Transdermal drug extended action with antiosteoporotic activity

 

(57) Abstract:

The invention relates to the field of medicine and relates to transdermal drug extended action with antiosteoporotic activity. Medication containing estrogen as the active substance at least one carrier or excipient, and these components and their number is selected for the continuous excretion of estrogen for at least 24 hours, at the same time as estrogen drug contains estriol in an effective amount. The proposed remedy can effectively deal with menopausal osteoporosis without any increased risk of cancer, particularly breast cancer. 2 s and 5 C.p. f-crystals, 4 PL.

The invention relates to the field of therapy menopausal osteoporosis, in particular transdermal drug extended action with antiosteoporotic activity.

Known transdermal drug extended action with antiosteoporotic activity containing estriol and at least one carrier or excipient (see special edition of Deutsches Arzteblatt - Arztliche]", 85, 1988, pp. 1322-1325).

Nedosekov osteoporosis is as side effects, you may receive cancer of the uterus (endometrial carcinoma) or breast cancer. Therefore, according to the application DE N 3010578, MKI A 61 K 31/565, 1990, serves to reduce the risk of cancer to the use of estradiol in combination with a gestagen.

However, the appropriate combination of estrogen and progestogen has a positive effect with respect to mortality due to breast cancer (see L. A. Brinton, "Menopause and ...", new York Academy of Science, 592, pp. 357 - 362, 1990, and R. A. Lobo, "Estrogen and Cardiovascular Disease" in "Multidisciplinary Perspectives on Menopause," edited by M. Flint, F. Kronenberg, and W. Utian, Annals of The N. Y. Acad. of Science, 592, pp. 286 - 294, 1990).

The task of the invention is to provide a transdermal drug extended action with antiosteoporotic activity, allowing to effectively deal with menopausal osteoporosis without any increased risk of cancer, particularly breast cancer.

The specified task in the proposed transdermal drug extended action with antiosteoporotic activity that contains estrogen as the active substance and at least one carrier or excipient, and these components and their number is selected with the oestrogen it contains estriol in an effective amount.

According to a preferred form of the invention offer the drug for prolonged action is executed in the form of strips. This adhesive preferably contains impermeable base layer, on which a layer extended to the containing estriol in an effective amount, for example, 1 to 60 wt.%, moreover, the supporting layer is made of adhesive or provided with adhesive layer and a removable protective layer, the overlying layer of the prolonged action and the adhesive layer, the adhesive may contain promotes penetration of the substance. This layer extended actions and possible adhesion layer is preferably made from a continuous selection of estriol in the amount of 5 - 25 mg for at least 24 hours.

The bearing layer is made preferably as an aluminum foil.

The patch can be obtained, for example, as follows:

The solution or suspension of from 1 to 60 wt.% the active substance, to a maximum of 45 wt.% promotes penetration of substances and 30 to 70 wt.% adhesives based on polyacrylate processed in the patch. This glue is based on the polyacrylate may or dissolved in a suitable volatile solvent, or in dispergirovannom in water Volga, dry and provide removable protective layer made, for example, siliconized fabric or paper, provided with a layer of fluoropolymer.

In that case, if you use a polyacrylate, after drying systems are not or not sufficiently adherent to the skin, before applying, remove the protective layer system can be coated adhesive glue. Usually this adhesive glue is also used polyacrylate. This method has the advantage that the manufacture or additional binding layers of the system by means of pressure (using calender) can be brought into close contact with each other. So get layered system (laminate), in which and from which the active substance can debendranath best way.

However, in the same way as a material layer of the prolonged action and the adhesive layer can also be used silicones, polyurethanes, and natural and synthetic rubbers. As further additives to the layer of the prolonged action may be cellulose and/or derivatives thereof, polyvinylene compounds, silicones or silicates.

According to a further preferred form of execution izaberete is an emulsion system water in the oil. This means that the active substance in the aqueous solution, which, if necessary, may contain promotes penetration of the substance added to usually used in pharmacy the basis of the type of water in the oil. Ready ointment is usually served in a volume of one individual dose, for example, in recesses made in a suitable film, preferably a plastic film. Deepening closed removable protective layer, and ready packaging such packaging type blister".

As the simple basics type of water in the oil within the framework of the present invention can be applied, for example, ointment alcohol-based wool wax. When using a suitable emulsifier may be difficult emulsions. Possible system oil/water/oil or water/oil/water/oil" if they meet the prerequisite of the invention, namely, a continuous selection estriol at least 24 hours, preferably in an amount of 5 to 25 mg.

Sometimes the emulsion can not or do not adequately adhere to the skin or penetrate into it. In this case, to the outer phase, you can add additional suitable substances that promote adhesion or penetration. For example, promotes penetration of spencie active substances, contains(s), 1 to 50 wt.% estriol, and the solution or suspension may be condensed(a) a stabilizer in an amount of about 12 wt.%. As the stabilizer may be, for example, aluminum stearate, bentonite, silicic acid or silicon dioxide.

Good antiosteoporotic activity, achieved by using the proposed drug for prolonged action is unexpected because in the official report of the society Deutshe Gesellschfat für Endokrinologie ("German society on issues of endocrinology") specifically pointed to the lack of efficacy of estriol relative to the prevention of osteoporosis (see Deutsches Arzteblatt - Arztliche], 85, pp. 1322 - 1325, in particular page 1325, left column, 1988).

In addition, the experiments described Lindsay and others (R. Lindsay, D. M. Hart, A. Mac-Lean, J. Garwood, A. C. Clakr and A. Kraszewski, 1979, Boneloss during oestriol therapy in postmenopausal women, Maturitas 1, page 179) for 2 years on 80 women in the period after menopause, it follows that at the giving by mouth in doses, comprising 12 mg per day, estriol showed no protective effect against osteoporosis in the bones of these women. No action estriol on the bone meanwhile, as public knowledge was included in textbooks (see, for example, Freimut A. Leidenber osteoporosis has estriol, which, however, suitable for the treatment of psychovegetative symptoms local symptoms in the genital organs."). In contrast to the prior art the invention is based on the unexpected results of studies showing that in continuous cottage estriol in an amount of 5 to 25 mg, preferably 10 to 15 mg per given unit, for at least 24 hours unexpected phenomenon occurs with respect to the content of active substance in the blood. Estrogens, including estriol, are deactivated in the liver by binding with glucuronic acid or sulfate. All previously obtained results indicate extremely rapid decontamination estriol (see H. Kuhl, "Pharmacokinetics of oestrogens and progesterons", Maturitas 12, pages 171 - 197, in particular, Fig. 4, page 178, 1990). However, according to the invention it was discovered that during the continuous giving of the given active substance is installed in essentially the same content to its active form in the blood. Obviously it regardless of the total amount of free and bound substances (see below) and seems to be regulated by endogenous installation mechanism, activated continuous cottage. Thus, when transdermal the country as part of the experience in humans (see example 7) got an unexpected result that p is trace remained virtually unchanged within 24 hours while the total number of free active substances and inactive metabolite varies greatly (see Fig. 1 and 2). Thus the measured concentration of free estriol in the blood are within appropriate physiological concentartion estrogenic hormones in the cycle of women (about 50 - 350 PG per ml), and why this concentration is suitable for optimum resolve the shortage of estrogen.

Due to the constant concentration of free estriol under varying concentrations of total estriol is assumed that the continuous part of the country metabolized to estriol is becoming once again in its original form, and, however, such transformation, it seems, is controlled by the software eventually constant concentration. Additional evidence that the observed according to the invention the effect is not linearly dependent on concentration, and is the result of active spotter, is a strongly varying the quotient of the disjoint estriol and total estriol (see Fig. 3 and 4). In the framework of the present invention can provide an advantageous mechanism for the protection of the body against overdose.

Reached with the invention, the effect and paradoxically transdermal systems (see examples). While the total number of free and metabolized active substances varied by an amount depending on the system being between 2 and 3, a completely unexpected way observed almost constant level of free estriol, which is crucial for action (see Fig. 5 and 6).

Because achieved by using the effect of the invention can also be used in the proposed drug or under constant harmoniosamente therapy. For constant giving with one hand effectively treated or prevented osteoporosis, and on the other hand recogiendo effect observed when giving normal estrogen, no, on the contrary, one might even expect anti cancer activity.

The invention is illustrated by the following examples.

Example 1

Preparation of transdermal patch

The patch is obtained from the two source fluids, which have the following composition:

The original mix of I:

Ingredients quantity (mg) per patch

estriol - 12

ethanol - 70

water - 18

The initial mixture II:

Ingredients quantity (mg) per patch

Eudragit L 1001- 14

Eudragit S 100 - dnya polymethacrylic acid, and Rudragit L is easily soluble in intestinal juice, and Eudragit S - little soluble in intestinal juice.

Mix the original mix I and II, and the thus obtained mixture suitable manner, for example by pouring or using a squeegee, a thin layer is applied on aluminum foil and dried to obtain a film. On a dried film of a thin layer is applied a suitable adhesive substance (e.g., from Durotac [trading product that is a polyacrylate]), resulting in a gain laminate, which is then dried again.

It is also possible to obtain a laminate by means of a so-called transfer method by calendering film containing medicines with a suitable adhesive layer. Before applying the transdermal patch of the adhesive layer in a known manner may be covered with a protective foil.

Transdermal patch sticks to the skin, even if it is slightly hairy. The contained active substances can diffuse through the adhesive layer to penetrate the skin and act according to the system.

Example 2

Receiving transdermal patch validity

Repeat example 1 with the difference that instead of Eudragit L 100 and S 100 use Softisan TSD 34M15/3A in prinova acid, 12% lauric acid and 40% stearic acid).

Example 3

Obtaining emulsion ointment transdermal action

Impermeable foil is subjected to deformation by heat and/or stretching of obtaining deepening capacity of 0.1 to 3 ml of the Recess is filled with ointment containing solution or suspension of the active substance in a concentration of 12 mg estriol 0.5 g of ointment. Ointment get the following from two different initial mixtures.

The mixture I:

Ingredients quantity (mg) per patch

estriol - 12

ethanol - 7

water - 81

mix 2:

Ingredients quantity (mg) 0.5 mg ointment

water - 30

glycerol - 15

triglycerides medium chain length - 55

ointment alcohol-based wool wax - 400

Mixture II homogenized and in a water bath heated to a temperature of 60oC. the mixture is Then I, also heated at a temperature of 60oC, portions mixed with II.

In depressions made in the foil as above described, serves to 0.5 g ointment and close.

The preparations according to examples 1 to 3 provide a continuous allocation contained in them estriol for at least 24 hours.

Drugs Nigella onanti - amount (mg) in 1 g of ointment

estriol - 20

dispersant - 80

freeze basis - 250

water - up to 1 g

Example 5 (patch)

The composition of the patch:

Ingredients quantity (mg) per patch

estriol - 20

dispersant - 50

emulsifier - 40

polyacrylate - 150

Example 6

Investigating the effects of estriol on osteoporosis in rats after oophorectomy

1. The purpose of the study

Within 2 weeks after oophorectomy rats-females breed Wistar age 11 weeks will lose a significant part of the bone mass. The aim of the research is to check whether it is possible to prevent this phenomenon by giving estriol. This hormone must be given to ensure an even level of the hormone for the entire study period. The basis of such experience on the hypothesis that the observed still no action estriol on the bone due to the fact that the number of estriol in the blood in two cottages in the day, for example, through the mouth, fell below the critical level. In addition, it is necessary to check whether estriol as a partial antagonist of estrogen lack of action on the bone.

2. Animals and method

In laboratory rats were supplied females of Wistar breed age 9 to 10 s at a temperature of 22oC 4oC in the light mode (14 hours light, 10 hours dark).

Animals were fed with standard food (formula R13) and drinking water at will.

Started experience at the age of animals average of 11 weeks, and their weight was about 220,

3. Giving the compounds

Subcutaneous installation osmotic pumps Alzet 2002 tank capacity 200 μl, a flow rate of 0.5 ml per hour. A solution of the compound in propylene glycol.

The total duration of studies - 3 weeks, namely, the week before oophorectomy and 2 weeks (15 days) after it.

In the weeks before oophorectomy, that is, before the loss of bone tissue, as "original values" defined characteristic parameters, namely the content of hydroxyproline in urine daily, and the content of hydroxyproline and the concentration of estriol in serum.

For the determination of hydroxyproline in urine by collecting urine received daily urine. For this animal once a week separately placed in a special cell in order to collect enough clean urine separated from the litter. Then determined the content of hydroxyproline in the collected urine of each individual animal.

In addition, the content was determined on the day of castration, and in the seventh and 14th day after castration.

4. Investigating the effects of estriol on the bone

At the end of the experiment animals were killed, and for histological examination were fixed femur were cut by microtome and examined qualitatively and quantitatively relatively morphological features.

5. The results of the experiment

The results are shown in tables 1 to 4.

6. Assessment

The results of the experiment show that in contrast to the literature data concerning the effectiveness of estriol this substance is protective against osteoporosis action.

According to the results of experience precondition of this action is the creation of a uniform level of active substance. The results confirm the use of estriol for treatment according to the invention.

Results

1. The allocation of hydroxyproline in the urine hydroxyproline in serum

Hydroxyproline released during the decomposition of collagen, which represents a significant proportion of the bones.

After oophorectomy in serum have found an increasing amount of hydroxyproline (see table 2), when the country estriol increased decreased depending on the dose.

In addition, after castration in the scrap (see table 3).

2. Effect on bone

As the parameter is protective against osteoporosis actions estriol determined the effect on the proportion of trabecular in square sections of bones. Table 4 shows that after castration decomposes a significant proportion of the bone. By giving estriol resolve this effect depending on dose.

Example 7

Study of the development level of estriol in the blood of healthy men after transdermal villas

The objective of the experiment is to study the concentration of estriol in serum during continuous the country using different transdermal systems within a few hours. Type of experience - clinical research the first stage (pilot experiment). The ethics Committee of the University. Friedrich Schiller, Jena allowed the experiment.

A clinical study conducted in healthy men as the object of study was the pharmaceutical properties of the drug, but not the metabolism of the active substance in the body. Therefore, it is necessary to exclude all the factors that could hinder comparability regarding the absorption, distribution, metabolism and elimination. Therefore, to make the experience not be used in people with a certain, perhaps izmenyayuschegosya drugs:

Explored three different transdermal drug, each of which contained 12 mg of estriol. These drugs were:

1.Type TTS-22 (patch A):

The patch with a diameter of 32 mm, a protective layer made of aluminum, the media estriol and adhesion layer of polyacrylate (carrier: Scopacrul [trading company's product Buna GmbH; polyacrylate], adhesion layer: Durotac [trading company's product Delft National Company; polyacrylate]). Estriol was distributed in the media and partly in the adhesive layer in molecular disperse form.

2. Type TTS-34 (patch B):

The patch with a diameter of 56 mm, a protective layer of tissue with skin color, in the center of the media in the form of a disk with a diameter of 36 mm, consists of a spongy material (Softisan TSD 34M15/3A), in which estriol has makercreate. The adhesive layer consists of usually taken for patches of glue.

3. Type estriol-TwS (emulsion ointment containing estriol):

Ointment with the concentration of the active substance, component 12 mg estriol 0.5 g

Size and type of experience:

Amounted to 3 groups of healthy men aged from 18 to 55 years, with each group consisted of 4 people. Each group was assigned one of these investigational drugs, and the patches were glued in the area between rooms, assigned on the basis of reliable paternal queue arrival. Blood was taken at the cottage and 0.5, 1,22 4,8, 12, and 24 hours after submission.

Conducting experience:

Investigational drugs gave the basis of reliable paternal on the day of the experiment at 8 am. For holding the level of estriol in these periods took 10 ml of blood by centrifugation separated the serum, which is to determine the concentration of the hormone was stored at -20oC.

The definition of the hormone content of:

Determination of total content of estriol and estriol, existing in a free form, was carried out by the method RIA (Amersham-RIA) in the relevant hospital laboratory Universitatsfrauenklinik, Tubingen (DE). For the determination of total estriol serum first incubated in medium glucoronidase and sulfatase and released desprately estriol was extracted with simple ether. The determination by RIA was performed on the available buffer extracts. Free estriol immediately was isolated from untreated samples, and its quantity was determined using the above method.

Assessment

Determined the concentration of free estriol and total content of estriol in serum human test subjects. Total estriol includes free and metabolized estriol. Each proband was identified after the ü estimated using the trapezoidal rule (in the intervals 0 - 24 hours after giving)

Cmax- the maximum concentration

Tmaxthe time to reach maximum concentration

Results

An unexpected result of the experience was the fact that the curve of the total quantity of the active substance in the blood and metabolized active substances (total estriol in serum) after transdermal villas with all systems has an uneven shape (see Fig. 1 and 2 basis of reliable paternal No. 2 and No. 7). Absolutely unexpectedly after a rise in the beginning of the experiment, the concentration of therapeutically active nematerializiranih hormone (unpaired estriol) remained almost straight during the day (see Fig. 1 and 2 basis of reliable paternal No. 2 and No. 7), and private free (unpaired) estriol and total estriol strongly varies (see Fig. 3 and 4 basis of reliable paternal No. 2 and No. 7).

It is interesting that determined the concentration of free estriol in the blood corresponded to the natural concentrations of estrogenic hormones in the cycle of women (about 50 - 350 PG per ml). Therefore, you should assume that all investigational transdermal systems are suitable to optimally address the shortage of estriol.

This is true especially because different drugs have caused different concentrations of total es is Anna ointment extended actions on the value 2 - 3 higher concentration achieved when applying the patch TTS 34 (patch B), and unexpectedly observed a nearly identical level of estriol, which is important in the body (unpaired estriol in serum) (see Fig. 6).

The result of the above experience suggests that in continuous cottage estriol endogenous mechanisms to regulate the level of estriol in the blood, which leads to advantages in the use of estriol in harmoniosamente therapy, in particular in the treatment of menopausal osteoporosis, as, for example, an overdose is practically eliminated.

1. Transdermal drug extended action with antiosteoporotic activity that contains estrogen as an active and a carrier or excipient, and these components are deposited on the supporting layer, provided with a protective layer, characterized in that as estrogen it contains estriol in the amount of 1 to 60 wt.%, and as the carrier or excipient is at least one component of the prolonged action selected from the group comprising cellulose, a derivative of cellulose, polyacrylate, butter, emulsifier.

2. The drug under item 1, characterized in that the layer staicases fact, the layer containing the active substance and the component is extended to the supplied adhesive layer.

4. The drug under item 1, characterized in that the layer containing active substance and a component of the extended action, includes in addition to promotes penetration of the substance in quantities of not more than 45 wt.%.

5. The drug under item 4, characterized in that as promotes penetration of substances contains one - or polyhydric alcohol.

6. Transdermal drug longitudinal steps antiosteoporotic activity in the form of ointments containing estrogen as the active substance, common in pharmacy based and water, characterized in that as estrogen it contains estriol in the amount of 1 to 50 wt.%, the substrate contains at least one component of the prolonged action selected from the group comprising cellulose, a derivative of cellulose, polyacrylate, oil and emulsifier.

7. The drug under item 6, characterized in that it further comprises promotes penetration of the substance.

 

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