UA77626C2 - Compositions comprising complexes of estrogen and cyclodextrin - Google Patents

Abstract

Pharmaceutical compositions comprising low doses of sensitive complexes of an estrogen and a cyclodextrin are provided with improved stability. In specific embodiments the composition comprises a complex between ethinyl estradiol and in a granulate preparation and in yet another embodiment the composition comprises a limited amount of polyvinylpyrrolidone since this excipient was found to degrade ethinyl estradiol. Furthermore, a method for improving the stability of an estrogen in a composition and for manufacturing such a stable composition is provided. Essentially, the granulate preparation are manufactured under careful control of the relative humidity.

Description

With 771626 4 16. The composition according to item 14 or 15, where drospirenone zero and did not exceed 6095 during its determination is present in an amount of approximately 0.4-20 mass.9o, pe- at a temperature of 20-407C, preferably approximately 0.8-10 mass. 9o, more preferably, if one or more excipients are approximately 1.5-5 wt. 9o. contains polyvinylpyrrolidone, then it is present 17. The composition according to any of the previous items, in the composition in a concentration not higher than 2 mabs.9o. where the granulated preparation has a relative humidity of 30. The method according to p. 29, where one or more excipients - not more than 5595, preferably not more than 4595, nites are polyvinylpyrrolidone, more preferably not more than 4095, when determining which is present in amount of no more than 1 wt.Oo, pe- at a temperature of 20-40. preferably not more than 0.5 wt.9o, more preferably not 18. The composition according to any of the previous items, more than 0.2 wt.vol. which contains no more than 1 mass.95, preferably no more than 31. The method according to p. 29 or 30, where the excipients are selected from 0.5 mass.b5, more preferably not more than from the group that includes starch, cellulose, 0 2 mass. 9o, polyvinylpyrrolidone. hydroxypropyl cellulose, hydroxypropylmethylcellulose, cellulose and maltodextrin. where one or more excipients are selected from 32. The use of a complex of estrogen and cyclodextrin, which includes starch, cellulose, hydroxystrin for female contraception, and com- propyl cellulose, hydroxypropyl methylcellulose and plex is in the form of a composition that contains maltodextrin. granular preparation of the specified complex, 20. The composition according to any of the previous items, and if the composition contains polyvinylpyrrolidone, the complex is finely divided. don, then it is present in a concentration not higher than 21. The composition according to any of the previous items, 2mabs.oo, which additionally contains an antioxidant. the composition has such stability that after storage, 22. The method of preparation of the composition containing fermentation for 12 months at 40"C, the relative content of the estrogen-cyclodextrin complex, which pre-weakness (KN) 7595 estrogen is present at least in the following stages: amount of 85 wt.bo relative to the initial content

Ж) obtaining a complex of estrogen and cyclo-estrogen. dextrin; 33. Application according to p. 32, where the composition is additionally

І) loading the complex and one or more is a composition according to any of paragraphs 2-21 excipients into the granulator; or item 28.

I) application of liquid to the loaded complex and 34. The use of a complex of estrogen and cyclodextrin or several excipients under such conditions of grastrin for the preparation of a medicinal product, priznulation to obtain granules, relative woolen for female hormone replacement therapy, the guest of which does not exceed 6095 when determining where the medicinal product is a complex of granulated drug with a temperature of 20-40"C, and if granulated, and if one or more excipients clearly contain polyvinylpyrrolidone, then it is polyvinylpyrrolidone, then it is present in a concentration not higher than 2 wt. 90, in the composition in a concentration not higher than 2 mabs. 905. the medicinal product has such stability that after 23. The method according to item 22, where the granulated preparation has storage for 12 months at 40 "C, relative relative humidity not more than 5595, preferably not humidity (KH) 7595 estrogen is present at least more than 4595, most preferably not more than 4095, in the amount of 8 5wt.9Uo relative to the initial content when determined at a temperature of 20-4070. estrogen 24. The method according to p. 22 or 23, where estrogen is chosen 35. The application according to p. 34, where the composition is additionally from the group that includes ethinyl estradiol (EE), estra- is a composition according to any of p. 2-21 diol , estradiol sulfamates, estradiol valerate, or item 28. estradiol benzoate, estrone and estrone sulfate or 36. The method of inhibiting ovulation in women, which pe- their mixtures. 25. The method according to any of items 22-24, where the estrogen gene and cyclodextrin and II) drospirenone, where the compound is ethinyl estradiol. plex is in the form of a composition that contains 26. The method according to any of items 22-25, where the content of polyvinylpyrrolidone, a granular preparation of the specified complex, does not exceed 1 wt.9o, preferably not, if the composition contains polyvinylpyrrolidone, exceeds 0, 5 wt.9o, more preferably not predon, then it is present in a concentration not higher than 2 more than 0.2 wt.9o. mass, 27. The method according to any of items 22-26, where one or the composition has such stability that after storage, several excipients are selected from the group, which fermentation for 12 months at 40"C, relative includes starch, cellulose, hydroxypropyl cellulose (KN) 7595 estrogen is present at least in cellulose, hydroxypropylmethylcellulose and maltose in an amount of 85% by weight relative to the initial content of dextrin. estrogen. 28. The composition obtained according to the method according to 37. The method according to item 36, where the composition additionally represents any of items 22-27. is a composition according to any of items 2-21 or item 28. 29. Method of increasing the stability of estrogen in 38. Method of hormone replacement therapy for women, which involves the following stages: involves the introduction of a combination of I) complex of estrogen

I) production of a complex of estrogen and cyclodextrin and cyclodextrin and II) drospirenone, where and the plex is in the form of a composition that contains

II) mixing in the conditions of granulation of the specified complex, the granulated preparation of the specified complex, complex with one or more excipients and, moreover, if the composition contains polyvinylpyrrolid, in such a way that the relative humidity of the final

don, then it is present in a concentration no higher than within 12 months at 40"C, relative humidity 2mass.9r, (AN) 7505. the composition has such stability that estrogen 39. The method according to item 38, where the composition is additionally present at least in amount of 85% by weight relative to the composition according to any of items 2-21 or item 28. of the initial estrogen content after storage

The present invention relates to pharmaceutical oxidative cleavage of 17-ox-ethinylestradiol, compositions and preparations that contain a complex that is cyclized during the formation of D-lodextrin-estrogen clathrates (complexes), which are characterized by cyclodextrin and 17-x-ethynylestradiol. high chemical stability of estrogen. The invention However, although the formation of estrogen complexes and allows improving the physical stability of CoM-cyclodextrins can be crucial for the solubility, bioavailability and stability of estrogens, such as catechtinyl estradiol, cyclodextrin-estrogen complexes and chemical stability, but at the same time, problems still remain. - storage. | | | us, which must be resolved before completing

The breakdown of estrogens, such as ethinyl estradiol, xy active substances, such as estrogens, and in standard pharmaceutical products is one cyclodextrins can be used in pharmaceu- from factors that are of decisive importance, which vtic products. Yes, the complexes are subject to determine the shelf life of the product. Stabilization - dissociation with the formation of free estrogen and cyclization of estrogen can be achieved either by upalodextrin, first of all, in contact with water. forging the product into hermetic containers, or, the lack of physical stability of cyc- which is more effective and is used in dalodextrin-estrogen leads to the fact that significant nome of the invention, by actually stabilizing the amount of free estrogen present in the compositions of the pharmaceutical product. what | as a result, for example, of the influence of aquatic environments in

Pharmaceutical products that contain natural or synthetically obtained sex hormones during the preparation process, in particular, during the granulation process. As a result, the shelf-life of mono-compositions, often including low doses of these active substances, decreases due to the decomposition of free estwin. Taking into account small amounts of active rogen. substances required for a single dose, which is In addition, an improved biological is needed to add 0.1-500Mkg, the production of compositions, the efficiency as a result of the formation of a complex of extraordinary doses AND RELATIVELY CONSTANT QUANTITIES of gene and cyclodextrin is not achieved due to the absence of of active substances, which would not change in each batch, the physical stability of the complex from batch to batch is difficult. Therefore, these produ- cyclodextrin-estrogen and chemical instability may not satisfy the requirements of protective estrogen organs. wounds of health, which concern the homogeneity of the content. Various attempts were made to stabilize the composite

In addition, the breakdown of such small quantities, which contain complexes of cyclodextrin and esters of the active substance, leads to additional rogen. For example, the composition can be stabilized by changing the amount of active substance in thread compositions by stabilizing the complex itself. Yes, in what doses. | | patent 5 4727064| stabilization attempts are described

In general, the preparation, storage and application of complexes using amorphous forms of comple- tion of these compositions with low doses, which mix. In another version, the complexes can stabilize unstable active substances, which is related to enriching and increasing their solubility, adding poly-dark problems, and therefore there is a need for measures in the reaction medium in the process of stabilizing such compositions. | complex formation, as described in Goyzvzop et al.

Preparation of estrogen complexes from cyclodec- (p. u. Rpappasetsshisv5, volume 110, 1994, p. 169-177). strina is widely used to increase IU EP 0579435) complexes of estradiol stability, solubility or biological availability and cyclodextrins, in which the addition of polymers in the carrier, are also described. (For example, in EP 0349091) described composi- reaction medium increased the constant of tion, which contain complexes of 17-p-estradiol and dime- stability of the complex. tyl-D-cyclodextrin, which are intended for the Composition can also be stabilized by improving nasal administration, Rhydhikzaonia, etc. abandoning the granulation stage in the process of preparation (Oie Rpagtalie, vol. 51, 1996, p. 39-42 | described the composition, (as described in MMO 00/21570). complexes of cyclodextrin and 17-p-estradiol, in this way , in this field there is a need to increase the solubility in water in the development of methods of obtaining physically stable solutions, as well as to improve the sublingual complexes of cyclodextrin and estrogen and composite use. Increased solubility is also an object that differs increased stability of both the volume (patent 5 4596795), in which the complex is described, and free estrogen. In addition, in the complex of o-, p- and y-cyclodextrins and their derivatives from this field, there is a need to create compo-testosterone , progesterone and estradiol in the form of granules, which are characterized by the physical properties of water-soluble complex cyclodextrin inclusion, which is obtained by forming a complex of steroid compounds, is described in patent 05 4383992| and, such as estrogen, with the object of this invention is stable and homo-D-cyclodextrin. generic pharmaceutical product that contains

In addition, (in patent 05 5798 338) it is described that estrogen, and the stability of estrogen is significantly increased in comparison with conventional products

7 771626 8 tames, which contain complexes including estro-cyclodextrin, where the production of granulated genes or sensitive complexes of cyclodextrin and estro-drug involves the following stages: rogen. The decomposition of estrogens, such as ethinyl estra- I) loading of a complex, one or decyldiol, in conventional products is one of the factors that excipients and not necessarily one or several are of the most important importance, which determines the therapeutic active substances in granulator; know the expiration date of the product. I) application of liquid to the loaded com-

During the creation of the invention, it was unexpectedly plex and one or more excipients in the conditions it was established that products with increased stability, granulation so as to obtain granules that have estrogen properties can be obtained by adding a relative humidity of no more than 6095 when it is determined by the ration of estrogen complexes and cyclodextrins , at a temperature from 20 to 4070. purposeful selection of excipients and/or pro- The term "complex" refers to a complex of thought adaptation of the preparation process. In retrogen and cyclodextrin, where the molecule of the specified result, the shelf life of the product that contains estrogen is at least partially embedded in the estrogen void, increases. present of one molecule of cyclodextrin. In addition,

Thus, an important object of the invention is a molecule of the indicated estrogen, which can be used for preparations and compositions containing complexes of estmni partially embedded in the cavity of several rogen and cyclodextrin, which are stable when they are cyclodextrin molecules, and two fragments of one obtained using granulation Thus, the first estrogen molecules can be embedded in one object of the invention is a composition containing a cyclodextrin molecule with the production of a co-complex of estrogen and cyclodextrin, where the composition of carrying cyclodextrin and estrogen is 1:2. This is a granulated preparation, this granulated form, the complex can be considered as a complex, the poured preparation has a relative humidity of no bi- inclusion (clathrate) of estrogen and cyclodextrin. only 6095 when determined at a temperature of 20 Similarly to this, the complex may contain more than 4076. one estrogen molecule, which at least often

The next object of the invention are compositions that are embedded in one or more molecules of cyclodextrin and contain I) a complex of estrogen and cyclodextrin; and II) lodextrin, for example, 2 molecules of estrogen, which one or more excipients, moreover, the composi- at least partially embedded in one molecule tion has such stability that after storage of pro- cyclodextrin, with obtaining a ratio of 12 months at 40"С and relative humidity of cyclodextrin and estrogen 1:2. To complexes, in (EN) 7595 estrogen is present at least in the amount in which one molecule of estrogen forms a complex with 85 wt. with respect to the initial content of estrogen. one or several molecules of cyclodextrin

According to the preferred variant of the implementation of well, usually belong to the complexes that contain 1 of the invention, the composition is a granulated molecule of estrogen and 2 molecules of cyclodextrin, a preparation that contains the specified complex. Corresponding to the cyclodextrin molecule. As a rule, in accordance with another preferred embodiment of the ethinyl estradiol-D-cyclodextrin plex, the obtained composition is pressed directly with it according to the present invention, preferably the preparation of tablets or equivalent forms is a complex that contains 1 molecule of ethinylestradiol standard doses. lestradiol and 2 molecules of p-cyclodextrin.

Thus, in contrast to known prototypes, the concept of "ethinyl estradiol-p- complex, it becomes possible to obtain stable compositions, cyclodextrin" or "EE-D-CD" refers to compounds that contain an estrogen-cyclodextrin complex in a plex that has any ratio of ethinyl - granular preparation. lestradiol and D-cyclodextrin.

Compositions according to the present invention can be used as medicinal products. Thus, the size of the powder preparation, in which the size of the powder particles is the main object of this invention, is increased either as a result of the above-described "composition for the preparation of the drug - treatment with a liquid, or with the help of pressing. The liquid can be an aqueous or organic replacement therapy or for the treatment of acne or solvents of any type or their mixture and neobo-

PMDN (disorders associated with premenstrual- must additionally include a binding substance, a dysfunction. And | such as starch. Thus, widely known

In a broad sense, this invention relates to the concept of "granular preparation" in relation to a method of increasing the stability of estrogen in granules, pellets and compressed powder or a pharmaceutical composition that contains a complex of any particles obtained with the help of gra-estrogen-cyclodextrin and one or several ex- nullation, tableting or pressing of the powder of the recipients in a granular preparation, the method is in such a way as to obtain particles, the average stage: | the size of which is at least approx

I) receiving a complex of estrogen and cyclodex - 100 μm. rub! and The concept of "cyclodextrin" refers to cyclode-

I) mixing in the conditions of granulation of the specified dextrin or its derivative, as well as mixtures of various complexes with one or more excipients of cyclodextrins, mixtures of various cyclodextrin derivatives in such a way that the relative humidity of the final dextrin and mixtures of various cyclodextrins and their granulate does not exceed 6095 when it is determined derivatives The concept of cyclodextrin will be additionally at a temperature from 20 to 407C. deciphered in the context of the invention.

Finally, the invention relates to a method of preparation. During the creation of the invention, the development of the composition, which is a granular product, was developed, in which a significant increase in the stability of the preparation, containing a complex of estrogen and rogen, was achieved with the help of a combination

9 771626 10 different ways. One of these ways is to protect est- to exclude them from compositions. Polyvinyl pilodextrin is one of these excipients with the help of the formation of a complex of cyclites, which are of decisive importance. Another way involves a well-thought-out rolidone, which is usually used as a binding adaptation of the granulation process, for example, into a pro-substance during fluidized bed granulation. during preparation of granules, it is possible to limit di- As noted in this description, ethinyl estradiol association of the complex to free estrogen and cyclode- is sensitive to the action of polyvinylpyrrolidone, and large number of extrins. During the creation of the invention, ethinyl estradiol decomposes in preparations and data that the complex of ethinyl estradiol and p-compositions, if ethinyl estradiol is not protected by cyclodextrin, has poor stability when exposed to the formation of a clathrate. For example, in compo water. In fact, in the case of dissolution of the complex in zits, which contain polyvinylpyrrolidone and obtained in water, approximately 5095 of the complex is decomposed into, according to example C of patent 05 5798338, free ethinyl estradiol and cyclodextrin during fluidized bed granulation,

Record (see example 6 of this description). Thus, the stability of ethinylestradiol is low. Without going into a specific theory, the stability of the creation of this invention was established that ducts can be at least partially increased in such a composition after storage for 12 by limiting the dissociation of the complex that at 40"C and relative humidity of 7595 the content leads to the formation of free estrogen during ethinyl estradiol decreases by 2595 relative to the preparation process, thereby limiting the initial content of ethinyl estradiol (see table 1.4, example 1, table A). Thus, one of the

Thus, the first object of the invention is compositions/preparations with a low composition that contains a complex of estrogen and a high content of compounds that have a high oxidizing capacity of dextrin, where the composition is a granularity, such , in which the oxidizing capacity is higher than that of the liquid preparation, and this is granular polyvinylpyrrolidone, or close to it. For example, the preparation has a relative humidity of no more than 60965 klad, in the compositions/preparations according to this invention, when it is determined at a temperature of 20 to 40"C, the content of polyvinylpyrrolidone is preferably more

Preferably, the relative humidity is not much lower than in compositions with (example C of the patent is 5595, more preferably not more than 4595, most 55798338). More preferably in accordance with more preferably no more than 40905 in its determination of distinct variants of implementation of the invention composition- at a temperature from 20 to 4070. tions/preparations contain no more than 2wt.9o polyvinyl-

It has been established that according to this invention of pyrrolidone, preferably not more than 1 wt. 90, it is possible to obtain stable products that contain preferably not more than 0.5 wt. 95, the most predominant complexes of estrogen and cyclodextrin. no more than 0.2 wt. 7% of polyvinylpyrrolidone. Except

Thus, the second object of the invention is a composition, according to especially preferred variants of the statement, which contains: implementation of the invention, compositions/preparations, practical

I) a complex of estrogen and cyclodextrin; and do not contain polyvinylpyrrolidone.

I) one or more excipients, and Individually or in combination with each other, the composition has such stability that after storage, the above-mentioned methods allow for the preparation of the mixture for 12 months at 40"C and the relative composition, in which estrogen is more stable than logosti (EN) 7595 estrogen is present in it in several traditional compositions that contain polyvinyl piste at least 85 wt. the mass content of estrogen included in the fluidized bed. Obtained in such a composition during the preparation of the final composition. method stable compositions differ in that

According to one of the variants of implementation, the estrogen content in them after storage for the period According to the invention, the composition is in the form of a tablet, dried at 40"C and relative humidity (RH) of 75905 pressed by direct pressing is at least 9Omas.9o relative to the original composition. Preferably, the composition contains an amount of estrogen. Preferably, the estrogen content of the polyvinylpyrrolidone as described after storage for 3 months at 40°C and below relative humidity (RH) 7595 is at least

According to another variant of the implementation of 92wt.9o, more preferably at least 94wt.95, the estrogen and cyclodextrin complex has more preferably at least 9bwt.95 and the most form of granular preparation, as it is determined - preferably at least 9Zwt.9o relative to the initial in this description. of estrogen content.

According to the preferred options, the compositions also have the stability of the invention. - at a relative humidity (RH) of 7595, the estrogen present in the product has such stability that after storage it is released in an amount of at least 9Omas. preferably at least 7595 estrogen is present in an amount of at least 97wt.oo, most preferably at least 85wt.bo relative to the initial estrogen content, 98wt.oo, relative to the initial estrogen content preferably at least 9Owt.9o, more preferably

Other ways of increasing the stability of estrogen at least 92wt.9o and even more preferably in such preparations and compositions involve me 94wt.9o, most preferably at least a well-thought-out choice of excipients in order to minimize 9bwt.9o relative to the initial content of estrogen. reduce the content of excipients, which have the ability It is important that the compositions according to the invention are more able to induce the decomposition of ethinyl estradiol, or stable in environmental conditions,

than traditional compositions. Thus, the composition as a whole is no more than 395 relative to the original, according to this invention, they have an increased stability of the molar content of ethinyl estradiol when stored for 12 months at 257C and marked after storage for 12 months at a relative humidity (RH) of 6095, at this estrogen is 40"C and the relative humidity (RH) is 7595. It is preferably present in an amount of at least 95 wt. because the relative molar sum of all products is no more than the initial content of estrogen. Preferably after 295 and more preferably no more than 0.695 when collected and stored for 12 months at 257 and relative humidity under the specified conditions, humidity (KN) 6095, estrogen content is Thus, the object of this invention is a pharmaceutical composition of at least 9bmas.9o, more preferably at least a pharmaceutical composition/ pharmaceutical preparation 97mas.oo, most preferably at least 9vmas. 9o-rates, which contain a complex of estrogen and cyclodextrin, in which the stability of estrogen to a significant extent ri

As should be obvious to a specialist in this field, estrogen can be selected from the group that includes/preparations. Thus, to additionally increase the stability of ethinyl estradiol (EE), estradiol, sulfamate or to ensure the stability of estradiol, estradiol valerate, estradiol benzoate - according to other variants of the invention, estrone, estriol, estriol succinate and conjugated compositions/preparations also contain an antioxidant. estrogens, including conjugated equine estrogens. The antioxidant can either be included in granules, such as estrone sulfate, 17p sulfate preparation, or added to the composition as an additional estradiol, 17o-estradiol sulfate, equilinsultic excipient. phate, 178-dihydroequiline sulfate, 17a-Cyclodextrin can be selected from the series, which dihydroequiline sulfate, equilenine sulfate, 17p- includes o-cyclodextrin, p-cyclodextrin, y-dihydroequilenine sulfate and 17a-cyclodextrin and their derivatives. Cyclodextrin can be dihydroequilenine sulfate or their mixture. Especially modified in such a way that some or all of the estrogens selected from the group that are guilty or secondary hydroxyls of the macrocycle or diol, estradiol valerate, estradiol benzoate, are acylated. Methods of modifying these estrone alcohols and estrone sulfates or mixtures thereof, in particular, are well known to those skilled in the art and many such ethinyl estradiol (EE), estradiol valerate, cyclodextrin benzoate are commercially available. Yes, some or all estradiol and estradiol sulfamates. The most hydroxyls of cyclodextrin in modified cyclodextrins are ethinyl estradiol (EE). lodextrins can be replaced by an O-H group or o-

In a preferred embodiment of the invention, C(O)-P, where K means optionally substituted C1- when the estrogen is ethinyl estradiol (EE), Swalkyl, optionally substituted Ce2-Swalkenyl, some decomposition products are well known. Thus, in optionally substituted C2-Svalquinyl, optionally unstable compositions, for example, which contain a covalently substituted aryl or heteroaryl. So, K can be a sensitive complex of ethinyl estradiol and cyclodext- means metal, ethyl, propyl, butylrin, which are prepared with the help of generally accepted well, pentyl or hexyl group. Therefore, О-С(0)-Н of granulation methods, the presence of decomposition products may mean acetate. In addition, when K stands for ethinyl estradiol, primarily after storage widely used for this purpose /2- for a certain period of time. In addition, since the hydroxyethyl group or 2-hydroxypropyl group in these traditional compositions is cleaved by PU, K can be used to obtain a larger amount of ethinyl estradiol compared to cyclodextrin derivatives. In addition, cyclodecompositions according to the invention (see example 2, tabstrine alcohols can be perbenzylated, page 1.3), then traditional compositions can include perbenzoylated, or benzylated, or higher amounts of these products decomposed on one and the same face of the macrocycle or giving. they can have only 1, 2, 3, 4, 5 or 6 hydroxyls

Thus, according to one of the options to be benzylated or benzoylated. The stability of the natural implementation of this invention is such that, bottom, cyclodextrin alcohols can be peral- that the molar amount of a product known to be alkylated or peracylated, for example, permethylol- it is a known decomposition product of ethinated or peracetylated or alkylated or nylestradiol , is no more than 0.895 relative to the acylated, for example, methylated or acetylated initial content of ethinyl estradiol. So, in the case of the same face of the macrocycle or only one of them, when the estrogen is ethinyl estradiol, 1, 2, 3, 4, 5 or 6 hydroxyls are alkylated or the molar sum of b-o-hydroxyethinyl estradiol, 8 - acylated, for example, methylated or ace-hydroxyethinyl estradiol, b-ketoethinyl estradiol, tylated. of d-6,7-ethinyl estradiol and A-9,11-ethinyl estradiol in the Estrogen-cyclodextrin complex can be determined using methods well known to those skilled in the art ( see, for example, the patent value after storage for 12 months at C 57983381. I I 2576 and relative humidity (RH) 60965. Predominantly Ethinylestradiol-B-cyclodextrin complex, the molar sum of all products is no more can also be obtained by co-precipitation in annealing in the indicated D-cyclodextrin is dissolved in water at 457C;

In addition, the stability is such that a molar solution of ethinyl estradiol is added to a solution of p-sum b-o-hydroxyethinyl estradiol, 6-p-cyclodextrin; the resulting suspension is mixed with hydroxyethinyl estradiol, b-ketoethinyl estradiol for several hours at 20-257C, and then with d-6,7-ethinyl estradiol and D-9,11-ethinyl estradiol at 2"C; the crystallization product is isolated and dried.

In another variant, the ethinyl estradiol-p-rogen complex is ethinyl estradiol and one or cyclodextrin can be obtained in the following way: dissolve ethinyl estradiol in acetone with several therapeutically active agents; /D- substance(s) is drospirenone. In this connection, cyclodextrin is dissolved in water at 452C; the solution in accordance with another preferred variant of ethinyl estradiol is added to the solution of the compound of the invention and the estrogen-cyclodextrin complex; the resulting suspension is mixed with cyclodextrin and finely ground drospirenone. for several hours at a temperature below Thus, the compositions and preparations contain 25"С; then the crystallization product is isolated and small doses of the active substance, for example, correspond to the representative variants of implementation of

Predominantly a complex of cyclodextrin and estrone, they contain an amount of estrogen that naturally has the required lipophilicity (hydrophobicity). indicates a therapeutically equivalent amount

Thus, the preferred variants of the implementation of vinacho-ethinyl estradiol, which is approximately 0.002-du, are such variants, according to which the ratio of 2mabs.r. separation of the complex in the n-octanol/water system at According to other representative variants - pH? is approximately 2-5, preferably about 3-4. Other preferred embodiments of the invention include estrogen, such as ethinyl estradiol, in particular the complex in crystalline form. bones approximately 0.002-2 mass.2o. The majority of

Thus, the limited object of the invention relates to more thalamic complexes of estrogen and cyclodextrin. preferably approximately 0.008-0.1 wt.", at most

The term "crystalline" refers to various modifications - preferably approximately 0.02-0.05 wt.7o. cations of the physical structure of the compound, and, taking into account the amount of cyclodextrin in the compound may be in an amorphous form. respectable variants of implementation of the invention, according to

Crystalline compounds can have a hydrated fo- by which estrogen is ethinylestradiol and cirum or contain water of crystallization. And, finally, clodextrin is a p-cyclodextrin, ethinylestradiol complexes can be complexes given in given estradiol is present in the amount relative to the complex description in the examples, for example, ethinyl estradiol-pD-cyclodextrin hydrate approximately 5-toned complexes with of example 12. In addition, the crystalline 20 wt., preferably approximately 8-15 wt. U5, the most numerous complex may contain fragments of free more preferably approximately 9-1Z wt. 9o. ethinylestradiol and free cyclodextrin. In addition, according to the invention, it is possible to regulate

Predominantly, the complex contains p-cdcyclodextrin to adjust the ratio of estrogen and cyclodextrin or its derivative, most preferably D-nu. Thus, according to the prevailing varia- cyclodextrins. Thus, in accordance with the ninth embodiment of the invention, estrogen is present in a more preferred variant of the invention, in such an amount relative to cyclodextrin that the molar ratio of estrogen and cyclodextrin is approximately 2:1 to 1:10, preferably a diol, and cyclodextrin is /D- from about 1:1 to 1:5, most preferably cyclodextrin. about 1:1 to 1:3, such as 1:1 and 1:2.

According to another embodiment, in the variants according to which the composition of the invention, the composition additionally contains one or more therapeutic active substance and this several therapeutic active substances. Thus, the substance is drospirenone, drospirenone according to this embodiment of the composition is present in an amount of approximately 0.4-20% by weight, and additionally contains a progestogen. The progestogen may be 0.8-10 wt.%, more preferably approximately 1.5-5 wt.%, which includes drospirenone. levonorgestrel, norgestrel, gestodene, dienogest. The next object of the invention is the composition of cyproterone acetate, norethisterone, norethisterone acetate or the drug according to the invention, which additionally has thysterone, desorgestrel, 3-ketodesorgestrel. One form of a standard dose, preferably such as a tablet, the preferred progestogen is a dropper, capsule or sachet. renon A representative variant of the implementation of

According to the preferred embodiment of the invention, there is a composition or preparation in the form of granules, the therapeutic active substance of the invention is pellets or dry compressed mixtures, which can be drospirenone, and drospirenone does not have to be filled in hard gelatin capsules or it can be finely ground. Accordingly, sachet or press to obtain tablet cores. to the preferred embodiment of the invention, the In this case, the composition or preparation contains raphepetic active substance is drospi- (wt.b): renon, moreover, all or almost all drospi- I) active substance: a complex of ethinyl estradiol and renon can be present in in the form of a complex of p-cyclodextrins; cyclodextrin. As it should be obvious fa- I) 0-95wt.9o of fillers, such as lactose, khivtsu in this field, dissociation of the drospic-starch complex, cellulose and/or others; renone/cyclodextrin can lead to the formation of I) 0-15wt.9o binding agents, such as crumbing of a mixture of drospirenone in the form of a complex with mal, cellulose, hydroxypropylcellulose, hydroxycyclodextrin and drospirenone, which does not include cypropylmethylcellulose, maltodextrin and / or others; in the complex, (free). As well as free dropsy - IM) 0-5 mass. substances that promote sliding, renon, drospirenone, which is part of the complex, such as colloidal silicon dioxide and/or others; to be finely chopped. M) 0-15 wt.95 leavening agents, such as starch,

Thus, a preferred variant of the effect of calcium carmellose, croscarmellose sodium, carbonation of the invention is a composition/preparation in which sodium estoxymethylstarch and/or others;

MI) 0-5wt.9o stabilizers/(antioxidants, and dextrin; and others such as tocopherol acetate, propyl gallate, ascorbic acid) and the addition of excipients in such quantities as acid, ascorbic acid palmitate and/or to minimize the total amount of excipients, etc. .; and which have a higher oxidation potential or

MI) 0-5wt.9o lubricants, such as stearate similar to the oxidation potential of polyvinyl pyromagnesium and/or other leadone. The task is to limit or minimize

In the variant, according to which the composition of the number of excipients that have an oxidizing potion/preparation additionally contains a compound that has a potential higher or similar to the therapeutic activity, such as a progestogen, of the oxidizing potential of polyvinylpyrrolidone. especially drospirenone, a representative composi- Thus, the method of stabilization can additionally contain 0.1-15 wt. the oxidation potential is higher or similar

The most preferred embodiment of the oxidation potential of polyvinylpyrrolidone, including the invention, is a standard dosage form containing a limit on the content of polyvinylpyrrolidone in such compositions/preparations. Thus, according to the most important variants of the invention, the compound hydrospirenone (finely ground) contains one or more excipients, which contain ethinyl estradiol in the form of a clathrate with polyvinylpyrrolidone in an amount no more than p-cyclodextrin (finely ground) 0.02 mg" 2 mass This amount preferably does not exceed lactose 48.18mg 1wt.95, more preferably does not exceed 0.5wt.9o, corn starch 28.00mg most preferably does not exceed 0.2wt.95. Magnesium stearate water (for processing) According to the most preferred embodiment of the invention, the method of increasing the stability of 0.02 mg means the concentration of ethinyl estradiol - involves the exclusion of polyvinylpyrrolidone from fadiol (without taking into account rD-cyclodextrin). The amount of the pharmaceutical composition. Yes, the method of stabilizing ethinyl estradiol in clathrate with B-cyclodextrin of estrogen in the pharmaceutical composition is 9.5-12.592. must be regulated because they do not contain polyvinylpyrrolidone. depends on the amount of D-cyclodextrin. And another object of the invention is a method of obtaining the compositions and preparations described above, which are stable and homogeneous. Acceptable conditions

Another object of the invention is a method of increasing the stability of estrogen in a pharmaceutical liquid for granulation, individual administration of a composition containing estrogen and one or more active substances and one or more excipients and excipients in a granulated preparation, method in a device suitable for granulation, the process involves the following stages: zeroing and drying. According to the predominant varia-

I) obtaining a complex of estrogen and cyclodexant granules obtained in this way have a difference; and the humidity of sleep is no more than a bean.

I) mixing under the conditions of granulation of the specified Thus, the invention relates to a method of ode-complex with one or more excipients of barking of a granulated preparation, which contains so that the relative humidity of the final granulate is not a complex of estrogen and cyclodextrin, where the product is from 20 to 402C. stage: Y ,

As noted above, this method of stabilization I) loading of the complex and one or several allows to obtain compositions, the stability of which all excipients into the granulator; , , is higher compared to the stability, known I) application of liquid on the loaded complex and mine for traditional compositions. These improved one or more excipients under granulation conditions provide increased stability, so that the obtained granules have a relative viscosity that is related, at least in part, to a flowability not higher than 6075 when determined at the temperature of granulation and with correctly selected excipients - from 20 to 40 C. | about you Yes, the way to increase the stability / The method allows to obtain new compositions, associated with the correct regulation of the relative humidity of the granulated drug. It is very important to reduce the amount of decomposition products in the flow, so that the relative humidity does not exceed 60965. relative humidity With the use of polyvinylpyrrolidone and/or percent must exceed 4595, most preferably in an appropriate manner. p should not exceed 4095 when determining Thus, for the preferred options, it is carried out at a temperature from 20 to 402С. of the invention, the conditions of granulation are even more

In addition, related to the above-mentioned limitations, for example, the relative humidity of the grains of the invention is a method of increasing the stability of the poured preparation does not exceed 5575, estrogen in the pharmaceutical composition, which preferably does not exceed 4596, will even more dominate estrogen and one or more excipients, but does not exceed 4095 when determined at a temperature of 20 to 40°C.

17 771626 18

Thus, the drug contains low doses of coagulation substances presented in this description and in the examples, in particular, the complex of ethinyl estradiol for the preparation of the medicinal product, prizol-cyclodextrin. This parameter is important for women's contraception, for hormone replacement, to achieve homogeneity of preparations, and for topical therapy or for the treatment of acne or PMD. Yes, important (disorder associated with premenstrual fact, which should be taken into account when preparing dysfunction). compositions/preparations that contain low doses of action- The use of the compound according to the present invention whose substance is the homogeneity of the granular pre- for hormone replacement therapy implies the treatment of parath. The usual practice of preparing menopausal, premenopausal or fasting preparations with a low content of substances predicts menopausal symptoms in women. Medicinal use of premixes (pre-prepared means can have a form well known to a specialist in them of mixtures) of an active substance with an excipient, in the field of pharmaceuticals, as a rule, a form for pe- examples, lactose. oral administration.

As a rule, the premix is obtained at a separate stage of mixing. However, during the creation of the invention, the drug can be used. A method of preparing preparations for inhibiting ovulation in women was developed. It was found that due to the low content of substances without a previous stage, in addition to the ability to inhibit ovulation, the composition by mixing the active substance with a suitable excipient can have pronounced antiandrogenic effects. properties and therefore can be used for

Thus, an important variant of the implementation of the prevention or treatment of induced androgens of the invention is the method described above, according to the nom of disorders, in particular, acne. Such use of which complex and optionally additional one(s) may not depend on the use for the described or several therapeutic active substances of the above contraception or may accompany it. are measured individually without prior measurement. In addition, since drospirenone is an antagonist of shunting with excipients. According to the addition of aldosterone, it has diuretic properties and therefore, related to the above option, it can be used to counteract water retention - the granulator injects one or more therapeutic properties of ethinyl estradiol. active substances such as drospirenone. Thus, the object of the invention is the application

Thus, the suitably adapted composition for the preparation of a medicinal product according to the invention allows for the preparation of a homogeneous batch of a granulated drug intended for oral administration. In addition, it is important to use compositions that contain the case when the method is aimed at obtaining a complex of ethinyl estradiol and B-cyclodextrin and standard dosage forms of the drug, additionally containing a therapeutic active substance. such as tablets, it allows to achieve homogeneity of the composition. Yes, according to the most perevanon. According to various preferred variants and variants of the implementation of the invention, the batch final implementation of the invention is a dose of ethinyl estradiol solid granulate and/or the final standard dosage form of 0.015-0.04mg, in particular approximately 0.015- forms of the medicinal product in relation to homogeneity - 0.OZmg, and the dose drospirenone is approximately 10% of the composition, which meets the requirements according to which 2.5-3.5 mg, in particular approximately Zmg per standard homogeneity of the composition should be 85-11595, a daily dose. More specifically, compositions for wines - preferably 90-11095, more preferably 95-10595. contain the amount of drospirenone corresponding to

The homogeneity of the composition is determined by selecting a daily dose of approximately 3.0-3.5 mg, and the number of random samples of the granulated preparation of ethinyl estradiol corresponding to a dose of approximately or by randomly selecting 10 tablets of 0.015-0.03 mg. lots of pills, quantitative assessment of estrogen content. The medicinal product for inhibiting ovulation can in each sample or pill and, finally, by presenting a single-phase composition, that is, pre-calculating the coefficient of variation based on the number of parats, in which the amount of any estrogen active substance in each sample or tablets. remains at a constant level for at least

The concept of "with low doses" in the context of 21 days, or the amount of either or both of the active description refers to compositions/preparations, which substances can change for at least 21 containing a complex in an amount of approximately 0.005- days, intended for the preparation of multiphase- 20wt.bo, preferably about 0.01-2wt.9u, of the preparation, for example, two- or three-phase more preferably about 0.05-Imas.9u, also of a preparation practically identical to the preparations, more preferably about 0.1-0 ,7mas.9U", the most described, for example, in ER 148724). more preferably approximately 0.15-0.5 wt.9o An important variant of the implementation of this invention

Granulation can be carried out with the help of a course is the use of a drug for inhibition of any equipment that allows you to receive ovulation, moreover, the drug is administered stable and homogeneous granulate according to the invention. every day for at least 21 consecutive days,

In other words, it is possible to use any daily standard dose containing a combination of dro- equipment that ensures the production of granules, spirenone in an amount from about 2 to about which have a relative humidity of no more than 6095 at 4 mg and ethinylestradiol in an amount from about a temperature of 20 to 40 "C. However, according to 0.01 to about 0.05 mg, followed by the introduction of the preferred embodiment of the invention, the conditions on each of the seven or fewer consecutive days of granulation are the conditions of granulation in a pseudo-dose without the active substance, or in another in the liquefied layer without further administration of any drugs

Another object of the invention is the use of means for seven days or less.

19 771626 20

According to another preferred variant, in example C one of the variants of the implementation of the invention is described. of tradiol, and they must be administered during 21, 22. Example 4 describes the morphology or some phy- 23 or 24 consecutive days, and each of the daily static characteristics of a standard dosed forndart doses without an active substance can be administered by us compositions according to this invention . if necessary, within 7, 6, 5 or 4 consecutive days. Example 5 describes a typical process of running days. In addition, daily standard doses that contain tablets. that combination of drospirenone and ethinyl estradiol, The example would describe a method that can be administered for 28 consecutive days or which has been studied for some physical properties, such as or 31 consecutive days. Predominantly, the dissociation rate constant of the complex, which involves such a medicinal product, includes EE and CD. It was established that the daily half-life of at least 21 consecutive 1:1 complexes was 155.8s, and the value of the daily standard dose constant, which contains dissociation compounds, was 4.45x103s71. 7 described the method, using about 4 mg and ethinylestradiol in an amount from which the equilibrium stability constant of about 0.01 to about 0.05 mg was estimated, followed by the (formation constant) of the complex that contains EE and administered daily for seven or less post-DM. It was established that the stability constant of complex days of the daily standard dose, which contains su 1:11, was 9.5x10"M". It was established that only ethinyl estradiol in the amount from about the solubility of ethinyl estradiol, which is included in the com- 0.01 to about 0.05 mg. plex, increased in comparison with free stereo-

According to this alternative method of dom. daily standard doses that contain a combination In example 8, a method is described, with the help of drospirenone and ethinyl estradiol, which can be administered, the equilibrium constant of stability was evaluated for 21, 22, 23, or 24 consecutive days, and the pre- (formation constant) of a complex that contains EE and bovi standard doses, which contain only ethinyles- DM, in an acidic environment. The data on vetradiol are presented, it can be introduced if necessary during the larval stability constants of the 1:1 and 1:2 complexes in 7, 6, 5 or 4 consecutive days. According to the acidic environment. It was established that in the acidic tissue version of the method, daily standard doses, the solubility of ethinyl estradiol in the medium, which contains a combination of drospirenone and ethinyl estradiol, is increased in comparison with vildiol. It is administered 2-4 times, preferably 2 or 3 times with a prolonged steroid. . gm for 28 consecutive days, followed by the introduction In example 9, a method is described, using daily standard doses, which contain a combination of which it was established that the amount of acidic long day, and then enter the daily standard media is approximately 10.51 in equal doses that contain only ethinyl estradiol, during nursing with pKa of the free steroid, which is approximately 7 consecutive days. lick 10.25.

Below, this invention is illustrated in more detail. In example 10, the method is described using examples. which was determined by the value of the distribution coefficient in

Example 1 describes the pharmaceutical process of the n-octanol/water (Rolu) complex of EE-CD and the duct that corresponds to some variants of its implementation depending on the pH value. The value of P of this invention, along with pharmaceutical products, is in the range from 3.20 to 3.53. ducts well known to a person skilled in the art. In Example 11, the issue of models is discussed in Table 1.3, the illustrated characteristic of the stability of the existence of the ethinyl estradiol complex in comparison with known drugs after cyclodextrins in the form of a set of forms that are found during a fixed period of time in a solid state, and methods of analysis, controlled environmental conditions, which can be used to find and distinguish such higher ones are described. The data indicate that the direct preform. stirring of the powdery mixture leads to In example 12, typical processes for obtaining good stability of ethinyl estradiol, EE-CD complex are described. which is used in the form of a complex with cyclodextrin (product G). Product D was prepared according to the present invention without the use of polyvinylpyrrolidone. Comparative data on stabilidone were obtained. This product was also distinguished by the good ness of the five tablet compositions that contained ethinyl ethinyl estradiol despite the fact that lestradiol. Different compositions differed from each other in that it was prepared using granulation. However, one method of obtaining, using ethinyl - if the product included polyvinylpyrrolidone in the form of a complex with cyclodextrin rolidone and it was prepared according to example C and using polyvinylpyrrolidone 25000 (PVP). of patent 05 5798338 (table A),|, the stability of Tablet A was obtained according to the method, the product was low. (described in patent 5 5798338, example ZI, for

Example 2 illustrates the stability of EE using granulation in a fluidized bed on compositions G and D in comparison with other compositions based on a premix that contains the active substance and varnishes from the point of view of decomposition products that were released from the tose, and without adjusting the relative humidity of the granules . samples, after storage for a fixed period of time. Tablets B, B and D were obtained according to the given period of time in controlled environmental conditions described in the method. his environment.

Table 1.1. Starch 500 |UU| |-1-1- ppv1i25000.77..7./DGCU|1U|1 |-1-1-

Generalization of data on the parameters of film tablets ab- : Y Results

The content of ethinyl estradiol was determined with the help of the HCVR directly after preparation (beginning) and after storage in various conditions during the liquefied layer of EE-B-uD 3 and 12 months. layer that was introduced into each composition.close: Kiwi NN AI to the liquefied layer Table 1.3.

Complex t vezhonetetoenya prrenya anv outside the fluidized bed EE-V-CD current 40"С, | 602С, | 257С, 40"s x Granulation in the fluidized bed takes place- 7590 | 7Bby | 6090 75 VN were registered accordingly (to the example of patent O5 VN VN VN and 5798338) "". Granulation in a fluidized bed was carried out according to the method described in B |98,9| 949 | 70.7 | 956 | 85.7 sanomo in example 5 of this description, PVP: polyvinylpyrrolidone polyvinyl. 99.1 96.2 | 861 99.1 92.1 102.7 | 100.7 | 98.6 | 101.8 | 100.0 103.3 | 102.0 96.6 | 101.8 | 99.3

The composition of the tested compositions

Example 2

Formation of products of oxidative decomposition of ethinyl GATVIVISrdDo 0 lestradiol with R t VV PO Content of known products of oxidative decomposition

EE-CD 00000000 1-1 -1 1-1 of ethinyl estradiol was determined using RHPR (Drospirenone (OB5R) | - | M | M | - HER - after storage for 12 months at 25"C and (Lactose 000000 IU MU In relative humidity (КН) 6095. The molar content of each decomposition product was expressed as a relative fraction of the initial molar content of ethinyl estradiol,

Lichna microcrystal, which was added to each composition. 4 microcrystalline 1.101141 compositions were studied, as well as pure ethinyl estradiol and the ethinyl estradiol-D-cyclodextrin complex.

Table 2.1.

Data on stability after storage for 12 months, 257, 6095 EN of products

EE | 0004 | 0005 | nv | 038 | 0389.74CM.

ЕВ ЦДд | 0002 | 0003 | nv | 038 | 09385 Sh

B (| 004 | 007 | 032 | 074 | i2g0 now: WE: LIN NO NO NO NO NNYA 0.04 0.07 0.08 0.70 0.91 0.01 0.01 N.V. 0.45 0.47 xx GE: 7 0.02 0.01 N.V. 0.40 0.43 n.v -: impossible to determine; 6-0-OH-EE //"6b-o-hydroxyethynylestradiol; 6-02 -OH-EE /--6-p- hydroxyethynylestradiol; b6-keto-EE -6-ketoethynylestradiol; A-9,11-EE -D-9,11-ethynylestradiol.

23 771626 24

Table 2.2.

Data on stability after storage for 12 months, 40"С, 7595 ВН

Formation of decomposition products (95 from the initial content of EE w Total content of known 0.004 0.005 | manifest. | 098 | 0.389

EE-R-CD 0.002 0.003. | nv | 058 2 sh /| 0.385

B | 016 | 025 | 792 | 314 | 7547 8 17517501 0.28 0.54 0.87 1.59 3.28 g 0.03 0.09 01o 0.79 1.01 0.03 0.10 0.09 0.79 0.98 0.08 0.19 0.30 0.93 1.50 0.08 0.19 0.41 0.89 1.58 n.v. - impossible to determine; 6b-50-OH-EE - 2b-o-hydroxyethynylestradiol; 6-0-OH-EE - 6-p- hydroxyethynylestradiol; b6-keto-EE - 6-ketoethinylestradiol; A-9,11-EE - D-9,11-ethynylestradiol.

Example C

A representative composition of the tablet core is described. You can optionally apply a film or sugar coating to the core of the tablet using the specified ingredients. Specific ingredients are, as a rule, ingredients that can be used according to the invention (but are not limited to them).

Table C

Ingredient Specific ingredients Amount of ed These ed (wt. obv)

The core of the tablet: (Diyucharechovina! | Estrogeniu formicomplexus cyclodextrin./// (Diyucharechovinay 0 | progestoevn////77777777777777111111111Ї11 in 0-95 ' starch, cellulose, hydroxypropyl cellulose, hydroxypropyl co

A substance that improves coagulation. -,. colloidal silicon dioxide 0-50 starch, calcium carmellose, sodium croscarmellose, sodium carboxymethyl starch. Tocopherol acetate, propyl gallate, ascorbic acid, palmi co

Stabilizer/antioxidant tat ascorbic acid 0-59

Pdroxypropylmethylcellulose, derivatives of polyacrylic acid! 20.4005/, 0-2096

Talc, titanium dioxide, calcium carbonate 0-2096 0-2096

Pigments based on iron oxide! 0-1095

Sugar coating: 30-9096

Povidone 700000, polyethylene glycol 6000 0-1095

Filler/agent for application

Talc, titanium dioxide, calcium carbonate 10-5095 titanium dioxide, calcium carbonate 0-1095

Pigments based on iron oxide() 0-1095 0-0.59o

Example 4 200,000-550,000 tablets (development stage) and 2.5 million

Preferable compositions of tablets up to 5 million tablets (industrial stage

Preferred compositions consist of intermission) respectively. Water was used from the components hidden below. The size of the batch was the purpose of processing for the preparation of mass for tablets

771626 26 tumbling (granulation in a fluidized bed) and for applying a film coating. 7; amount in terms of the amount of ethinyl estradiol.

Example 5

The cooking process

The cooking process included the following stages:

Preparation | Corn starch is suspended in purified water and, with stirring, this liquid for greasing is added to the purified water. zeros:

Add lactose, drospirenone micro 15, ethinylestradiol-D-cyclodextrin complex, micro and

Preparation corn starch (part) In a fluidized bed granulator. Granules are activated: a continuous fluidized bed and a liquid for granulation is introduced. Drying Define

And the relative humidity of the granulated mass. If necessary, the granulated mass is dried to reach the desired range of relative humidity (330-459).

Preparation |Introduce corn starch (part) and magnesium stearate into a granulator with a pseudo-liquid mass for a thin layer. They stir. vacation:

Pressing ma- Pressing is carried out on a rotary tabletting machine to obtain tablet cores. for tableting:

Preparation | Suspend talc, pigment based on iron oxide (III), red and titanium dioxide in eye-suspension for drinking water and homogenize the suspension. Dissolve with stirring the hydroxypropyl-me film pok-| cellulose in purified water. Combine and homogenize the mixture and evaluate the yield. digging:

Placing the tablet cores are introduced into a suitable coating device and heated. Dust-free coating - the appropriate amount of suspension is continuously sprayed to apply a film coating on the rotating cores, drying them in warm air. Polish and evaluate the homogeneity of the mass,

And the time of decay and exit.

Example 6 C EECDe

Dissociation of the EE-B-CD complex Kg - sys

The rate constant of the di-EE-ZD association constant of the EE-B-ZD complex in an aqueous solution was determined. In this experiment, the rate of dissociation of the complex

The 1:11 analysis method was evaluated using the relaxation method

When dissolved in water, the complex of ethinyl estradiol with conductometric ol-B-cyclodextrin dissociates on detection. The indirect method was based on its component, ethinyl estradiol (EE) and ligand B - a competitive reaction using dodecylsu-cyclodextrin (CD) according to the law of equilibrium of sodium sulfate (DSN), which also forms co-acting (reacting) masses. plex Since DSN is a salt, its dissociation occurs in the aqueous solution of 1. EE-CDOEE-CD, which significantly affects

SEcD for conductivity. When the DS" anion binds to p-

Ku ----- with cyclodextrin, a complex is formed, which is

Svv Sud is less mobile in water than the free DS ion and the electrical conductivity of the solution should decrease.

27 771626 28

Differences in the conductivity of the free DS anion: and the anion included in the complex were used (Complex stability constant) K1i1-1.56x107M" to evaluate the kinetics of ethinyl estradiol release. complex 1:2: 1.6x10M" jet equipped with a conductivity detector. I I I Zev-1.68x10-

It was established that the rate constant | di-?X10zmol/l dissociation of the 1:1 ethinylestradiol-p-cyclodextrin complex is: Ka-4.45x103s7. Figure 7: the half-reaction time of the dissociation of the 1:1 ethynyl-tradiol-D-diclodextrin complex is: (/2-155.8s Example 9 (2.6 min).

Example 7 (about bottom solution

The stability constant of the EE-B-CD complex in aqueous solution was determined. | n plexus EE-B-CD complex in aqueous media.

The equilibrium constant of stability of the EE-B-CD complex was determined. Nylestradiol-B-cyclodextrin is a clath-

The essence of the method | rat complex, which contains one molecule of ether

Medicinal substance in the form of a complex of ethinylestradiol and two B-cyclodextrin molecules. Nylestradiol-B-cyclodextrin is a complex that dissociates in an aqueous solution and contains one molecule of ethinylestradiol-B-cyclodextrin complex to nylestradiol and two molecules of p-cyclodextrin. its components according to the law of active masses.

Formation of clathrate of ethinyl estradiol-p- In order to limit the dissociation of the ethinylestradiol-cyclodextrin complex in an aqueous solution from its component diol-B-cyclodextrin, for measuring the utilization of ethinyl estradiol (5) and the B-cyclodextrin ligand, approximately 300-fold (0.0114 molar) was used (U was estimated with the help of the following equations - the excess of B-cyclodextrin relative to ethynyl esters in accordance with the law of active masses of tradiol. The value of pKa was determined by the method of photometric titration 1. 5-51 | And according to the manual, 2. ЗИ -ВИ» What is given in Epmigoptepia!Azzez5tepi Thesppisai

The equilibrium constant of stability (Naparooki constant. formation) of Kii was determined using the method of Summarizing the results of phase solubility. For Ki value, the acid dissociation constant of the ethyl complex was obtained - only an approximate estimate. nylestradiol-B-cyclodextrin when determining at

Generalization of results | still 202C was: pKa-10.51-0.03.

Using the method based on the phase diag- For comparison: the pKa of ethinyl estradiol according to solubility buckets (FDR) in aqueous solutions in the presence of B-cyclodextrin is: 20"C, the following results were obtained. pKa-10.25:0.04

Example 10. 11: The essence of the method

ЗЕв-2.17х10: Medicinal substance in the form of a complex of ethyl

Solubility of ethinyl estradiol:| "moles/l (6.43x10 nylestradiol-B-cyclodextrin is a clath-

Zg/l rat complex, which contains one molecule of ethyl and zl. Zy-1.92x10-nylestradiol and two molecules of B-cyclodextrin.

The distribution of the ethinyl estradiol-p-cyclodextrin complex was determined under equilibrium conditions in a mol/l (3.7 g/l) two-phase system, n-octanol/water. Only the total amount of ethinyl estradiol in aqueous and

Example 8 in the octanol phase. The result was visible

The stability constant of the EE-R-CDu 01M complex, the distribution coefficient of ethinyl estradiol in the system n-

NSI octanol/water. To determine the dependence on the

The equilibrium stability constant (pH constant of the apparent coefficient of distribution of ethene formation) of the EE-B-CD complex in 0.1M HCl of estradiol was determined in the n-octanol/water system. Measurements were carried out according to the method described in carried out at pH5, 7 and 9 using the 7. shake flask method according to the manual

Generalization of the results of OECD 1077. Measurements were carried out in water

Using the method based on the phase diag- in solutions buffered to pH 7 and 9. The solubility concentrations (FDR) in 0.1 M HCIII at 202С were tion of ethinyl estradiol in each phase after equalization- the following results were obtained. mastication at 25"C was determined using RHVR.

Generalization of solution results or at relative humidity exceeding 9795. Thus, any discussion

Table of solid state forms of the ethinyl estradiol complex

B-cyclodextrin should be based mainly on

The dependence on pH can be seen in the characteristics of various hydrates, which distribution coefficients of ethinyl estradiol have intermediate water contents that do not exceed the upper limit of water saturation. oh And Trust inter- Hydrate water is part of crystal lattices, and

The average apparent R Я - : : ' :ami ; Visible shaft (9595) for that change in water content is associated with changes in the curve

RN ol with standard Jud Roll / visible steel grates. This can be detected by the distinct deviations of the Ia and P lines in the X-ray diffraction pattern on the powder of batches of clathrate with different water content.

According to these pictures, 4 different 9| 15794505 | 3.20 | 3.08-3.29 | types Parties of type | contained less than 195 of water. In batches of types II and II, from 4 and 1095 water to 8 and

Example 11 1590 water respectively. IM-type parties differed

The solid state forms of the ethynyl ester complex contain more than 1575% of water. However, no diol-B-cyclodextrin was found to be distinctly different between two adjacent ones

Defined a set of solid state forms by types. The position of the diffraction peaks gradually changed in the ethinyl estradiol-B-cyclodextrin complex, which appeared as a result of swelling and compression, and methods were used that allow crystal lattices in the process of sorption and desorption to detect and distinguish such forms. d. The study of four types using di-

Different products of crystallization were studied, differential thermal analysis in combination with obtained in different conditions of crystallization, drying and thermogravimetry allowed to establish that de-storage, in relation to their solid state form. hydration took place at a temperature of 25 to

How appropriate and possible for use were 170 p. and the following analytical methods were chosen for the identification and characterization of solid state forms easily and reversibly. This behavior indicates

KU (HERO), pronounced stability of the structural frame, which is not differential thermal analysis (OTA). y allows for a noticeable change in the main structure - in combination with thermogravimetry (TS), tours of elementary units B - differential scanning calorimetry of the cyclodextrin/ethinylestradiol solid product (05С) in combination with thermogravimetry (TS). in the process of hydration! and dehydration!.

Generalization of results Example 12

Data on the formation of the complex were obtained by studying pure ethinyl estradiol and p-cyclodextrin cyclodextrin, mechanical mixtures of both substances, as well as samples of the ethinyl estradiol-p-cyclodextrin complex were obtained by co-precipitation according to cyclodextrins with the help of X-ray diffraction - the processes described below: X-rays on powder and thermal analysis. Process 1 (RI): Ethinylestradiol was dissolved in

According to the obtained during the creation of the invention and ethanol, P-cyclodextrin was dissolved in water with them at least approximately 9095 ethinyl estradiol 4576. The ethinyl estradiol solution was added to the solution should be bound into a complex. B-cyclodextrin. "The resulting suspension will be mixed

The predominant form of the complex was ethynylated for several hours at 20-25 s and then tradiol-p-cyclodextrin is a hydrate, which contains at 2"C. The crystallization product was isolated and dried with different amounts of water. The variability of the water content using the methods described below depends Process 2 (Pg): Ethinyl estradiol was dissolved in lodextrin, as well as its inclusion compounds in acetone, B-cyclodextrin was dissolved in water with (complexes or clathrates) equilibrating at least 4576. The ethinyl estradiol solution was added to different parts of hydrated water with the help of atmospheric B-cyclodextrin. The obtained suspension of a perferable humidity. During storage, it was stirred for several hours at the temperature of the new water content, which depends on the temperature, below 257C. Then the crystallization product of pressure and relative humidity. Hydrated water can be isolated and dried with the help of the crystal lattices described below. In more strict methods. that all the crystalline Mechanical mixtures of B-cyclodextrin and ethynyl water can be removed during drying, but the product formed is very hygroscopic- tradiol was obtained by weighing and pouring. him, and this is unacceptable for a medicinal substance. humus homogenization by grinding in an agate

This applies to hydrates completely saturated with water, mortar. which are stable only in the presence of the mother

Table 12.1a.

Crystallization products of the complex

Batch Solvent/ processing conditions Contents | Contents

EE (96) | water 96)

It2180 RI, dried in a chamber for vacuum drying

It2181 RI, dried in a chamber for vacuum drying

It2182/1 RI, dried for 1 hour at CT over P2Ovz in a vacuum desiccator | new | 6.5

It2182/2 RI, dried for 2 hours at CT over P2Ovz in a vacuum desiccator | new | 6.5

It2182/3 RI, dried for 4 hours at CT above RgOv in a vacuum desiccator | nv | 64

It2182/4 RI, dried for 4 hours at CT over RgOvz in a vacuum desiccator | new | 7.7

It2182/5 RI, dried for 43.5 hours at CT over RoOv in a vacuum desiccator

It2182/6 RI, washed with acetone, dried for at 27C give two

Asi Рg2О5 in a vacuum desiccator 10.9 4.65

It?182/7 RI, washed with acetone and water, dried during at 27C over P2O5 in a vacuum desiccator 10.6 4.47

It?183/U was dried for several hours at CT over Рg2О5 in a vacuum BO

It2183/UT

IT2188/.-

It?183/ut shchi was dried in a chamber for vacuum drying and then stored in a sealed container

It2184 RI, dried in a chamber for vacuum drying

It2188 RI, 8 p.m. with CT 11.85

IP2190. (RI, dried in a chamber for vacuum drying-food./:/ | nav.

It21917. RI, dried in a chamber for vacuum drying - 1 day | nv | -

It2190 RI, dried in a chamber for vacuum drying - 5 days

It2191 RI, dried in a chamber for vacuum drying - 5 days 28052591 |Batch of It2190 finely ground

It2220

It2221 RI, dried in a chamber for vacuum drying

It2222 RI, dried in a chamber for vacuum drying

It2223 RI, dried in a chamber for vacuum drying

Ito224

Table 12.16.

Crystallization products of the complex and U and EE |65|water (96

It2225/1 RI; washed twice with water; dried in a chamber for vacuum drying t2225/2 RI; washed twice with water, once with acetone; dried in a chamber for vacuum drying 10.5 3.31

It2225/3 P1; washed 2x with water, 1x with acetone, their water; dried in a chamber for vacuum drying 10.9 3.8

P1; washed with water, acetone, 1x water; dried in a chamber for

It2230 and vacuum drying 10.8| 4.35

P1; washed 1x with water, 1x with acetone, their water; dried in a chamber for

It2231 and vacuum drying 11 2.53

P1; washed with water, acetone, 1x water; dried in a chamber for

It2240 and vacuum drying 10.5 6.71 28052591.0М51I batch 28052591 after one cycle of sorption/desorption, which collected 8 st on at 096 KEN "1955

It2180,0M51 batch of It2180 after the sorption/desorption cycle, which was stored at 0905

It2180,0М51 4595 y y o batch of It2180, which was stored at 4595 ЕН yav вв я У partyaitotvo yaazbertvlsatvytoetn ОЙ dv) ov batch of It2180, which was stored at 7095 ЕН at 9.55

33 771626 34

Continuation of table 12.6 batch It2180, which was stored at 7595 EN in 955 povo, rUVI 937 batch of It2180, which was stored at 9396 EN ox

It2180, Zdi. . .

Mas" batch of It2180, which was kept since days above Ma(С104)2

It2190, 5d 9795 VNI batch of It2190, which was stored for 5 days at 9795 VNI | new | 16.75

It2190, 7d 9795 VNI batch of It2190, which was stored for 7 days at 9795 VEN | n.v. | 16.55 28052591, 7 days. . .

Ma(Sg" batch 28052591, which was stored for 7 days over Mo(C104)2 nvosomv d) vza vvI, td 91 batch 28052591, which was stored for 7 days at 9795 EN in yav 28052591, wet | batch 28052591, suspended in water, without drying 1-1 g) per vvI, td TI batch 28052591, which was stored for 7 days at 7595 EN volo with calculated, based on the water content of the initial product and the detected change in mass

Computer typesetting by T. Chepelev Signature Circulation 26 approx.

Ministry of Education and Science of Ukraine

State Department of Intellectual Property, str. Urytskogo, 45, Kyiv, MSP, 03680, Ukraine

SE "Ukrainian Institute of Industrial Property", str. Glazunova, 1, Kyiv - 42, 01601