RU2500395C1 - Ointment composition for local application having antiacneic pharmacological activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and concerns an ointment composition for treating acne containing isotretinoin, α-tocopherol as an antioxidant, as well as emulsion wax, Vaseline oil, glycerol, ethanol and water.

EFFECT: composition possesses lower side effects and high efficacy.

3 tbl, 2 ex

Description

The invention relates to pharmacy and for the creation of an ointment composition for topical use containing isotretinoin, an active pharmaceutical substance with sebostatic and keratolytic effects, intended for the pathogenetic treatment of acne.

Acne is a common skin disease that affects mainly young people. Often, acne becomes a factor that reduces the self-esteem of a young man and prevents his social adaptation. Currently, the most effective treatments for acne are drugs containing retinoids, as these substances inhibit the process of terminal differentiation of sebocytes, which leads to a decrease in the size of the sebaceous glands [1] and a decrease in the production of sebum [2]. Having a keratolytic effect, retinoids promote exfoliation of the stratum corneum of the follicular and interfollicular epithelium, facilitate the release of contents from sebaceous hair complexes, reduce the number of Propionibacterium acnes and gram-negative microorganisms, and have anti-inflammatory effects [3].

Thus, the treatment of acne with the use of agents containing retinoids is pathogenetic, since these substances have pharmacological activity against the main pathogenetic links of this disease.

The most effective anti-acne retinoids currently are retinoic acids - fully trans-retinoic acid (the international nonproprietary name is tretinoin) and 13-cis-retinoic acid (the international nonproprietary name is isotretinoin). In our opinion, the use of isotretinoin in external anti-acne drugs is preferable due to its lower toxicity. So, there is evidence that it has less local irritating properties than tretinoin [4], and, very importantly, less teratogenic effects [5]. In addition, isotretinoin is a naturally occurring biologically active form of vitamin A; without additional biochemical transformations in the body, it can be recognized by cellular receptors and penetrate into target cells [6].

Known drug "Retinoic ointment", prepared on a water-based basis, which includes isotretinoin (0.01%, 0.05% or 0.1%), and as antioxidants butyloxytoluene (syn. - butylhydroxytoluene, BOT) and butyloxyanisole ( syn. - butylhydroxyanisole, BOA) [7]. In animal experiments, it was shown that cutaneous application of retinoic ointment over two weeks leads to a statistically significant decrease in the size of the sebaceous glands, a change in their cellular composition in the direction of increasing the proportion of undifferentiated sebocytes, loosening and thinning of the stratum corneum [8]. When treating patients with papulopustular and comedonal acne with retinoic ointment, its high therapeutic efficacy was demonstrated [9, see 1].

Retinoids are unstable, easily oxidized compounds, and therefore the preparations in which they are included must contain components that prevent their destruction. As the latter, antioxidants are most often used - butylhydroxytoluene (BOT) and butylhydroxyanisole (BOA). However, they also have some undesirable effects, for example, potential carcinogenic properties [10, 11], the ability to increase cholesterol, irritate the skin, eyes and mucous membranes [12], which entails an additional risk when working with these substances. For this reason, their content in medicines and food products should be regulated [13].

Thus, the search for modern non-toxic antioxidants, preferably of natural or close to natural origin, effectively inhibiting the decomposition of retinoids in the composition of drugs, is relevant.

The present invention is the development of an ointment composition with an anti-acne effect, devoid of these disadvantages.

There are many patents (foreign) that protect the composition of anti-acne cosmetics and medicines containing retinoids (tretinoin, isotretinoin, retinal, retinol and its esters), stabilized with α-tocopherol and other excipients [butyl-hydroxytoluene (BOT), butylhydroxyanisole ( BOA), ethylenediaminetetraacetic acid (EDTA), vitamin C, etc.]; as a rule, these compositions are hydrogels and oil-in-water emulsions.

An analogue of the claimed drug is patent RU 2111745 (Hoffman-La Roche), which describes a liquid composition containing isotretinoin (0.05-0.2%) and α-tocopherol (0.005-5.0%) [14]. Also known European patent EP 0439042 (Hoffman la Roch AG), describing solutions that can be further used to prepare gels, one of which includes isotretinoin (0.05%), α-tocopherol (0.01%) in combination with disodium EDTA, lecithin, glycocholic acid, etc. [15].

Closest to the medical indications and technical nature of the claimed composition is patent RU 2004240 (A drug for the treatment of the conglobate form of acne and skin diseases associated with impaired keratinization) containing a biologically active pharmaceutical substance - isotretinoin, and butyl oxitoluene as stabilizers (syn. - butylhydroxytoluene, BOT) and butyloxyanisole (syn. -butylhydroxyanisole, BOA) [16].

In order to improve the quality of the drug, safety profile and consumer properties, BOT and BOA antioxidants were removed from the composition, and the content of liquid paraffin was reduced to reduce oily skin after application of the ointment.

In accordance with the invention, an ointment composition for topical application with anti-acne activity is described, containing isotretinoin retinoid, α-tocopherol antioxidant, vaseline oil as an ointment base phase, emulsion wax as an emulsifier, and ethyl alcohol, glycerin and water in the following the ratio of components, wt.%:

Isotretinoin 0.05-0.1 α-tocopherol 0.025-0.2 Emulsion Wax 6.0-10.0 Vaseline oil 4.0-6.0 Glycerol 5.0-15.0 Ethanol 7.0-15.0 Purified water up to 100.0

The composition reduces or eliminates acne.

The use of α-tocopherol avoids the use of components such as BOT and BOA while maintaining high anti-acne and operational properties of the drug.

Laboratory research

Experiment 1

In the claimed composition of the ointment composition, α-tocopherol was introduced to stabilize the retinoid, and therefore, at the first stage of laboratory studies, the stability of isotretinoin was studied using model mixtures as an example.

Purpose: to study the stability of the substance isotretinoin stabilized by α-tocopherol.

The object of the study was model mixtures - the substance isotretinoin in liquid paraffin without antioxidant (1) - control - and a similar combination, characterized by the presence of 0.025% α-tocopherol (2) - in it. The initial concentration of isotretinoin in model mixtures was 0.05%. The samples were laid on “accelerated aging” in glass jars with a wide neck with free access of air at elevated temperatures (60 ° C).

Method: spectrophotometry with respect to a solution of a standard sample.

The result of quantitative determination of 13cRK in these mixtures is presented in table 1.

Table 1 Dynamics of isotretinoin content in model mixtures without an antioxidant and with α-tocopherol as an antioxidant under storage conditions at 60 ° C and free access to air Shelf life, days The amount of isotretinoin in the model mixture,% without α-tocopherol with α-tocopherol one 0,0447 0.0472 fifteen 0,0385 0,0451 19 0,0395 0,046 34 0,0387 0,0451 41 0,0371 0.0475 53 0,0359 0,0469 63 0,0349 0,045 70 0,0342 0,045 83 0,0358 0,0455 137 0,0345 0,0446 183 0,0343 0.0435 203 0,0335 0.0433 257 0,0318 0.0417

As can be seen from the data presented, the content of isotretinoin in the model mixture containing no antioxidant is slowly decreasing. Over the 257 days of the experiment, the initial concentration of the substance decreased from 0.0447% to 0.0318%, i.e. by 30%. Over the same period, the content of isotretinoin in a mixture with α-tocopherol decreased from 0.0472% to 0.0417%, i.e. by 12%.

For a comparative assessment of the stabilizing activity of α-tocopherol, the initial content of isotretinoin was taken as 100%, and its decrease during accelerated storage was also expressed as a percentage. The results are presented in Figure 1, from which it follows that the decrease in the concentration of isotretinoin in the mixture without a stabilizer is linear and is described by the regression equation. The correlation coefficient between the content of isotretinoin in mixtures (without α-tocopherol and with α-tocopherol) and their shelf life is 0.860 and 0.897, respectively, which indicates the presence of a close relationship between these parameters. As calculations showed, α-tocopherol inhibits the destruction of isotretinoin by 2.6 times.

Thus, the experiment proved that α-tocopherol has a stabilizing effect against isotretinoin. Its content in the model mixture in the amount of 0.025% increases the stability of the substance by 2.6 times.

Experiment 2

Purpose: to establish the stability duration of a pharmaceutical substance (isotretinoin) in ointment compositions containing different concentrations of α-tocopherol.

The object of the study was samples of ointment compositions with 0.1% isotretinoin that did not contain α-tocopherol (control) and containing different amounts of α-tocopherol as a stabilizer (from 0.025 to 0.25%). To establish the optimal concentration of α-tocopherol, ensuring the stability of isotretinoin in ointments, the prepared samples of ointments were laid for accelerated storage at 40 ° C. The stability criterion for the drug was the results of the quantitative determination of the substance in the preparation obtained at different periods of its storage. The duration of observation of the series with the appropriate recalculation corresponded to 2.5 years of experimental storage. The identification at the end of this period of a satisfactory quality of the drug should guarantee the stability of the drug for 2 years.

Method: high performance liquid chromatography.

Ointment Technology

1. The required amount of water is placed in the reactor 1 and heated to 80 ° C.

2. In parallel, the necessary quantities of liquid paraffin (part of the total content in the preparation) and emulsion wax are placed in the reactor 2. Heated to a temperature of 75 ° C, melting the loaded substances.

3. Estimated amounts of isotretinoin and α-tocopherol are placed in a small amount of liquid paraffin. The mixture is thoroughly mixed.

4. After melting the fatty components of the base (item 2), a mixture of isotretinoin and α-tocopherol (item 3) is added to reactor 2 and mixed until the substance is dissolved.

5. The head of the homogenizer is lowered into the reactor 1 (p. 1), it is turned on (8-10 thousand rpm) and with active stirring of the mixture the melt of the fat components of the ointment is slowly and thinly added (p. 4). After 2-5 minutes [depending on the volume of the reactor used (0.5-3.0 L)] after mixing all the components of the preparation, the ointment is finally homogenized. After 2-5 minutes, a mixture of ethanol and glycerol is added to the reactor, after which the ointment is further homogenized for 2 minutes.

6. Due to the fact that the ointment contains thermolabile components (isotretinoin, α-tocopherol), the destruction of which is enhanced at high temperatures, it should be forced to cool. After cooling the ointment to 35-40 ° C, it is transferred to the packaging section in tubes.

Ointment should be stored at a temperature of 2 to 8 ° C. Freezing is not allowed.

Examples of the preparation of specific compositions

Example 2

In the reactor 1 with an effective load of 100 kg of ointment, 65.7 liters of purified water are measured and heated to a temperature of 75-80 ° C.

8 kg of emulsion wax and 5 kg of liquid paraffin are weighed into reactor 2, the engine of the frame mixer is turned on, and, heating the mixture to a temperature of 75-80 ° С, it is melted.

1 kg of liquid paraffin, 0.10 kg of isotretinoin and 0.20 kg of α-tocopherol are weighed into a special container. Heat the mixture to a temperature of 50-55 ° C, mix thoroughly and transfer to reactor 2.

The movement of lipophilic components of the ointment is carried out using a flow-type rotary pulsation apparatus built into the reactor system. The mixing of the components of the two reactors is continued for 20 minutes, until a homogeneous emulsion is obtained, into which a mixture of 10 kg of ethyl alcohol and 10 kg of glycerol is gradually added.

The resulting mixture is finally homogenized for 15 minutes, cooled to a temperature of 30-35 ° C and Packed in aluminum tubes.

Similarly (according to the same scheme), ointments were obtained (examples 3, 4, 5, 6), the composition of which is presented in table 2.

The composition of the studied ointments are presented in table 2.

table 2 Composition of ointments with isotretinoin without an antioxidant and with α-tocopherol added in various concentrations Example Number The amount of ingredient in ointment,% Isotretinoin Vaseline oil Emulsion wax α-tocopherol one 0.1 47.5 2,5 0 2 0.1 47.5 2,5 0,025 3 0.1 47.5 2,5 0.05 four od 47.5 2,5 0.10 5 0.1 47.5 2,5 0.20 6 0.1 47.5 2,5 0.20

The results of a quantitative determination of the concentrations of the pharmaceutical substance isotretinoin in these ointments at different storage periods are presented in table 3.

Table 3 The concentration of isotretinoin in ointments stabilized with α-tocopherol, when determining their shelf life by the method of “accelerated aging” (quality index according to FSP - from 0.09 to 0.11%) Experimental term The content of isotretinoin in ointments,% Example 1 Example 2 Example 3 Example 4- Example 5 storage, months; in parentheses - the corresponding term for the Federal Tariff Service without α-tocopherol 0.025% α-tocopherol 0.05% α-tocopherol 0.1% α-tocopherol 0.2% α-tocopherol After manufacturing 0.10 0.11 0.11 0.10 0.10 6 (0.5 years) 0.80 0.10 0.09 0,095 0.09 12 (1 year) 0,034 0.10 0.09 0,093 0,095 18 (1.5 years) 0,028 0,092 0,092 0,091 0,091 24 (2 years) 0,025 0,093 0.09 0,092 0,092 30 (2.5 years) 0,022 0,095 0,092 0,095 0,091

Analysis of the results of determining the quality indicators of retinoic ointment with different antioxidant contents shows that the ointment without α-tocopherol does not meet the requirements of the FSP after 0.5 years of experimental storage. The drug is rejected according to the low value of the indicator "Quantitative content" of isotretinoin in the ointment and the indicator "Foreign impurities". The addition of a-tocopherol to the ointment prevents the destruction of isotretinoin. As follows from the data presented in the table, α-tocopherol in a concentration of from 0.025 to 0.2% by weight of the ointment under conditions of determining the shelf life using the Accelerated Aging method ensures the safety of isotretinoin in the ointment composition in the acceptable limit (not lower than 0.09% )

Literature

1. Nozdrin V.K., Albanova V.I., Sazykina L.N. Morphogenetic approach to acne treatment with retinoids. - M .: ZAO ″ Retinoids ″, 2005. - 127 p.

2. Zouboulis, S.S., Korge B., Akamatsu H. et al. Effects of 13-cis-retinoic acid, all-trans-retinoic acid and acitretin on the proliferation, lipid synthesis and keratin expression of cultured human sebocytes in vitro // J. Invest. Dermatol. - 1991. - Vol. 96, No. 5. - P.792-797.

3. Harms M. Systemic isotretinoin (active ingredient of Roaccutane). A unique therapeutic effect and its implications in the pathogenesis of acne. - Edit. Roche. Basel (Switzerland), 1994 .-- 93 c.

4. Zabnenkova O.B. Surface chemical peels // Dokl. Scientific and practical. Conf. “The use of chemical peels in dermatocosmetology”, December 6-7, 2002, Moscow. - http: // www. http://Estemed.ru/press/publication-profahayel.php.

5. Kochlar D.M., Penner J.D., Tellone C.I. Comparative teratogenic activities of two retinoids: Effects on palate and limb development // teratogenesis, Carcinogenesis and mutagenesis. - 2005. - Vol. 4. - N 4. - P.377-387.

6. Nozdrin V.I. Morphofunctional manifestations of reactive changes in epithelial, myeloid, and lymphoid cell populations when retinoic acid derivatives are introduced into the body: Abstract. dis. ... Dr. honey. n - M., 1989 .-- 48 p.

7. Almanac ″ Retinoids ″. - M .: ZAO ″ Retinoids ″, 1997. - Issue 4. - C.3-8.

8. Belousova T.A., Albanova V.K., Zhuchkov S.A. and other Histostructural manifestations of the dermatotropic activity of retinoic ointment // Ros.zh. skin and veins. diseases. - 2005. - No. 2 - S.61-66.

9. Ivanov O.L., Grabovskaya O.V. Clinical efficacy of retinoic ointment for skin diseases // Almanac ″ Retinoids ″. - M .: ZAO ″ Retinoids ″, 1997. - Issue 4. - S.50-55.

10. Inai K., Kobuke T., Nambu S. et al. Hepatocellular tumorigenicity of butilated hydroxytoluene administered orally to B6C3F1 mice // Jpn. J. Cancer Res. (Gann). - 1988. - Vol. 79. - P. 49-58.

11. Kahl R., Kappus H. Toxicology of the synthetic antioxidants BHA and BHT in comparison with the natural antioxidant vitamin E // Z. fur Lebensmittel-Untersuchung und-Forchung. - 1993. - Bd. 196, N 4. - S.329-338.

12. Decision of the Commission of the Customs Union of May 19, 2011 No. 646. About the draft drug labeling requirements. - Minsk.

13. SanPiN 2.3.2.1293-03. - Clause 3.4.4.

14. Patent RU 2111745. - Publ. 05/27/98.

15. Patent EP 0439042 - Publ. 07/31/91.

16. Patent RU 2004240. - Publ. 12/15/93.

Claims (1)

A topical ointment composition with retinoid-based anti-acne pharmacological activity, characterized in that it contains isotretinoin, α-tocopherol, emulsion wax, liquid paraffin, glycerin, ethanol and water in the following ratio, wt.%:
isotretinoin 0.05-0.1 α-tocopherol 0.025-0.2 Emulsion Wax 6.0-10.0 Vaseline oil 4.0-6.0 Glycerol 5.0-15.0 Ethanol 7.0-15.0 Distilled water up to 100.0

Images