MX2007005757A - Antibiotic compounds, compositions and medical uses - Google Patents

Abstract

Antibiotic compounds and compositions and methods for the treatment of dermatological conditions including a sulfoxide or sulfone derivative of an antibiotic from the lincomycin family of antibiotics, or pharmaceutically acceptable salts thereof, optionally including a peroxide component.

Description

ANTIBIOTIC COMPOUNDS, COMPOSITIONS AND TREATMENT METHODS FIELD OF THE INVENTION This invention relates to novel antibiotic compounds, pharmaceutical compositions and methods useful for the topical treatment of acne, acne rosacea, and other dermatological diseases, and to the use of antibiotics selected from sulfoxide or sulphone derivatives of compounds of the lincomycin family.

BACKGROUND OF THE INVENTION Acne is an inflammatory disease that is very common at puberty and occurs in areas of the skin where the sebaceous glands are the largest, the most numerous, and the most active. In its milder forms, acne is a superficial disorder that is evidenced by slight irritations with pimples, and that can be successfully treated by normal skin hygiene. However, pilosebaceous follicles occur and result in the formation of pustules, infected cysts and, in extreme cases, infected and inflamed channeled sacs, which can become extensive and leave permanent disfiguring scars. One aspect of the present invention relates to an improved anti-acne topical composition.

Exemplary antibiotics incorporated into compositions are described in U.S. Pat. No. 3,969,516 (lincomycin family), GB Patent Specification No. 1,594,314 (erythromycin); and U.S. Pat. No. 3,952,099 (tetracycline). Compositions containing a peroxide are disclosed in U.S. Pat. No. 3,535,422; 4,056.61 1; 4,387,107. Combinations of erythromycin and peroxides are disclosed in GB Patent Specification No. 1,594,314 and in U.S. Pat. No. 4,497,794. Antibiotic-containing compositions that may also include anti-inflammatory steroids are described in U.S. Pat. No. 4,132,781.

Topical anti-acne preparations that include combinations of a peroxide, such as benzoyl peroxide and an antibiotic, such as an antibiotic of the lincomycin family, are described in U.S. Pat. Nos. 5,466,028, 5,767,098 and 6,013,637, all of which are incorporated herein by reference. U.S. Pat. No. 5,690,923 relates to compositions containing retinoids and clindamycin and their derivatives. However, it has been found that in compositions containing benzoyl peroxide and antibiotics of the lincomycin family, the interaction of the peroxide with the lincomycin antibiotic can result in the degradation of the antibiotic. Therefore, there is a need for an antibiotic that has greater stability in formulations with peroxides.

COMPENDIUM OF THE INVENTION In accordance with the present invention, it has been found that sulfoxide and sulfone derivatives (hereinafter collectively "SOx") of antibiotics of the lincomycin family have greater stability in formulations containing peroxides than the other lincomycin antibiotics. previously used in such formulation. Thus, the present invention provides a composition for the treatment of acne, acne rosacea and other dermatological diseases comprising a topically effective amount of a SOx derivative of an antibiotic of the lincomycin family. One embodiment of the present invention includes the SOx derivatives of clindamycin, hereinafter collectively referred to as CSOx.

The formulation may further comprise a topically effective amount of a peroxide. Another aspect of the present invention is to provide a stable composition comprising a topically effective combination of a SO x derivative of an antibiotic of the lincomycin family and a peroxide. Benzoyl peroxide (BOP) is a peroxide particularly suitable for use in the present invention.

Another aspect of the present invention is to provide a method for the treatment of acne, acne rosacea or other dermatological diseases comprising the topical administration, to a patient afflicted therewith, of a topically effective amount of a SO.sub.x derivative of an antibiotic of the lincomycin family, optionally in combination with a topically effective peroxide.

These and other aspects of the present invention are described in more detail below.

DESCRIPTION OF THE DRAWINGS Figure 1A is a graph showing the stability of 1% clindamycin analogs with 5% BPO in pH 3 buffer solution at room temperature (RT), i.e., room temperature in the range from 15 to 30 ° C.

Figure 1B is a graph showing stability of 1% clindamycin analogs with 5% BPO in pH 3 buffer at 50 ° C.

Figure 2A is a graph showing the stability of 1% clindamycin analogs with 5% BPO in pH 5 buffer at RT.

Figure 2B is a graph showing the stability of 1% clindamycin analogs with 5% BPO in pH 5 buffer at 50 ° C.

Figure 3A is a graph showing stability of 1% clindamycin analogs with 5% BPO in buffer solution of pH 6 at RT.

Figure 3B is a graph showing stability of 1% clindamycin analogs with 5% BPO in pH 6 buffer at 50 ° C.

Figure 4 is a graph showing the pH of samples of clindamycin sulfoxide A and BPO at RT and 50 ° C.

Figure 5 is a graph showing the pH of sulfoxide B samples of clindamycin and BPO at RT and 50 ° C.

Figure 6 is a graph showing the pH of clindamycin sulphone and BPO samples at RT and 50 ° C.

Figure 7 is a graph showing the pH of clindamycin sulphate and BPO samples at RT and 50 ° C.

Figure 8 is a graph showing the pH of clindamycin and BPO hydrochloride (HCI) samples at RT and 50 ° C.

Figure 9 is a scaled chromatogram of clindamycin sulfoxide A.

Figure 10 is a scaled chromatogram of clindamycin sulfoxide B.

Figure 11 is a scaled chromatogram of the clindamycin sulfone.

In the drawings, the following abbreviations are used: CSOA - isomer A of clindamycin sulfoxide CSOB - isomer B of clindamycin sulfoxide CS02 - clindamycin sulfone ClinP04 - clindamycin phosphate ClinHIC - clindamycin hydrochloride DETAILED DESCRIPTION The terminology "antibiotic of the lincomycin family" is used herein to refer to a class of antibiotic substances originally recovered from streptomyces lincolnensis.

Exemplary antibiotics of this type include lincomycin and clindamycin and their pharmaceutically acceptable salts and esters such as hydrochlorides and phosphates. Lincomycin is a derivative of the trans-L-4-a-propyl-hygroic acid amino acid coupled to an octose derivative comprising a pyran ring substituted with a methylsulfanyl group, and may be named as (2S-trans) -methyl. , 8-dideoxy-6 - [[(1-methyl-4-propyl-2-pyrrolidinyl) -carbonyl] -amino] -1-thio-D-er / fro-tf-D-ga / acfo-octopyranoside.

Preferred antibiotics of the lincomycin family for use in the present invention can be represented by the following formula I: wherein R is hydroxy or halogen, and R 'is hydrogen or methyl, and their pharmaceutically acceptable salts and esters.

When R is Cl and R 'is methyl, the compound is clindamycin.

When R is Cl and R 'is hydrogen, the compound is N-desmethyl clindamycin. When R is OH and R 'is methyl, the compound is lincomycin. When R is OH and R 'is hydrogen, the compound is N-desmethyl lincomycin.

The term "sulfoxide or sulphone derivative of an antibiotic of the lincomycin family" means a lincomycin antibiotic in which the sulfanyl bond of the methylsulfanyl group of the pyran ring has been replaced by a sulfoxide (SO) or sulfone (SO2) bond. , collectively referred to hereafter as a "SOx" link.

The sulfoxide derivatives of antibiotics of the preferred lincomycin family can be represented by the formula I (a) below: where R and R 'are as defined above. The sulfur atom of the sulfoxide group is a chiral site so it can form two stereoisomeric forms of the sulfoxide.

The sulfone derivatives of antibiotics of the preferred lincomycin family can be represented by the formula I (b) below: where R and R 'are as defined above.

Clindamycin is the 7-deoxy, 7-chloro derivative of lincomycin, and may be named as (2S-trans) -methyl 7-chloro-6,7,8-tridesoxy-6 - [[(1-methyl-4 -propyl-2-pyrrolidinyl) -carbonyl] -amino] -1-thio-L-rreo-oD-ga / acio-octopyranoside, or as [2-chloro-1 - (3,4,5-trihydroxy-6- 1-methyl-4-propyl-pyrrolidine-2-carboxylic acid methylsulfanyl-tetrahydro-pyran-2-yl) -propyl] -amide. Clindamycin can be represented by the following formula II: Lincomycin antibiotics are described in U.S. Pat. No. 3,475,407; 3,509,127; 3,544,551 and 3,513,155.

In one embodiment of the present invention the SOx derivative of lincomycin is the clindamycin sulfoxide of the following formula I I I: As indicated above, the sulfur atom of the sulfoxide group is a chiral site whereby it can form two stereoisomeric forms of the lincomycin sulfoxide derivative, in this case clindamycin sulfoxide. The clindamycin sulfoxide compound of formula III may include one or both of the stereoisomeric forms of clindamycin sulfoxide selected from the following formulas lll (a) or lll (b): The sulfoxide derivatives of any of the antibiotics of the lincomycin family according to the present invention also include the sulfoxide phosphate derivatives, such as the 2-phosphate sulfoxide derivative of the following formula IV: where R and R 'are as defined above. The sulfoxide phosphate derivative may also be the 3-phosphate or 4-phosphate derivative.

In a particular embodiment of the present invention, the SOx derivative of the antibiotic of the lincomycin family is clindamycin sulfoxide 2-phosphate, which may be represented by the following formula V: The clindamycin sulfoxide 2-phosphate compound of formula V can include one or both of the stereoisomeric forms of clindamycin sulfoxide 2-phosphate selected from the following formulas V (a) or V (b): In another embodiment of the invention, the SOx derivative of lincomycin is the sulfone derivative, and may be represented by the following formula VI: wherein R is hydroxy or halogen, and R 'is hydrogen or methyl, and their pharmaceutically acceptable salts and esters.

A particular lincomycin sulfone for use in the present invention is the clindamycin sulfone, which can be represented by the following formula Vl (a): In a particular embodiment of the present invention, the SOx derivative of lincomycin is administered in combination with a peroxide. The term "peroxide" means an organic compound that contains an oxygen-oxygen bond capable of cleaving and forming oxygen-free radicals. The peroxides include peroxyacids of carboxylic acids, peroxy esters of carboxylic acids and the dimer product of carboxylic peroxyacids. Exemplary peroxides include t-butyl peroxyesters of straight and branched chain aliphatic carboxylic acids, and dimers peroxides such as lauroyl peroxide and benzoyl peroxide. A special peroxide suitable for use in the present invention is benzoyl peroxide, more especially micronized benzoyl peroxide.

The method of the present invention comprises administering an antibiotic selected from the SO x derivatives of an antibiotic of the lincomycin family, or a pharmaceutically acceptable salt thereof. The SOx derivative antibiotic can be administered alone or in combination with other active ingredients. In one embodiment, the SOx-derived antibiotic can be administered to the skin of a patient suffering from acne or simultaneously with or shortly before or after the application of a peroxide, as defined above. Accordingly, the two ingredients can be applied to the skin as a mixture or can be applied to the skin separately. In the last practice the antibiotic is applied first to the skin and immediately or soon after that the peroxide is applied. Or, you can reverse the order of application.

In one embodiment of the present invention, the composition includes benzoyl peroxide and a SOx derivative of an antibiotic of the lincomycin family. In a particular form, the composition comprises micronized benzoyl peroxide and a SOx derivative of clindamycin or a pharmaceutically acceptable ester or salt thereof. Examples of pharmaceutically acceptable salts are formed by the combination of the antibiotic of the lincomycin family with hydrochloric acid, nitric acid, succinic acid, maleic acid, fumaric acid, tartaric acid, etc. Pharmaceutically acceptable esters include phosphates, succinates, etc., particularly at the 2-position on the sugar moiety.

Particularly good results are obtained using the clindamycin sulfoxide of formula III, which includes one or both of the chiral forms of clindamycin sulfoxide represented by the formulas III (a) and III (b), and using the clindamycin sulfone of formula VII (to).

In a particular embodiment, the antibiotic should be present in the composition in an amount of from about 0.01 to about 10 weight percent of the total composition, and more particularly from about 0.1 to about 5 weight percent.

When the composition includes a peroxide component, the peroxide is present in the composition in an amount of from about 0.1% to about 30%, and particularly about 2.5% to about 15%, all percentages herein by weight and based on the total weight of the composition, unless otherwise indicated. More particularly, the amount of peroxide can be about 3% to about 10%. Desirably, the peroxide must be of high purity. An exemplary material includes peroxide in an amount that is not less than about 98% of the concentration established in the labeled raw material and in the form of finely divided crystalline particles, such as micronized particles having an average particle size of less than about 35. microns.

A composition is in the form of an aqueous gel, and which may include an aqueous alcoholic gel. However, liquid suspensions and emulsions are acceptable, as well as creams, solutions, foams, pastes, lacquers, ointments and powders.

The gelling agents used in the aqueous gel composition of this invention can be selected in both type and quantity to give products of various viscosities. A variety of gelling agents, both natural and synthetic, can be used for the present purposes. Suitable gelling agents include, but are not limited to, cellulose based polymers such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose; polyacrylamide; a sodium acrylamide / acryloyldimethyl taurate copolymer product (such as Simulgel®); aluminum magnesium silicate (such as Veegum®); guar gum; carrageenan; gum arabic; xanthan gum; ceína; polyethylene-propylene glycol copolymers, such as poloxamers; polyoxyethylene alkyl ethers (such as Brij®); crosslinked acrylate / alkyl acrylic polymers such as Pemulen® and polyacrylic acids, such as carbomers.

The amount of gelling agent included in the present gel composition can range from about 0.1 to about 20% by weight, and particularly from about 0.5 to about 5% by weight, based on the total weight of the composition.

The composition of the present invention may include a surfactant or dispersing agent to uniformly disperse the active ingredients. A composition may also include a second surfactant. Such agents include the polyol and sugar esters, the condensation products of ethylene oxide with fatty acids, fatty alcohols, long-chain alkyl phenols, long-chain mercaptans, long-chain amides, polyhydric polyhydric alcohols and ethers of polyhydric alcohols. alkyl polyglycol which are included in an amount of from about 0.1% to about 6% by weight.

Another embodiment of the composition of the present invention has a pH that is effective to stabilize the antibiotic and peroxide ingredients over a period of time. An effective stabilizing pH is in the range of from about 2 to about 7, particularly about 3 to about 5, more particularly about 4.

A further composition of the present invention may include a stabilizing agent that acts as an effective barrier to the possible degradative interaction of the peroxide and the antibiotic and / or antioxidant (s). A suitable stabilizing concentration is about 0.1 to about 0.6% by weight, and more particularly about 0.5% to about 3% by weight. Suitable antioxidants include those commonly used in topical medicinal preparations, such as alpha-tocopherol, ascorbic acid, etc.

One type of preparation comprises a composition in which the two active ingredients are premixed (as in a one-component system) and are stable at temperatures normally employed for the storage of clindamycin solutions. Another type of preparation may comprise a two component system, wherein one component comprises the antibiotic and the other component comprises the peroxide component. Conventional pharmaceutical procedures can be used to make these common forms of topical medicinal compositions.

As mentioned above, a basic type of topical preparation comprises a mixture of peroxide powder and antibiotic with an inert diluent. Such preparation should be applied in small amounts to the skin.

The following examples are illustrative of the present invention.

EXAMPLE 1 The following ingredients; they can be mixed together to form a powder that can be sprinkled over the affected skin area, one to four times a day. Percent P / P Benzoyl Peroxide 0.1 - 30 Calcium Phosphate 63 - 98.5 CSOx 0, 1 - 5 EXAMPLE 2 A liquid suspension of the present invention can be prepared by combining the following ingredients. Both percent P / P CSOx 0, 1 - 5 Benzoyl peroxide 0, 1 - 30 Surfactant 0, 1 - 5 Water, purified C.S. -100 The following examples include other preparations that are representative of the present invention.

EXAMPLE 3 A cream can be prepared by mixing the following ingredients with the appropriate ingredient.

Percent P / P Polyoxyl Stearate 40 4 Stearic Acid 3 Cetyl Alcohol 4 Sorbitone Mono-Stearate 1 Isopropyl Myristate 1, 8 CSOx 0, 1 - 5 Benzoyl Peroxide 0.1 - 30 Glycerin 8 Xanthan Gum 0.05 Water, purified CS - 100 EXAMPLE 4 A gel according to the present invention is prepared by combining the following ingredients. Percent P / P CSOx 0, 1 - 5 Benzoyl peroxide 0.1 - 30 Carbomer 2 Lauryl sulfosuccinate disodium 0.04 Sodium hydroxide 0.3 Disodium edetate 0.1 Glycerin 4 Silicon dioxide 0,25 Dimethicone 0, 1 Poloxamer 182 0.2 Water, purified CS-100 EXAMPLE 5 A gel according to the present invention is prepared by combining the following ingredients. Percent P / P CSOx 0.1 - 5 Veegum® 1, 5 Carbomer 1 Dioctyl sulfosuccinate sodium 1 Diisopropanolamine 0.75 Ethyl alcohol 35 Benzoyl peroxide 0, 1 - 30 Water, purified C.S. -100 EXAMPLE 6 A suspension in two parts is prepared from the ingredients Percent P / P First Veegum® Container 1, 5 Carbomer 0.25 Dioctyl sulfosuccinate sodium 1 Diisopropanolamine 0.18 Ethyl alcohol 25 Hydroxyanisole butylated 0.1, Benzoyl peroxide 0, 1 - 30 Water, purified CS - 100 Second Container CSOx 0.1 - 5 (w / w based on total composition) EXAMPLE 7 An aerosol spray according to the present invention can be prepared as follows. The following ingredients, in amounts within the ranges indicated below, are mixed together and the resulting mixture is loaded into a chamber of a dual chamber aerosol container. Percent P / P Benzoyl Peroxide 0.1 - 30 Calcium Phosphate 65 - 97 Calcium Stearate 1 - 10 PPG-15 Stearyl Ether 0.5 - 5 The sulfoxide or clindamycin sulfone (0.1-5% by weight) is charged into the second chamber of the container and the container is pressurized with the aerosol propellant.

EXAMPLE 8 An aqueous gel composition can be prepared according to the following formulation: Both percent P / P CSOx 0.1-5 Carbomer 2 Dioctyl sulfosuccinate sodium 0.2 Sodium hydroxide 0.4 Benzoyl peroxide 0.1-30 Water , purified CS - 100 EXAMPLE 9 An aqueous gel composition can be prepared according to the following formulation: Both percent P / P CSOx 0, 1 - 5 Carbomer 1, 5 Xanthan Gum 1, 0 Sodium Hydroxide 0.4 Glycerin 5.0 Benzoyl Peroxide 0, 1 - 5.0 Water, purified CS - 100 EXAMPLE 10 An aqueous gel composition can be prepared according to the following formulation: Both percent P / P CSOx 0.1-5 Simugel® 5.0 Hydroxyethylcellulose 0.5 Citric acid 0.03 Benzoyl peroxide 0.1-5, 0 Water, purified CS - 100 EXAMPLE 1 An aqueous gel composition can be prepared according to the following formulation: Both percent P / P CSOx 0, 1-5 Simugel® 5.0 Gum Xantana 0.5-1, 0 Citric acid 0.03 Benz peroxide 0, 1 - 5.0 Water, purified CS - 100 Comparative studies have shown that unexpectedly pH is a significant factor in determining the stability of the composition of the present invention. The active ingredients included in the compositions having a pH in the range described above are physically and chemically more stable than the ingredients included in compositions having a pH outside the defined range. This work is discussed in more detail below.

The Applicant has found that when compositions having different pH are subjected to accelerated decomposition conditions of 50 ° C, compositions having a pH below about 3 and above about 7 show signs of clindamycin degradation. However, after 4 weeks, compositions having an initial pH of about 3 to about 5 show better stability. The degradation of sulphoxide or clindamycin sulfone appears to be negligible as measured by HPLC. The 4-week old compositions show that at least about 90% of the clindamycin sulfoxide or sulfone is retained in the composition.

The composition of the present invention can be applied to the affected skin of an acne patient for a period of time on a regular basis in such a way that the acne complaint is kept under control. A treatment regimen comprises the application of the composition from about one to about four times a day.

As discussed above, in the clindamycin sulfoxide (CSO) represented in formula III there is a chiral site in the sulfoxide bond that allows two stereoisomeric forms of clindamycin, represented by the formulas lll (a) and l l l (b). The stereospecific forms of CSO were separated, for example by HPLC techniques, and are referred to herein as "CSO A" and "CSO B". However, it is not currently known which of the formulas lll (a) or lll (b) specifically represents CSO A or CSO B. Stereospecific synthesis methods have also been developed that favor the production of CSO A or CSO B, reducing or eliminating the need for a separation stage. These synthesis methods are discussed further below.

In the following examples, the tests were performed using stereospecific forms of CSO A and CSO B, as well as various pharmaceutically acceptable salts thereof. The tests were also performed using the clindamycin sulfone ("CS02"), as represented by the formula Vl (a). The syntheses of these compounds are discussed further below.

EXAMPLE 12 - IN VITRO MICROBIOLOGICAL EVALUATION The microbiological activity of the clindamycin analogs was evaluated by measuring the minimum inhibitory concentrations (M IC, for its acronym in English) of each compound against Staphylococcus aureus (S. aureus) and Propionibacterium acne (P. acnes). These two microorganisms were selected, since it is known that they are usually the factors that contribute to acne. The compounds evaluated were the following: a. Isomer A of clindamycin sulfoxide (CSO A) and its salts b. Isomer B of clindamycin sulfoxide (CSO B) and its salts c. Sulfone of clindamycin (CS02) and its salts d. Clindamycin phosphate e. Clindamycin-HCI f. Erythromycin The dindamicin phosphate, clindamycin «HCI and erythromycin are known, commercially available anti-acne compounds and were included in the experiment for comparison purposes (as controls). MIC is defined as the concentration of the test compound at which growth is completely inhibited. Thus, the lower the MIC value the more potent the compound. The MIC values of four sets of tests are shown in Tables 1 and 2.

The MIC data in Table 1 show that the CSO B isomer is more active than the CSO A and the dindamicin phosphate, and that the CSO A is more active than the dindamicin phosphate. Clindamycin-HCl and erythromycin show the highest potency of all the compounds tested.

Table 1 . Results of MIC against S. aureus ATCC 6538 and P. acnes ATCC 1 127 The data from additional trials presented in Table 2 are consistent with the MIC data presented in Table 1.

Table 2. Results of MIC against S. aureus ATCC 29213 and P. acnes ATCC 1 1827 EXAMPLE 13 - STABILITY STUDIES WITH BENZOYL PEROXIDE The stability of CSO A, CSO B, CS02 in buffer solutions of different pH in the presence of peroxide Benzoyl (BPO) was carried out at room temperature (RT) and at 50 ° C. For comparison purposes, clindamycin phosphate and clindamycin * HCI were included in the experiment as controls. The concentrations of each of the clindamycin analogues and the BPO in the mixtures were 1% (w / w) and 5% (w / w), respectively.

The samples were prepared by dissolving each of the clindamycin analogs and suspending the BPO powder in the buffer solutions of different pHs. The samples were placed either at RT or at 50 ° C. Samples were taken at time intervals and assayed for the appropriate clindamycin analog and pH.

Figures 1 (A, B), 2 (A, B) and 3 (A, B) show the stability results of 1% clindamycin analogues in the presence of 5% BPO in buffer solutions at pH 3.5. , 6, respectively, at RT and 50 ° C. The figures show the graphs of the remaining percent (% of the initial) of the clindamycin analog against time. The percentage of the initial is obtained by normalizing the concentration at each time point to the initial concentration.

All samples stored at RT showed negligible loss of activity at the 12 week time point (24 week time point for CSOx) (see Figures 1A, 2A, and 3A). The decrease in concentration was generally less than 10%. On the other hand, some samples stored at 50 ° C showed substantial degradation (see Figures 1 B, 2B and 3B). The degradation, however, was slower for the CSO A, CSO B and CSO2 compared with the clindamycin phosphate and clindamycin »HCI. In general, the higher the pH of the buffer solution and the higher the temperature, the faster the degradation of the compound.

It was found that Sulphoxides A and B of clindamycin and clindamycin sulfone prepared in pH 3 buffer at 50 ° C were more stable than clindamycin phosphate and clindamycin-HCI. They show a much slower degradation than clindamycin phosphate and clindamycin «HCI (see Figure 1B). Already after 4 weeks of storage, clindamycin phosphate and clindamycin HCI showed 40% and 60% loss of activity in the sample, respectively, while the CSO A, CSO B and CS02 showed less than 10% loss.

After 8 weeks of storage at 50 ° C, only about 30% of the clindamycin phosphate and less than about 10% of the clindamycin-HCl remained in the solution. In comparison, after the same period there remained approximately 90% of the CSO B, approximately 85% of the CS02, and approximately 70% of the CSO A. After 12 weeks of storage, there was approximately 80% of the CSO B, approximately 70% of the CS02 and approximately 60% of the CSO A remaining in the samples (see Figure 1 B). After 24 weeks of storage, the concentrations of CSOx remaining in the samples were approximately 40-60%.

The pH values of all samples of mixture of clindamycin analogs and BPO after filtration were plotted versus time in Figures 4-8. The addition of CSOx analogs to the buffer solutions generally resulted in an increase in pH of about 0, 8-0.9 pH units (Figures 4-6). The addition of clindamycin phosphate to the buffers also yielded an increase in pH but to a lesser extent (with the exception of the pH 3 buffer, which remained essentially unchanged) (Figure 7). No pH shift was observed in the buffer solutions from the addition of clindamycin «HCI (Figure 8). It can be seen from Figures 4-6 that a pH of about 4 appears to provide good stability of the clindamycin sulfoxides and the clindamycin sulfone when benzoyl peroxide is mixed.

SYNTHESIS OF COMPOUNDS The forms of clindamycin sulfoxide CSO A and CSO B can be manufactured by a non-stereospecific method, and then separated by an appropriate method, such as chromatography.

A stereospecific method for synthesizing CSO A is explained in Scheme 1 below. It was found that the oxidation of clindamycin hydrochloride with iodobenzene dichloride preferably yielded CSO A (MW = 440.98). An assay of this synthesis method yielded CSO A with a purity greater than about 94%, as measured by HPLC. A scaled chromatogram of the CSO A produced by this procedure is presented in Figure 9.

SCHEME 1. SYNTHESIS OF CSO A: A stereospecific method for synthesizing CSO B is explained in Scheme 2 below. It was found that oxidation of clindamycin hydrochloride with sodium perborate (NaBO3) at a pH between about 8 and 9 preferably yielded CSO B (MW = 440.98). An assay of this synthesis method yielded CSO B with approximately 93% purity by HPLC. A scaled chromatogram of the CSO B produced by this procedure is presented in Figure 10.

SCHEME 2. SYNTHESIS OF CSO B.

The clindamycin sulfone (CSO2) can be prepared directly by the oxidation of clindamycin * HCI with hydrogen peroxide (H2O2), catalyzed by sodium tungstate (NaWO4) at a pH of less than about 1, as shown in the Scheme 3 below. In one trial, this oxidation method yielded the clindamycin sulfone (MW = 456.98) with approximately 95% purity by HPLC. A scaled chromatogram of the CSO2 produced by this procedure is presented in Figure 11.

SCHEME 3. SYNTHESIS OF CSO2.

Claims (18)

1 . A composition for the topical treatment of a dermatological disease, comprising a sulfoxide or sulfone derivative of an antibiotic of the lincomycin family or a pharmaceutically acceptable ester or salt thereof.

2. The composition of claim 1, wherein the antibiotic of the lincomycin family is clindamycin or lincomycin, or a pharmaceutically acceptable ester or salt thereof.

3. - The composition of claim 2, wherein the sulfoxide or sulfone derivative is unsubstituted of the formula I (a) below:

wherein R is hydroxy or halogen, and R 'is hydrogen or methyl, or a pharmaceutically acceptable ester or salt thereof.

4. The composition of claim 3, wherein the sulfoxide or sulphone derivative is a clindamycin sulfoxide of the following formula III, or a pharmaceutically acceptable ester or salt thereof:

5. The composition of claim 4, wherein the sulfoxide or sulfone derivative is one or both of the stereoisomeric forms of clindamycin sulfoxide selected from the following formulas lll (a) or lll (b), or a pharmaceutically acceptable ester or salt thereof :

6. The composition of claim 2, wherein the sulfoxide or sulphone derivative is a clindamycin-2-phosphate sulfoxide of the following formula V, or a pharmaceutically acceptable ester or salt thereof:

7. The composition of claim 6, wherein the sulfoxide or sulphone derivative is one or both of the stereoisomeric forms of the clindamycin-2-phosphate sulfoxide selected from the following formulas V (a) or V (b), or an ester or salt pharmaceutically acceptable thereof:

8. The composition of claim 2, wherein the sulfoxide or sulfone derivative is a compound of the following formula VI, or a pharmaceutically acceptable ester or salt thereof:

wherein R is hydroxy or halogen, and R 'is hydrogen or methyl, and their pharmaceutically acceptable salts and esters.

9. The composition of claim 8, wherein the sulfoxide or sulphone derivative is a sulphone of the clindamycin of the following formula V1 (a), or a pharmaceutically acceptable ester or salt thereof:

composition of any one of claims 1 9, further comprising a peroxide.

eleven . The composition of claim 10, wherein the peroxide is benzoyl peroxide.

12. The composition of claim 10 or 11, wherein the sulfoxide or sulfone derivative of the antibiotic is present in said composition in an amount of about 0.01 to about 10 weight percent of said composition and the peroxide is present in said composition in an amount of about 0.1 to about 30 weight percent of said composition.

13. - A method for treating a dermatological disease, comprising topically administering to an affected patient with such dermatological disease an effective amount of the composition of any one of claims 1 to 12.

14. - The method of claim 13, wherein said dermatological disease is acne.

15. - The method of claim 13, wherein said dermatological disease is rosacea.

16. - A pharmaceutical kit for the topical treatment of a dermatological disease comprising a first set and a second set of components, wherein said first set of components comprises the composition of any one of claims 1 to 9, and said second set of components comprises a peroxide.

17. - An antibiotic compound selected from the group consisting of

wherein R is hydroxy or halogen, and R 'is hydrogen or methyl, and the esters and pharmaceutically acceptable salts thereof.

18. - The antibiotic compound of claim 17, selected from the group consisting of

, and the pharmaceutically acceptable esters and salts thereof.