MXPA99011785A - Polymer comprising unsaturated ester units and pharmaceutical and cosmetic compositions thereof - Google Patents

Abstract

Disclosed is a polymeric molecule comprising a plurality of repeat units having the structure -(O2C-R-CO2)-, wherein R is a substituted or unsubstituted, unsaturated hydrocarbon radical having 14 or more carbon atoms. Also disclosed are pharmaceutical and cosmetic compositions comprising a polymer having a plurality of repeat units having the structure -(O2C-R-CO2)-, wherein R is a substituted or unsubstituted, unsaturated hydrocarbon radical having 10 or more carbon atoms, and various uses of said compositions.

Description

malignant (US 4,818,768); dermatosis (EP 0,229,654); hyper-pigmentary dermatosis and eczema (US 4,292,326); il rosacea (EP 0,890,308); lentigo (JP 91024412) and seborrhea (DE 3133425) and impetigo. -?! WO 94/07837 teaches that the unsaturated dioic acids and derivatives thereof are generally more effective than their saturated counterparts, having higher anti-microbial activity and skin lightening. The WO 94/07837 also describes a microbial method for XI make unsaturated dioic acids. There is no description of polymers comprising unsaturated dioic acicycles. WO 94/12652 discloses a method for producing z i ti a polyester, which comprises as a repeating unit. "at least one aliphatic dicarboxylic acid". He ? 15 document states that (page 5 ^: "Suitable aliphatic, dicarboxylic acids include those of the formula H02C-R5-C02H, where R5 is a bond or is a radical i 1 divalent defined as for R1"(R1 which has been previously defined in the document as an" alkyl group of one J3 f 20 to twelve carbon atoms, substituted or unsubstituted, which optionally has one or more carbon-X carbon double bonds ... ") Polyesters" produced by the process described in WO 94/12652 are said to be that "find uses as •? Foam shaped articles, particularly for "Ti 25 motor vehicles' There is no suggestion of the use of f F - l polymers that include dioic acids in any other. 1 technical field BRIEF DESCRIPTION OF THE INVENTION, _. In a first aspect, the invention provides a polymer molecule comprising a plurality of i repeat units having the structure - (02C-R-C02) -, __ wherein R is a substituted or unsubstituted, unsaturated hydrocarbon radical having 13 or more carbon atoms. It is preferred that the polymer be a lipase-degradable polyester, which upon exposure to a lipase releases a compound having a beneficial effect on a human subject. Therefore, the released compound will be a substituted or more substituted dioic acid, : t 15 unsaturated. In a second aspect, the invention provides a composition suitable for topical application to the human body, the composition comprising: a polymeric f-f molecule having a plurality of units of Repetition having the structure - (02C-R-C02) -, e'n _- * - _- r where R is a substituted or unsubstituted, unsaturated hydrocarbon radical having 10 or more atoms of - = - t carbon; and a carrier substance, acceptable. In a preferred manner, the composition comprises a molecule polymer according to the first aspect defined above. These compositions have unexpected properties and are suitable for a wide range of purposes, discussed subsequently in a manner - Additional i _ r __ Preferably, in the repeating units of the polymer molecule, R is aliphatic and advantageously comprises 16 carbon atoms (such that the repeating units comprise by themselves 18-22 carbon atoms), and preferably three, or more preferably two or one, double carbon-carbon bonds, repeating units (derived from dioic acids) that appear to have optimal anti-microbial activity when released from the polymer by lipase-mediated degradation. In the preferred embodiments, R will comprise a C16:! 1 portion, C16: 2, C16: 3, or C20: l (therefore, the repetition units are units C18: l, C18: 2, C18: 3 or C22: l, which i can be obtained respectively, conveniently, to Advantageously, the composition of the invention will comprise the preferred, as defined above, modalities of the polymeric molecule delf.

First aspect of the invention It will be appreciated by those skilled in the art that a number of compounds can be used as reactants with the two-dioic acids to form polymeric molecules as defined above., the polymeric molecule i can be a homopolymer, consisting of l identical repeating units of dioic acid monomers. Alternatively, a copolymer can be formed from mixtures of two or more different dioic acids (such as combinations of unsaturated dioic acids with saturated dioic acids, or combinations f of unsaturated dioic acids of different chain lengths). Conveniently, the polymer molecule comprises a co-polymer of a dioic acid esterified with one or more di- or polyols. Examples are glycerol if 15 and butanediol, which have certain useful properties beneficial to the skin and / or are particularly suitable in the preparation of useful compositions. Other polyols useful in the preparation of polymer molecules are polyols of 6 to 10 carbon atoms, I Which are those easily miscible with the preferred dioic acid monomers. The average preferred molecular weight of the polymer molecule will also be dependent, in part, on the proposed use of the composition comprising the I 25 polymer molecule. The lower and upper limits are approximately 1 kDa and 50 kDa, respectively. A polymer of molecular weight of about 1 kDa [will have approximately 3 or 4 repeating units. The preferred general interval is 3.5-10kDa. Polymers of this size are generally liquid and thus can be easily processed. The compositions of the invention have a considerable number of possible uses, all of which are considered as if they are within a further aspect of the invention. The nature and structure of the polymer molecules can be adjusted to the proposed purpose of the composition. In fact, in some circumstances, it will be advantageous if the composition comprises two or more polymer molecules other than the previously defined type with complementary characteristics. The compositions of the invention are formulated for topical application to the human body, which are advantageously suitable for application to skin, scalp or hair. In general, it is contemplated that, as the compositions described in WO 94/07837, the compositions of the present invention are useful in combination with cosmetic compositions, improving the quality and complexion of the skin, and as pharmaceutical compositions having anti-microbial effects. (which also improve the condition of the skin). Specifically, the compositions of the invention may be useful in the treatment of: acne; wrinkles; malignant melanoma1; i dermatoses; hyper-pigmentary dermatosis and eczema; rosacea; lentigo; seborrhea * and impetigo; and in the treatment of bad body odor. Additionally, the compositions can be used for skin lightening. In particular, the compositions are useful as anti-perspirants and / or deodorants. The compositions can take the form, inter alia, of gels, creams, lotions, oils or waxes (harsh or I love den uni lib efe pol deg sup se is liberation of monomeric units of dioic acid (or substituted derivatives thereof) of the polymeric molecule, monomeric units having desirable cosmetic and anti-microbial properties. In this way, there is a controlled release of the active agent from the polymer molecule, which is presented The fastest way in response to high concentrations of "2 <lipases, which will be present in sites of maximum microbial colonization (eg, spots, localized areas of skin, pores of the skin).

Most lipases have greater freedom -! to act at the ends of the polymer molecules', 1 instead of the midpoint of the polymer chain, where r the spherical conditions can inhibit the action of the enzyme? Accordingly, the concentration of "free ends" available for mediated degradation by lipases is relatively greater for a composition comprising short polymer molecules than for compositions comprising polymeric molecules X i long. Also, it is thought that the polymers of lower molecular weight are of a less crystalline structure and thus more accessible to lipases. Therefore, it will be advantageous for some uses (for example, x r as topically applied cosmetic agents) if the compositions according to the invention comprise polymer molecules with a molecular weight range, increase the hydrophobicity of the resulting polymeric molecule -f. The anti-microbial, occlusive characteristics of the compositions according to the invention are ideal for use in dressings to promote wound healing, especially burn healing., where properties are desired, both moisture retention and anti-microbial properties) '. Thus, in another aspect, the invention provides a medical dressing (such as a bandage, plaster, mesh, wound dressing, etc.) for application to the skin of a human subject, the dressing comprising a dressing substrate impregnated and coated with a polymer molecule according to the invention. The formulations suitable for the compositions of the invention will be apparent to those skilled in the art and include, for example, 1, J **** 1 those taught by US 4,818,768. I In particular, it will be preferred that § 20 compositions for direct application to the skin comprise a relatively volatile organic solvent (such as lower alcohols, of 2 to 4 carbon atoms). The mixing of an organic solvent with the polymer molecule causes a substantial decrease in the viscosity of the composition, thereby facilitating the application of the composition as a liquid or a spray; after application, a relatively volatile organic solvent will evaporate, leaving a film of the polymeric molecule (which can be hydrolyzed I subsequently by the lipases). The polymeric molecules for inclusion in the composition of the invention, can be synthesized by chemical, normal methods, and can be produced via biocatalytic methods, as described in the examples ? M) and in WO 94/12652. Suitable lipases are also described in the present invention. The lipases obtainable from Cánida anárcti ca are particularly suitable. The biocatalytic methods will be preferred in general * when the formation of I | Polymers comprising polyols, such as the substrate specificity of lipases, ensure a greater degree of uniformity of the product (with the reaction i mainly in the primary -OH groups) than that which can be obtained by the chemical methods. conventional. In particular, the use of an enzyme prevents excessive cross-linking (with the reaction occurring _ mainly in the primary -OH groups), ensuring a biodegradable, essentially linear polymer. In contrast, conventional chemical methods can result in diethyl cross-linking / ethanol (1: 1) and be titrated with 100 M NaOH in f water / ethanol (1: 1) until a color change was observed. r The increase in the molecular weight of the polymer was followed by gel permeation chromatography (GPC) on a TSK 1000 column and a TSK '3000 of Supelco used in series at 30 ° C. The solvent used was tetrahydrofuran (THF) at a flow rate of 1 ml / min. A differential rate (Gilson) index detector was used as the detector. Calibration was done with commercial polystyrene standards except where indicated otherwise. Mass molecular weights and numbers TMp and Mn) were calculated by the use of a computer program (TURB0GELMR) of P_E Nelson. (i 1 Results: The polyester produced with the conditions described above was a viscous liquid of amber color at room temperature.The Mp was 4800, - _ i the polydispersity (Mp / Mn) of 2.2 and the acidity index (mg of KOH / g of sample) of 27.8. j - - í - By repeating the reaction with more catalyst and / or more reaction times, higher molecular weights of the polyester were achieved. The products were all liquid ^ and showed an increase in viscosity with Glycerol, 99%, ex Aldrich, 14.7_g. Distilled water, 645 μl. Immobilized Lipase from Rhi zomucor miehie (Lipozyme IM60) 2.0 g. - Reaction: t - go The reaction was carried out as described in - _! Example 1, except that the initial vacuum applied was 100 mbar This vacuum was gradually lowered during the course of the reaction at 50 mbar and finally at 11 mbar. The reaction was stopped after 4 days and the catalyst was removed by vacuum filtration at 80 ° C. The polyester produced was a translucent viscous liquid. The Mp (PEG-Standard) of 4600, Polydispersity of 3.3 and the acidity index of 33.1.

E ^ GEMPLO 3 Materials: 'Dicarboxylic acid, monounsaturated, medium chain /! mixed, 25.00 g. [ [Composition, main peaks ^ in gas chromatography: ' DCA C6: 0-1.2%. DCA C8: 0-7.2%, DCÁ 010: 1-16.1%, DCA C10: 0- - t . 0%, DCA C12.2-0.5%, DCA C12: 1-38.0%, DCA C12: 0-4. 6%, '• C14: 2-2._9%, DCA C14: 1-18.7%, p-produced by the fermentative method described in WO 94/07837.] 1,4-butanediol, ex Fluka, 10.01 g. 1 B-lipase immobilizes from Candida anárcti ca, SP 435, ex Novo Nordisk, 1.00 g.

Reaction The reaction was carried out as in Example 1, r except that the reaction temperature used was 70 ° C and the vacuum (100 mbar) was not applied until the end of the reaction to six days, to remove the condensates in the reaction. the reactor vessel. The product was isolated by vacuum filtration at 70 ° C to give a yellow oil having an acid number of 71.6, Mp of 4,800 and polydispersity of 3.5.

EXAMPLE 4 Materials: 9-octadecen-l, 18-dioic acid, ex Unichema, 25.00 g. 1, 12-dodecanediol, ex Fluka, 14.98 g. Immobilized B-lipase from Candida an tacti ca, SP 435 (Novo Nordisk, Denmark), 1.00 g.

Reaction The reaction was carried out as in Example 1, except that the reaction temperature used was 70 ° C in order to start the melting of the reaction mixture, and the vacuum of 100 mbar was applied after 1 '. "" "minutes and remained until the end of the reaction at 22 hours.To remove the catalyst from the reaction products," * u solvent, methyl ethyl ketone "was used, to lower the viscosity and this slurry it was filtered under vacuum at 70 ° C. The solvent was removed at 90 ° C under vacuum.The product was a wax and had an acid value of 23.5.1 Mp of 18500 and polydispersity of 4.0. d EXAMPLE 5 Materials: - J. J 9-octadecen-l, 18-dioic acid, ex Unichema, 15.00 g. 1, 12-dodecanedioic acid (DCA 12: 0), ex Aldrich, 9,905 1,4-butanediol, ex Fluka, 7,752 g. \ B-lipase; immobilized from Candida an tarti ca, SP 435 (Novo Nordisk, Denmark), 1.00, g.

Reaction: d The reaction was carried out as in Example 1, except? that the reaction temperature used was 70 ° C. ¿- - _ | Initially, the reaction was initiated with only DCA C18: l and butanediol. After 1 hour of reaction, when the formation of some low molecular weight polymers, and the oligomers has occurred, C12: 0 DCA was added. HE ! slowly applied a vacuum of 100 mbar to free space between the surface of the liquid and the lid at 3 hours and remained until the end of the reaction at 22.5 hours. After six hours, the reaction mixture became homogeneous. The lipase catalyst was removed by vacuum filtration at 70 ° C. The product was a soft r wax at room temperature, and had an acid number of 23.5, Mp of 10400 and a polydispersity of 3.5! EXAMPLE 6 Measurement and Anti-microbial properties F Materials: i Coryneform (G42) ba cteri um: is a human skin isolate at Colworth Laboratories, Bedford, United Kingdom.

It is a Gram + organism producing lipase. The Corynebacteria are commonly found on human skin 1 and are associated, inter alia, with the - I provocation of bad smell. __ I _ * - f Emul if pol on ter: the polyester prepared in Example 1, 1 g / 1, aseptically emulsified with 5 g / 1 def Triton XlOO in 10 mM Na-phosphate buffer, pH 6. big enough to tell Results: TABLE 2 Viable Count Total cells / ml) These results are also shown graphically in Figure 1. The data shows that free. In the presence of free acid, a logarithmic reduction of > 2 within the first hour.

In the presence of the polyester (MW 4,800) there was a minor loss of viability (> 1 log in 2 hours), presumably because the polyester must first be hydrolyzed to give the active anti-microbial substance. However, the final viable account was virtually zero, as with the cells treated with free acid.

EXAMPLE 7 Anti-microbial properties in the presence or absence of added lipase This study was carried out essentially as in Example 6 above.

Result: Coryneba cterias were incubated with a polyester emulsion made with a polyester of DCA C18: l-20 butanediol with MW = 4800, as described in Example 1. In one test, extra lipase (10 μl of t) was added. Lipozyme, 10000L, Novo) together with the bacterial cells. The results are shown in Table 3 to 2 - f below, and graphically in Figure 2. 25 the molecular weight of dioic acid polyester C18: 1 / butanediol, the initial rate of antimicrobial activity was decreased because there is a lower concentration of polymer "free ends" available for lipase-mediated degradation of the free acid. The rate of loss of cell viability is lower with the polyester based on f6 glycerol of 4,600 PM than with the polyester based on butanediol of an equivalent molecular weight. This is It is presumably due to a slower hydrolysis, which in turn is probably a result of steric hindrance problems caused by the presence of limited esterification in the secondary -OH group of the glycerol molecule. However, it is still degradable «15 polymer. i - - i¡ Figure 3 shows the results of the initial 6 hours of the experiment. The final time point r f has been omitted from the graph to emphasize the? difference in the initial rates of hydrolysis II 20 (after 23 hours of incubation, the cell viability is <10 cells / ml for all polymers used). In conclusion, the experiment shows that the nature of the polymer molecule can be altered to affect the rate of release of the active substance. 25 *** EXAMPLE 9 __ L ; = This example investigates the effect of an emulsion of polyester emulsion with monounsaturated, medium, mixed DCA (with average molecular weight of about 4,800) of Example 3 in Coryneba cterias cells. This study was performed as described in Example 5. The results are shown above in Table 5.

TABLE 5 Effect of the polyester emulsion on the TVC of Corynebacteria cells

Claims (3)

1. CLAIMS 1. A polymeric molecule comprising a plurality of repeating units having the structure - (02C-R-C02) -, wherein R is a substituted or unsubstituted hydrocarbon radical, unsaturated having 13 or more carbon atoms.
2. 2. A molecule according to claim 1, where e is a C16: l, C16: 2, C16: 3 or C20: l moiety, and wherein the molecule is a copolymer of a dioic acid esterpiclated with glycerol, butand ol or a polyol of 6 to 10 carbon atoms. .
3. 3. A molecule according to claim 1 or 2, wherein R is aliphatic. - t 4. A molecule according to claim 1,? The claim 3 as dependent on claim 1, wherein R comprises from 16 to 20 carbon atoms. ! t = 5. A molecule according to claim 3 or 4 as dependent on claim 1, wherein R is mono-, di- or tri-unsaturated. , = t 6. A molecule according to any of claims 3, 4 or 5 as dependent on the - claim 1, wherein R is a portion C16: 1, C 16: 2, C16: 3 or 'C20: 1. t? 7. A polyester according to any of claims 1-10. , i-r 14. A composition according to any of claims 11-13, formulated for use as a pharmaceutical or cosmetic product. . 15. A composition according to any of claims 11-14, which is buffered to a pH in the range of 4-7, preferably pH 5.5-6.5. ! 16. A composition according to any of claims 11-15, comprising one or more of the following: a volatile organic solvent, an emollient, or an emulsifier. _ i 17. A composition according to any of claims 11-16, for use in the formation of an occlusive film, moisture retainer. 18. A medical dressing for the application to the skin of a human subject, the dressing comprising a dressing substrate impregnated or coated with a polymeric molecule in accordance with any of the 1-- i claims 1-10, or a composition according to any of claims 11-17. 19. A method for treating the skin of a human subject, comprising applying to the skin a composition I according to any of claims 11-17. - 20. The use of a degradable polyester with lipase according to any of claims 1-10, in the manufacture of a pharmaceutical composition for the treatment of a human skin condition caused or exacerbated by, or associated with, growth microbial!. 21. A method for making a cosmetic or pharmaceutical composition for topical application to a human subject, comprising effectively mixing a polymer having a repeat units having the structure - (02C-R-C02) -, wherein R is a substituted or unsubstituted hydrocarbon radical I, unsaturated having 10 or more __ i atoms. carbon, with a carrier substance, acceptable. 22. A method according to claim 21, wherein the composition comprises a polymeric molecule _ _ r according to any of claims 1-10. i