particle size of about 10 to 30 microns, which is readily and rapidly soluble in water.

Although some elements of the process of the invention, such as the formation of acid addition salts of organic bases more soluble in water, increasing the solubility of the active ingredient by the use of hydrotropic excipients and micronization by spray drying are known in the art. , it was not at all foreseeable that the combination of these operations in the present invention would result in an increase in the solubility of the active ingredient far beyond the additive belief of each of the process elements. To demonstrate this, comparative experiments were conducted to determine the solubility of vinpocetine (apovincaminic acid ethyl ester 36) in various known solubility enhancers and in the compositions of the present invention. The experiments were performed in the XX. by spectrophotometric determination of 1 g of active ingredient (based on vinpocetine base) in 900 ml of distilled water or acid solution at 37 ° C in a rotating basket at 50 rpm according to USP XX. the results are summarized in the table below:

preparation

Vinpocetine base dissolved in water 0.7 µg / ml vinpocetine base in 5% urea solution 5.1 µg / ml vinpocetine base in 0.01 N hydrochloric acid 430 µg / ml spray-dried vinpocetine hydrochloride in 84.1 µg / ml spray-dried vinpocetine base in 0.01 N hydrochloric acid, spray-dried with 661 _M g / ml vinpocetine hydrochloride + urea acid solution, water 1750 µg / ml

As shown in the table above, the solubility of vinpocetine base, which is practically sparingly soluble in water (0.7 µg / ml), is increased to only 84.1 µS / ml after conversion to hydrochloric acid and spray drying. the composition according to the invention exhibits a solubility in excess of that of all other solubility enhancers. A similarly favorable picture is obtained with respect to the dissolution rate of the composition prepared by the process of the present invention. 60% of the amount of drug dissolved in 90 minutes at 37 ° C was dissolved in 5 minutes and 70% dissolved in 10 minutes. Similarly, the cinnarizine formulation of Example 2 showed excellent solubility, with 80% of the amount of salt dissolved within 90 minutes already dissolved in the first 2 minutes of the experiment. These results clearly demonstrate that in accordance with the invention the hard and / or slow the solubility and dissolution rate increases to known such methods surpasses extent and thereby considerably enhances ⁵⁰ gyászati possibilities of application of such drugs MEDICAL ⁴⁵ soluble pharmaceutically active substances .

Practical embodiments of the process of the invention are illustrated by the following examples.

into the arrangement. Drying is carried out at a temperature of between 100 ° C and 130 ° C, preferably about 125 ° C, to give a dry product consisting of regular pellets. By dissolving the product so prepared in water, a solution containing about 50 mg / ml of ethyl apovicaminic acid ester may be prepared, which represents an increase in solubility of about 2500 times the water solubility of the apovic acid ethyl ester of 20.5.

Example 2

In a mixture of 910 ml of distilled water and 30.0 ml of n-hydrochloric acid heated to 70 ° C, 2.50 g of cinnarizine, 16.50 g of urea are dissolved under stirring, and 10.0 g of 2.5% methylcellulose is added. The solution is homogenized by addition of distilled water to 1000 g and evaporated in a NIRO rotary atomiser using an air stream at 110 ° C to give an elongated, predominantly dry product having a particle size of up to 30 µm and a maximum diameter of 10 µm. The product prepared as above dissolves in distilled water at 20 ° C about 6.25 mg / ml cinnarizine per minute, which corresponds to an increase in solubility of about 4000 times the water solubility of cinnarizine at 1.4 µg / ml.

Example 1

In a mixture of 400 ml of boiled distilled water and 20.0 ml of n-hydrochloric acid was dissolved 5.0 g of apovincamic acid ethyl ester and 42.5 g of urea, 50.0 g of 5% aqueous hydroxyethylcellulose solution were added and the mixture was diluted with 1000 ml of distilled water. to g. This solution is a .NIRO '

Claims (3)

CLAIMS 1. A process for the preparation of water-soluble and fast-dissolving compositions from low-and slowly-soluble basic nitrogen containing drugs by converting the active ingredient into an acid addition salt and spray-drying a solution of said salt with a highly soluble excipient. a non-toxic, water-soluble solid excipient, preferably 80 to 90% by weight of urea and / or 3 to 10% by weight of soluble cellulose fiber, preferably hydroxyethylcellulose or methylcellulose, based on the dry matter of the solution to be sprayed , and by adding an excess of a pharmaceutically acceptable acid, 30 to 50% relative to the stoichiometric amount, to an acidified aqueous solution at a pH of 1 to 2 and evaporating the acidic solution by spraying forming a mixture of the drug substance and the highly soluble excipient into a particulate solid formulation. 2. A process according to claim 1, wherein the basic nitrogen containing agent is selected from the group consisting of apovincaminic acid ethyl ester or l-einnanoyl-1-benzhydrylpiperazine. Process according to claim 1 or 2, characterized in that hydrochloric acid is used to prepare the acid addition salt of the basic active ingredient.