TOPICAL COMPOSITION AND PREPARATION METHOD OF CLINDAMYCIN PHOSPHATE, ADAPALEN AND BENZOYL PEROXIDE WITH LIMITED FREE HYDROXYL EXCISE CONTENT

Abstract

The invention relates to topical pharmaceutical compositions containing clindamycin phosphate, adapalene, and benzoyl peroxide. The composition comprises an aqueous continuous phase and a hydrophilic gelling / suspension polymer network with 1.0–1.5% clindamycin phosphate, 2.5–3.5% benzoyl peroxide, and 0.10–0.20% adapalene by weight; benzoyl peroxide and adapalene are held in suspension predominantly as solid particles. The total amount of propylene glycol, glycerol, glycols, polyethylene glycols with a molecular weight less than 1000 Da, sugar alcohols, ethanol, and isopropanol, including raw material residues, is less than 0.10% (w / w); in preferred applications, this limit applies to the total amount of all free hydroxylated organic compounds with a molecular weight less than 1000 Da. The composition is preferably presented in a single primary package, pre-mixed during production.The invention aims to limit the formation of benzene and oxidative interaction with clindamycin phosphate in the continuous phase of dissolved benzoyl peroxide pools, while compensating for the functions of hydroxylated solvents through an aqueous polymer network, wetting / dispersion system, transition metal control, controlled particle size, and a low-temperature process. Hydroxybenzoyl peroxide, a pH-independent gelling agent, and a process temperature not exceeding 35 °C are preferred.

Description

FREE HYDROXYLY EXTRACTOR CONTENT LIMITED CLINDAMYSPHOSPHATE,ADAPALENANDBENZOYLPEROXYTOPICAL COMPOSITION AND PREPARATION METHOD Technical Field The invention relates to the field of dermatological topical pharmaceutical compositions. More specifically, The invention describes a device containing clindamycin phosphate, adapalene, and benzoyl peroxide in fixed doses. low molecular weight hydroxylated organic compounds present as free molecules in the formulation aqueous gel or suspension-gel with total amount of compounds quantitatively limited It relates to their compositions and preparation methods. State of the Art In the treatment of acne vulgaris, deretinoids, benzoyl peroxide, and topical antibiotics alone are used. or in combination. Clindamycin phosphate, benzoyl peroxide and triple fixed-dose topical compositions containing adapalene from the application date This has been explained previously. Therefore, the novelty of the present invention lies in the fact that the three active substances in question It is not based on their being together. Specifically WO2021019092A1 and EP4007566A1 and US11389467B2, which are in the same patent family, US12128059B2, US12133859B2, US12138278B2 and US12616710B2 (publication: In documents numbered US20250352569A1 (priority: US62 / 881,836, 1 August 2019), by weight approximately 1-1.5% clindamycin phosphate, 2.5-3.5% benzoyl peroxide and 0.1-0.2% adapalene gelling agent, topical gel compositions in which a polyhydric alcohol and water are present. It has been explained that in the family in question, the gelling agent, polyhydric alcohol, and water act as carriers. Polyhydric alcohol is taught as the basic elements of the system; in various application forms. as propylene glycol, ethoxydiglycol, polyethylene glycol or glycerol; as gelling agents; carbomers, cellulose derivatives, xanthan gum, acrylamide / sodium acrylodimethyltaurate Copolymers and similar systems are explained. In the same patent family document, US11389467B2, application forms 1.56 and 1.57 The formulation is stable at room temperature for at least six weeks, e.g., at least one week. It is possible; also, it should be kept in the refrigerator at 2-8°C before being given to the patient, and then at 25°C. It is stated that it can remain stable for at least six weeks, for example, at least one week. This 1. Explanation: In the aforementioned triple system, room temperature stability is a matter that is also considered. It is a development parameter and limited room temperature use after refrigeration. This shows that it was specifically foreseen in the patent application. A commercial product containing the same combination of active ingredients is clindamycin phosphate 1.2%. It is licensed as a topical gel containing 0.15% adapalene and 3.1% benzoyl peroxide. The subject of the commercial product is the approved excipient composition of carbomer homopolymer type C. It consists of carbomer 980, potassium hydroxide, propylene glycol, and purified water. This product... Approved storage conditions: The product should be stored in the refrigerator at 2-8°C until it is given to the patient. to be stored and given to the patient only with an expiration date of ten weeks. It requires. In contrast, clindamycin phosphate-free dual adapalene / benzoyl peroxide fixed dose These combinations are licensed as commercial products that can be stored at room temperature. The approved excipient composition of the binary products is acrylamide / sodium acrylodimethyltaurate. copolymer, sodium docusate, disodium medetate, glycerol, isohexadecane, poloxamer124, It consists of polysorbate80, propyleneglycol, sorbitanoleate and pure water. Although the dual adapalene / benzoyl peroxide product contains propylene glycol and glycerol. can be stored at controlled room temperature, low molecular weight hydroxylated solvent. Its presence alone is the element that determines the cold chain in all benzoyl peroxide products. This shows that there is no third element dissolved in the aqueous phase in the binary system, which is susceptible to oxidation. No active ingredient is present. In contrast, clindamycin phosphate aqueous solution is present in the triple system. Since it can be found dissolved in the continuous phase, dissolved benzoyl peroxide in the same phase The probability of molecular contact with the pool is increasing. Therefore, the technical teaching of the current invention... in general to remove hydroxyl solvents from all benzoyl peroxide formulations No; it's a ternary system containing clindamycin phosphate, adapalene, and benzoyl peroxide. specifically reducing the dissolved benzoyl peroxide pool while hydroxylated solvents wetting, dispersion, moisture retention, water activity and processability functions in another It is aimed at compensating with physical architecture. The three existing commercial products must be stored in the refrigerator until administered to the patient. Having a limited room temperature window during use; especially during production Distribution, pharmacy stock in terms of a pre-mixed, single-container, three-active ingredient product. It is a practical limitation aimed at being improved in terms of management and patient use. In older clindamycin / benzoyl peroxide two-component kits, room temperature after mixing. Since its stability has been demonstrated, the present invention is suitable for clindamycin / benzoyl peroxide without refrigeration. Its determination is not, in general, a claim to be the first to resolve the issue. The solubility and stability of benzoyl peroxide strongly depend on the composition of the carrier medium. It is known to be related to the preformulation reported by Chellquist and Gorman. In their studies, benzoyl peroxide was used as a cosolvent for ethanol, propylene glycol, and PEG 400 / water. The saturated solubility and decomposition kinetics in the systems were investigated; in solution. The stability depends on the solvent, concentration, and temperature, while in suspensions it is more... Lower resolution has been shown to be associated with better stability (Chellquist EM, Gorman WG, Pharm. Res. 1992;9:1341-1346, DOI:10.1023 / A:1015873805080). Word the subject of the study is quantitative resolution values ​​in the adapalene / benzoyl peroxide patent literature It has been transferred; however, the technical teaching of the current invention is limited to a single digital resolution value. It is not related. US8936800B2 and related adapalene / benzoyl peroxide family; at least one dispersed retinoid, containing dispersed benzoyl peroxide and a pH-independent gelling agent, The gelling agent is polyacrylamide gelling agents, acrylic polymer linked to hydrophobic chains. gelling agents and modified starch gelling agents were selected; the composition is between 4°C and 40°C. gel compositions in which the active ingredients maintain good chemical stability. It has been explained that this family involves keeping benzoyl peroxide in a dispersed solid phase and changing its pH. along with teaching the preferability of an independent polymer network in terms of stability, quantitative amount of low molecular weight hydroxylated solvent in the carrier It does not contain any doctrine regarding its limitation. The degradation pathway of benzoyl peroxide has been described in the literature: homolysis of the peroxide bond. It forms benzoyl oxyradicals, and carboxylation of these radicals gives phenyl radical. And phenyl radical removes hydrogen from the environment to form benzene. Containing benzoyl peroxide. Benzene formation in pharmaceutical products by Kucera et al. in Environ Health Perspect. 2024;132(3):037702 (DOI:10.1289 / EHP13984) and subsequently J Invest Dermatol. 2025;145(5):1147-1154.e11 (online 2024; DOI:10.1016 / j.jid.2024.09.009) This has been evaluated in studies. United States Food and Drug Administration, March 11 In its 2025 statement, it announced that it had tested 95 acne products containing benzoyl peroxide. Benzene was undetectable or detected at very low levels in more than 90% of the products. that it was found in a limited number of products, and that high levels were detected in some products. It has been reported that a voluntary recall has been initiated. This distribution addresses the entire benzene problem. Benzoyl peroxide products are not unavoidable; formulation, production, packaging and 3. This indicates that there may be a product-specific problem depending on the storage conditions. Packaging Differences between types by Hoveark. JCosmetDermatol.2025;24(10):e70470 This was also examined in the study (DOI:10.1111 / jocd.70470). Analytical analysis of BPO samples. in vitro due to radical decomposition of dissolved benzoyl peroxide during preparation Benzene formation and the resulting possibility of achieving artificially high results. Dang and This has also been reported by et al. (J Pharm Biomed Anal. 2025;264:116946; DOI:10.1016 / j.jpba.2025.116946). Therefore, sample preparation in benzene analysis. Temperature and contact time, matrix-specific blank and spike / recovery controls are also validated. It is done. Barbieri et al. (JAMA Dermatol. 2025;161(4):442-444; DOI:10.1001 / jamadermatol.2024.6443), formulation in products containing benzoyl peroxide It evaluated its relationship with benzene formation. However, the publication in question; triple linomycin Which low molecular weight hydroxyl compound is in the phosphate / adapalene / benzoylperoxide system? below which quantitative threshold the class will be reduced, the dissolved benzoyl peroxide pool how to manage clindamycin phosphate stability together with hydroxylated solvents wetting, dispersion, water activity, microbial quality and other issues that arise when it is removed. a specific carrier architecture for simultaneously compensating for rheological losses It does not explain. The current state of the art is that low molecular weight hydroxyl compounds are never abandoned. It is not feasible to draw a general conclusion that it was not done. Instead, the previous The documents show two distinct doctrines: on the one hand, clindamycin / benzoyl peroxide. pH and room temperature stability could be achieved in their systems using a two-component kit approach; On the other hand, polyol and polyole ether are used for wetting and dispersing benzoyl peroxide in aqueous medium. or the addition of other water-soluble organic solvents is particularly recommended. Available Instead of simply repeating these two known approaches, the meeting involved a pre-mixed, single-pot solution. clindamycin phosphate / adapalene / benzoyl peroxide ternary system free low molecular weight while quantitatively limiting the pool of hydroxylated excipients, the consequences of this losses in wetting, dispersion, rheology, microbial quality and processability are examined differently. It is designed for compensation with an aqueous suspension-gel architecture. Aqueous gel compositions containing damicin and benzoyl peroxide, document number US5733886. and two component liquids have been described. Claim 1 of the document states that benzoyl peroxide is in the gelling agent. in suspension and clindamycin solution, at room temperature for at least one This is intended for a stable, mixed topical gel composition; also Claim 2 and In the four examples, the benzoyl peroxide suspension and the aqueous clindamycin solution were in separate containers. The two component liquids, which are retained and combined during the administration to the patient, are described. Table 1 shows the range of 0-30% (w / w) for humectant, preferably 5-15% (w / w); Table 2 This describes a preferred formulation containing 10% (w / w) propylene glycol. Next to Example 7, a benzoyl not containing propyleneglycol but containing 0.3% (w / w) imidure The document shows a peroxide suspension. It describes a mixture of clindamycin and benzoyl peroxide. the gel can be stable at room temperature for at least one month and in samples for several months and pH This teaches that control is an important variable in the stability of inclination. Table 8 of the same document shows the clindamycin determination value at room temperature for Sample 10. Initially 1.20%, then 1.08% in the second month and 1.01% in the third month; benzoyl peroxide determination. The value was initially 5.87%, then 5.83% in the second month, and 5.97% in the third month. It has been reported. Therefore, the technical problem of the present invention is clindamycin / benzoyl peroxide. not only was room temperature stability achieved in the system for the first time; but also that of adapalene. It contains three active ingredients that are pre-mixed during production and distributed in a single container. a carrier architecture compatible with low levels of free hydroxyl excipients in the system It has been framed as a development. In Sample 13 of document US5733886, Sample 1 contains clindamycin solution (8g) and Sample 7 contains (22g) Benzoyl peroxide suspension is combined. From the compositions given in the document. When calculated, the final mixture contained approximately 0.22% (w / w) imidurea and methylparaben. The levels are approximately 0.027% (w / w) and propylparaben approximately 0.005% (w / w). When the structural definition in the application is applied, these three free hydroxyl-bearing auxiliaries The total amount of matter is approximately 0.25% (w / w), and thus the sample in question is present in the invention. This remains above the defined limit of 0.10% (w / w). This calculation is based on propylene in US5733886. glycol-free example, the total free low molecular weight hydroxylated compounds in the current application This is provided to show that it does not directly explain the auxiliary substance limit. Also... The mixture obtained in the sample in question contains approximately 2.8% (w / w) clindamycin phosphate (as phosphate). (measured value) contains 1.0-1.5% (w / w) clindamycin phosphate of the current application. It is outside the range. Table 7 data of US5733886, after coexistence of clindamycin and benzoyl peroxide It also shows that pH is a known stability variable. The document states that at 40°C... Clindamycin loss after one month of accelerated aging was 43.3% at pH 6.96; pH 25.5% at pH 5.99; 21.6% at pH 5.32; 20.5% at pH 4.85; and 15.9% at pH 4.03. It has been reported. Therefore, the current application and H control will be considered as a new technical element. 5. It does not apply; while using pH as a known control variable, it also contains adapalene. Pre-mixed single-pot triple system for wetting and dispersion of low-coseolvan load. and the results on the dissolved benzoyl peroxide pool as a separate technical problem It is addressing the issue. Document number US20100099733A1 describes the use of hydrophobic benzoyl peroxide powder in aqueous environments. polyol, polyoleic ether or low-grade polyol is used for wetting and preparing stable microsuspensions. The document teaches the use of wetting liquids containing carbonaceous organic alcohols. their requirements for these organic liquids are approximately 5% (w / w) or higher, also Dependent claims for concentrations of approximately 10% and 15% or higher. The document also lists clindamycin as one of the preferred antibiotics. Adapalene is mentioned among topical anti-acne active agents. This teaching is based on low molecular weight. Reduction of predominantly hydroxyl wetting fluids, benzoyl peroxide wetting and dispersion a deterioration in performance is a technical outcome that an expert might expect. This shows that it is. In the document No. US20110092562A1, benzoyl peroxide powder is dissolved in water and one or more water. wetting with a soluble organic solvent; the surface tension of the wetting liquid should be 64 dyn / cm or teaches how to lower it below that level. In the experiments in the document, pure water has a high surface tension. and shows weak wetting, propylene glycol, polyethylene glycol, ethoxydiglycol and others in water Better wetting has been reported in samples where soluble organic solvents were used. Similarly... The document lists clindamycin as an additional antibiotic and adapalene as a retinoid anti-acne active ingredient. This has been explained among them. Also, propylene carbonate and dimethyl, which do not contain free hydroxyl groups. Isosorbide is considered among the water-soluble organic solvent options. Therefore... In the present invention, not only the pool of hydroxylated excipients but also the preferred one in applications of water-soluble and free hydroxyl group-free organic cosolvans Additionally, a backup application format is provided for its limitation. US8288434B2 and related WO2009148584 family, low concentration benzoyl peroxide suspended in an aqueous carrier containing water and a water-miscible organic solvent. It describes the topical formulations in which it is kept. Sample 2 of US8288434B2 contains 2.5%. (w / w)benzoylperoxide,5.0%(w / w)propyleneglycol,1.2%(w / w)clindamycinphosphate,1.75%(w / w) Carbopol 980 is supplied as a gel containing 0.5% (w / w) potassium hydroxide and water; the document also states... The document lists adapalene and averatinoids among the anti-acne active ingredients. It also mentions benzoyl peroxide. a portion of it being dissolved in an organic solvent and in the presence of an organic solvent the concentration of dissolved benzoyl peroxide is higher than that in a medium containing only water. It teaches that holding something close is a positive design element. Therefore, the aforementioned The approach is based on the present invention in a three-active substance system with low total free hydroxyl groups. excipient / cosolvan load and a small pool of free dissolved benzoyl peroxide. It differs in terms of its intended design; the current invention in question concerns benzoyl peroxide. The suspension or known polymer selection is not being put forward as a new element. The document states that the organic solvent must be miscible with water and contain benzoyl peroxide at temperatures between 0-40°C. chemically non-reactive, liquid within this temperature range, ambient temperature Benzoyl peroxide ienase has a solubility and surfactant level of 0.1% (approximately 1 mg / g). In its absence, the criteria for dispersing benzoyl peroxide in the water-based gel are reported. The same The document states that HPLC was used to detect benzoyl peroxide in 100% propylene glycol at room temperature. Its solubility is 0.2-0.3% (w / w), and its solubility in ethoxydiglycol is approximately 4.9%. It has been reported that (a / a). The document states that the water-miscible organic solvent is benzoyl peroxide. It is positive in terms of wetting, dispersion and maintenance of the saturated dissolved phase. It teaches the formulation as a liquid. These values ​​are the free components in a multi-component aqueous gel. This is not interpreted as a measurement of the amount of dissolved benzoyl peroxide; in the present application. dissolved benzoyl peroxide pool phase separation and chromatography as defined in the specification. It is also determined quantitatively through the assignment approach. WO2008017914A2 (US20090318371A1 in the same description line), as a retinoid. tazarotene or adapalene, clindamycin phosphate as antibiotic and micro-as a keratolytic topical acne gel / cream systems containing benzoyl peroxide in a sponge (microsponge) The document explains that the carrier components include propylene glycol, glycerol, and ethanol. carbomer, disodiumEDTA, polyoxyl35 castor oil, polysorbates and other excipients It is considered to limit the reaction of benzoyl peroxide with retinoids and clindamycin phosphate. For this purpose, coating / encapsulating in micro-sponge is specifically taught. The preferred architecture of the present invention does not rely on obligatory microencapsulation. While keeping benzoyl peroxide and adapalene suspended mainly as solid particles total free low molecular weight hydroxylated auxiliary pool as a result It is aimed at restriction. In the current state of the art, benzoyl peroxide / adapalene combinations are also used in two-phase applications. systems, encapsulation approaches, various gelling agents, and different excipients It has been explained. Therefore, only one known gelling agent can be combined with another known gelling agent. Modifying the existing invention is not suggested as a technical contribution. 7. The Purpose of the Invention and the Technical Problem It Solved The purpose of the invention is to produce pre-mixed containers suitable for presentation in a single container during production. In a triple topical composition containing clindamycin phosphate, adapalene, and benzoyl peroxide, low The total amount of molecular weight free hydroxylated excipients can be measured. that it is limited in this way; benzoyl peroxide and adapalene are predominantly in solid particles. the aqueous solution is kept in a continuous phase; however, physical homogeneity is maintained for topical use. suitable rheology, acceptable microbial quality and pharmaceutically acceptable active ingredients The goal is to create an alternative carrier architecture that ensures a sustainable distribution. The specific technical problem that the invention aims to solve is: pre-mixed, single-container clindamycin phosphate / adapalene / benzoyl peroxide triple composition with free low molecule It is obtained by reducing the predominantly hydroxylated excipient pool to below 0.10% (w / w). Compensation for losses in wetting, dispersion, rheology, microbial quality, and processability. while doing so, the dissolved benzoyl peroxide pool and benzene due to the decomposition of benzoyl peroxide The aim is to provide an alternative water carrier architecture suitable for limiting the risk of formation. Long-term storability at room temperature is the targeted technique for verifying this architecture. one of the results; presented as an experimental result obtained at the time of application. It is not being driven. In a preferred product application, the composition is completely mixed during production. It is then filled into a single tube, pump or equivalent single-coated primary package and used. or the pharmacist prepares a separate clindamycin phase and a benzoyl peroxide phase before administering to the patient. or does not require joining by the patient. This single-coating application method allows for two The components differ from liquids in terms of structure and usage. First technical lesson: Limitation of the dissolved benzoyl peroxide fraction. The invention is based on the following technical principle, without being bound by any particular theory: benzoyl Peroxide has low stability in solution and its stability in suspension systems is poor. The solubility of benzoyl peroxide in the carrier can improve as it decreases. Therefore, quantitative amount of low molecular weight hydroxylated solvents that can dissolve benzoyl peroxide limiting the dissolved fraction of benzoyl peroxide in the continuous phase to reduce and keep the active ingredient mainly in suspension as solid particles. It is suitable for holding. Although the dissolved fraction at equilibrium is small compared to the total amount of benzoyl peroxide Furthermore, when dissolved benzoyl peroxide decomposes, new benzoyl peroxide dissolves from the solid phase. It can resaturate the continuous phase. Thus, a small instantaneous pool of dissolved solution can be stored. It can sustain cumulative degradation by acting as a dynamic reservoir throughout. This Therefore, the technical effect is determined not only by the suspension percentage at a single time point, but also by the dissolution rate. It is evaluated by the cumulative effect of the decay balance over time. In this context, the distinguishing magnitude is not the percentage value of the suspension refraction, but rather the refraction in the continuous phase. It is the absolute size of the pool of dissolved benzoyl peroxide. Benzoyl peroxide in water solubility in low molecular weight products such as propylene glycol or polyethylene glycol 400. Since the concentration is orders of magnitude lower than in hydroxylated solvents, it is only a few percent in the carrier. Even with the presence of a hydroxyl solvent at a certain level, the majority of the composition remains solid. It may remain in the form of particles; in contrast, the dissolved pool contains no hydroxyl solvent. It becomes measurably larger compared to a carrier. The dissolved pool in question Using the ratio, carrier composition, and saturation resolution values ​​reported in the literature, estimation with known resolution models, such as the log-linear Kosolvan approximation. It is possible; the expected difference at low cosolvane concentrations is of an order of magnitude. Since this may not be possible, direct measurement in dissolved pool comparative studies It is verified. Second technical lesson: Limitation of hydrogen donor sources. The discovery also relates to the benzene formation pathway without being bound by any particular theory. It also takes into account a complementary mechanistic hypothesis. Benzoyl peroxide inhomolysis benzoyloxy can form radicals; their decarboxylation leads to the formation of phenyl radicals and hydrogen from the environment. Transfer can lead to benzene. Free, low molecular weight hydroxylated solvents can cause this. It can provide accessible hydrogen sources and / or reaction environments for radical chemistry. Its relativity contribution depends on the formulation matrix and was experimentally determined at the time of application. It is not presented as a quantified fact. Cellulose ethers, gums, or cross-linked polyacrylic acids form an aqueous polymer network. Although their derivatives also have hydrogen-containing bonds, these are macromolecular structures. It depends. Unlike free small molecule solvents, the diffusion of polymer chains and its molecular mobility is limited. This distinction applies to the polymer class limited in the invention. as free and low molecular weight hydroxylated compounds that are not covalently bonded This is one of the technical reasons for its definition. Third technical instruction: clindamycin phosphate in dissolved benzoyl peroxide pool. its effect on 9. Clindamycin phosphate is found dissolved in the continuous phase; benzoyl peroxide is predominantly present. It is in the form of dispersed solid particles. Benzoyl peroxide in the form of solid particles... While the interaction of dissolved clindamycin phosphate is mainly limited to the particle surface, it is continuous. Benzoyl peroxide dissolved in the phase can spread homogeneously in the same phase and dissolved This may increase the likelihood of molecular contact and oxidative interaction with clindamycin phosphate. Therefore, reducing the dissolved benzoyl peroxide pool in the continuous phase alone not only the degradation of benzoyl peroxide itself, but also the oxidative degradation of clindamycin phosphate. It is expected to be suitable for limitation. This mechanistic hypothesis should be evaluated in a system-specific manner. Dual adapalene / benzoyl a third oxidation-sensitive substance found dissolved in the aqueous phase of peroxide products Since no active ingredient is present, the size of the dissolved benzoyl peroxide pool is proportional to the product. Its stability may not be as decisive as in the triple system; therefore, in binary products The presence of propylene glycol and glycerol does not necessarily conflict with room temperature stability. In contrast, since clindamycin phosphate is dissolved in the aqueous continuous phase in the ternary system, The probability of direct molecular contact with the dissolved benzoyl peroxide pool in the same phase increases. The technical teaching of the invention is therefore not a repetition of a general low-resolution principle, but three Limiting the dissolved benzoyl peroxide pool specific to the multi-component system and This involves managing the effect of clindamycin phosphate on stability. However, the removal of low molecular weight hydroxylated solvents reduces water activity. By increasing the hydrolysis, it can accelerate the hydrolysis of clindamycin phosphate phosphate ester. Thus, two opposing forces... The effect is: oxidative stress due to the reduction of the dissolved benzoyl peroxide pool. Increased hydrolytic decomposition due to decreased degradation and increased water activity. These two The net result of the effect is determined experimentally; clindamycin phosphate in the development of the invention Determination value and degradation products are therefore among the primary parameters to be monitored. and, when necessary, pH, chelating agent and hydroxyl solvent class that affects water activity. It is optimized by removing any missing auxiliary substances. Technical losses that need to be compensated Reducing the amount of low molecular weight hydroxylated solvent simultaneously with more than one Technical losses may occur. These components are involved in wetting and dispersion, moisture retention, and water retention. reducing activity, limiting microbial load, application on the skin subsequently forming a persistent solvent phase, resulting in active substance partitioning and processability. It can contribute. The second technical problem of the invention is that the aforementioned functional losses; in an aqueous solution 10 gelling / suspension polymer mixture, suitable mixing and dispersion conditions, as required. low molecular weight hydroxylated solvent-free compatible wetting / dispersion a suitable protective system, a chelating agent, and active ingredient particles It is to compensate by controlling its size. Thus, the positive technical architecture of the invention is not merely the absence of a component; it is the low-level one. Hydroxyliated solvent level, benzoyl peroxide and adapalene suspended in solid particles, aqueous polymeric network that holds these in suspension, limiting transition metallic analytic peroxide decomposition It is a system formed by the combination of a chelating agent and a controlled particle size. Definitions The term "low molecular weight hydroxylated compound" refers to compounds that exist as free molecules in the formulation. including residues from raw materials or auxiliary materials, covalent to the polymer unbound, molecular weight less than 1000 Da and at least one free hydroxyl group It refers to organic compounds that carry this group. When calculating the total amount of this class... clindamycinphosphate, benzoylperoxide and adapalene and their degradation products; disodium Chelating agents such as edetate, calcium disodium edetate, and sodium phytate; potassium pH regulators such as hydroxide, sodium hydroxide, citric acid and phosphoric acid; and potassium Preservatives such as sorbate, which are also described in the specification, are not taken into account. However... propyleneglycol,glycerol,ethoxydiglycol(diethyleneglycolmonoethylether),polyethyleneglycol400 and other polyethylene glycols with molecular weight less than 1000 Da, 1,3-butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol, ethylene glycol, sorbitol, mannitol, Xylitol, ethanol, and isopropanol; regardless of their function in the formulation. This is included in the calculation of the total amount of this class. Compounds not on the list. In its evaluation, molecular weight, free hydroxyl group, miscibility with water, and Capacity to dissolve benzoyl peroxide in a defined equilibrium solubility method at 25 °C. They can be used as auxiliary functional criteria. In polydisperse oligomeric mixtures, especially polyethylene glycols, "molecular weight" Unless otherwise stated, in the relevant pharmacopoeia monograph or supplier specification It expresses the given nominal / average molecular weight. The expression "predominantly" refers to the quantity of the active substance that is most abundant in the total amount. the fraction, i.e. more than 50%, being in the form of undissolved solid particles It also indicates the preferred quantitative ranges for higher suspension refractions. It is explained in the specifications. 11. In an alternative application, low molecular weight hydroxylated compounds a functional subclass; molecular weight less than 1000 Da, miscible with water, containing at least one a polymer containing a free hydroxyl group, not recovalently bonded and defined at 25°C In the sudden solubility method, benzoyl peroxide solubility is higher than 1 mg / g. They can be characterized as organic compounds. In other applications, the functional aspects in question... The threshold can be defined as 0.5 mg / g or 2 mg / g. This functional definition replaces the structural definition. It does not have to pass; especially the bottom that affects the dissolved benzoyl peroxide pool. It is a backup definition method for the experimental separation of classes. The phrase "limited content of low molecular weight hydroxylated compounds" is used above. The total amount of compounds identified and included in the calculation of the total amount, total It refers to a system where the composition weight is less than 0.10% (w / w). Preferred In applications, the total amount is less than 0.05% (w / w), preferably less than 0.02% (w / w). From raw materials, surfactants or other additive grades derived from free propylene glycol, glycerol, ethylene glycol, diethylene glycol, low molecular weight Predominantly PEG or similar target compound residues are also included in this total amount, and It is determined by a validated analytical method. A limitation in the form of an application, only the compounds listed above (propylene glycol, glycerol, ethylene glycol, diethylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, hexylene glycol, ethoxydiglycol, polyethylene glycols with molecular weight less than 1000Da, sorbitol, mannitol, xylitol, ethanol (and isopropanol) is applied to the total amount, and this total is the raw material or auxiliary material. including source residues, from 0.10%(w / w), preferably from 0.05%(w / w), even more preferably 0.02% It is less than (a / a). In this application method, the composition contains significantly less benzoyl peroxide. It may contain other non-dissolving free hydroxyl compounds; however, these also have low... It is preferable to keep it in check. A more preferred form of implementation is restriction, the name of which is... It applies to the entire class defined above, including the compounds listed. The expression "organic cosolvan that is water-soluble and does not contain a free hydroxyl group"; present in the composition as free molecules, not polymers that are recovalently bonded, preferably with a molecular weight less than 1000 Da, water-soluble or miscible, and It refers to organic auxiliary liquids that do not contain a free hydroxyl group. Propylene carbonate and Dimethyl isosorbide is an example of this class. A compound's solvent, co-solvent, or penetrating agent. Using it as an enhancer or under the guise of another function does not change this classification. Another preferred application method involves a water-soluble substance with a free hydroxyl group. The total amount of non-organic co-solvents is also limited. An example of this class is... 12-propylene carbonate and dimethyl isosorbide can be given; however, the class is not limited to these two compounds. The total amount of these hydroxyl-free inorganic cosolvanes is preferably the total composition. from 0.10% (w / w) of weight, preferably 0.05% (w / w), most preferably 0.02% (w / w) It is scarce. In a more general form of reserve application, low-molecular-weight with or without hydroxyl groups. The total amount of predominantly organic cosolvanes is kept less than 0.10% (w / w). Thus, hydroxylated In addition to the excipient limit, wetting of benzoyl peroxide or in the continuous phase low-cosolvan in terms of hydroxyl-free cosolvans that can increase the dissolved pool A specification basis is provided for a continuous phase. The term "approximately" means ±5% (relative) of the stated numerical value unless explicitly stated otherwise. It means; when used in a dependent request, the interpretation is in no case dependent on the request. It does not exceed the numerical range in the request. “Aqueous continuous phase” is a composition in which the continuous phase is predominantly water by weight. It refers to the system. In preferred applications, the amount of water is the total composition. It is in the range of 80-95%(w / w) of weight, preferably 85-93%(w / w). “Gelling / suspension system”, benzoyl peroxide and adapalene particles one or more suitable flow and geology for limiting sedimentation and topographic application. It refers to a more pharmaceutically acceptable hydrophilic polymer. “Suspended refraction” refers to active substances present in the composition as undissolved solid particles. It expresses the ratio of the amount of a substance to the total amount of that active substance in the sample. centrifugation at a controlled temperature or filtration through a membrane with a suitable pore size Afterwards, the clear phase obtained is analyzed to determine the active substance, thus validating the analysis. It is determined by chromatographic method. “Dissolved pool” refers to benzoyl groups that are molecularly dissolved in the aqueous continuous phase. It expresses the ratio of peroxide amount to the total composition weight. Surfactant In compositions not containing this substance, centrifugation at controlled temperature and / or appropriate It can be determined by chromatographic analysis in the clear continuous phase after membrane filtration. In compositions containing surfactants, in micelles or other colloidal structures Separation of soluble benzoyl peroxide from the free molecular dissolved fraction for this, a valid ultrafiltration membrane suitable for retaining micelles (surface-active surfactant used) selected to hold the unimmers and micelles of the substance, e.g., nominal 3-30 kDa a membrane with a molecular weight cutoff value), ultracentrifugation or equivalent Separation method is used. Carrier controls containing and without surfactant are performed on the same carrier. The contribution of micelle-derived solubilization is evaluated by working within 13 analytical sequences. Phase Separation and determination conditions significantly alter the solubility equilibrium of benzoyl peroxide during the process. It is validated in a way that does not alter the form. In the preferred reference measurement procedure. Sample is stored at 25±2°C; micelle and colloidal fraction nominal 3kD molecular weight It is separated by an ultrafiltration membrane with a cutoff value, and the benzoyl peroxide in the filtrate Determined by validated HPLC method. Nominal 3kDa cutoff value, poloxamer188 surfactants with an average molecular weight below 10 kDa and low Aggregation is preferred to limit the passage of micelles into the filtrate; surfactants In compositions without harmful substances, a nominal cutoff value of 10 kDa can also be used. Membrane adsorption and benzoyl peroxide, where the membrane retains the solubilizing structures. Recovery is verified with matrix-specific spike / recovery. Detailed Description of the Invention Active ingredients Composition: 1.0-1.5% (w / w) clindamycin phosphate, 2.5%- by total composition weight. It contains 3,5(w / w)benzoyl peroxide and 0.10-0.20(w / w)adapalene. In a preferred application... The amounts in question are approximately 1.2%, 3.1%, and 0.15% (w / w) respectively. Benzoyl peroxide and adapalene are predominantly dissolved in the composition instead of being completely dissolved. It is suspended as solid particles. High suspension for benzoyl peroxide. Fraction is preferred. Depending on the application method, the suspended fraction should be at least 95%, and at most... It can be at least 97%, at least 98%, or at least 99% (w / w); analytically reliable. in applications where it can be demonstrated at least 99.5%, preferably at least 99.7% and even more preferably At least 99.9% suspension fractionation can be targeted. These values ​​can be obtained in the initial application. These are not presented as experimental results, but rather as a phase-separation and assignment in the future. These are described as alternative application intervals that can be supported by the method. Adapalene It is preferably present predominantly as solid particles. Clindamycin phosphate is preferably aqueous. It exists in a dissolved or molecularly dispersed state in the phase. An alternative and preferred form of definition is composition, dissolved pool. It is characterized by its size. In preferred applications, it is dissolved in aqueous continuous phase. The amount of benzoyl peroxide should not exceed 0.05% (w / w) of the total composition weight. preferably less than 0.02% (w / w), more preferably less than 0.01% (w / w), preferably less than 0.005% (w / w) It is small. In preferred applications, the dissolved pool in question contains the same active ingredient. amounts and dissolved in the comparison composition containing 5%(w / w)propylene glycol Of the 14 pools, it is measurably smaller when measured using the same method; preferably in comparison composition at most 90% of the value, more preferably at most 70%, at most preferably a maximum of 50%. Hydroxybenzoyl peroxide is moistened with water to reduce flammability and shock sensitivity. It is supplied in this form. As a starting raw material in the preferred applications of the invention. Hydroxybenzoyl peroxide is used. The amount of hydrogenated raw material by weight determines the effectiveness of the raw material. Based on the benzoyl peroxide content, the active benzoyl peroxide equivalent in the final composition. It is adjusted to achieve its target; included in the final balance sheet from raw materials. The hydrous form facilitates the transfer of benzoyl peroxide to the aqueous polymer phase. It provides a starting material that has been in contact with water beforehand; this results in complete wetting. Deagglomeration and homogeneity are verified by process parameters and only in hydrolyzed The existence of the form is not presumed. Support system The composition is an aqueous solution with limited content of low molecular weight hydroxylated solvents. It contains a continuous phase and a gelling / suspension system. The gelling / suspension system is single. It can consist of a single polymer or a combination of two or more polymers. Suitable hydrophilic polymers, including but not limited to hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose and Pharmaceutical acceptable salts include xanthan gum, sclerotium gum, and gellan gum. carrageenans, carbomers, cross-linked acrylic acid polymers, acrylate copolymers, Polyacrylamide gelling agents, acrylamide / sodium acrylodimethyltaurate copolymer and related products. sulfonated acrylamide copolymers, acrylic polymers linked to hydrophobic chains, modified starches (e.g., hydroxypropyl starch phosphate, sodium starch octenylsuccinate) and their derivatives Combinations are included. Total gelling agent / suspension system amount preferably 0.20%. 6.0(a / a), preferably in the range of 0.5-4.0(a / a). The composition includes an electrolyte load resulting from clindamycin phosphate and a pH regulator. because it contains and its pH value is below the full neutralization range of carbomer-type ionic networks Gelling systems that are pH-independent and have high electrolyte tolerance, as they can be maintained. It is particularly preferred. For this purpose, acrylamide / sodium acrylodimethyltaurate copolymer and similar sulfonated acrylamide copolymers, polyacrylamide gelling agents, hydrophobic chains Bonded acrylic polymers and modified starches can be used. These polymers have a wide pH range. Because they can provide a yield voltage within the range, benzoyl peroxide and adapalene particles To limit sedimentation and maintain rheological stability throughout storage. It is suitable. When acrylamide / sodium acrylodimethyltaurate copolymer is used, the amount is... Preferably 0.5-6.0% (w / w), calculated according to the form in which it was supplied. preferably in the range of 1.0-4.0%(a / a). Some commercial grades of these polymers are in reverse emulsion form, a hydrocarbon. It is supplied with a carrier and one or more emulsifiers. In this case, the carrier and In addition to free polyethylene glycol and free polyol residues, the emulsifier system contains a free hydroxyl groups such as sorbitan esters present as a conscious component of the supply grade Low molecular weight emulsifier components (named) are also included in the relevant total calculations. For the enumerated compounds, in Request 1, for the functional subclass, in Request 2, the defined class that the total (included in Request 3) is included; that the aforementioned total limits are not exceeded and The system's chemical compatibility with benzoyl peroxide is confirmed. If necessary. low molecular weight emulsifier-free polymer grades containing free hydroxyl groups It is preferred when using emulsifier systems containing unsaturated fatty acid esters. Oxidative stability in the presence of benzoyl peroxide is also evaluated; the components in question... Since benzoyl peroxide is known to be used in commercial topical products, these components are included in the invention. not excluded from the scope, but with formulation-specific compatibility data. It is supported. In one embodiment the composition includes a carbomer-based gel lacquer. In another embodiment The composition is an aqueous suspension formed by the combination of a cellulose derivative and xanthan gum. It relies on a network. In another application, hydroxypropylmethylcellulose / xanthan gum or Hydroxyethylcellulose / xanthan gum combinations are used. In another application... The composition is based on a pH-independent sulfonated acrylamide copolymer network. This Alternatives that will limit the sedimentation of benzoyl peroxide and adapalene particles, The ionic strength aqueous containing clindamycin phosphate will constantly be highly compatible and storage It is chosen in a way that will maintain its rheological stability throughout. Polysaccharide-based gelling agents (xanthan gum, gellangam, cellulosic ethers, hyaluronate) Chain breakdown and associated viscosity due to radical reactions caused by benzoyl peroxide. It can suffer losses. Polyacrylic acid and acrylamide-based networks are relatively resistant in this respect. It is possible. Polymer selection considers electrolyte tolerance, pH independence, and oxidative resistance together. This is done by evaluating and accelerating long-term stability conditions with viscosity. The flow voltage is monitored. 16In a manner consistent with the goal of limiting benzene, when carbomer is used Benzene was not used in the polymerization; ethyl acetate or ethyl as a solvent. Grades produced with acetate / cyclohexane systems are preferred; polymerization of benzene Historically used grades are avoided. The polymerization solvent of the polymer used and The residue solvent profile is verified with supplier documentation. Low molecular weight substances are released during storage through hydrolysis or other degradation. Polymers with the potential to release hydroxyl compounds are not preferred, especially. Propylene glycol alginate is preferred due to the formation of free propylene glycol. It is not among the gelling / suspension systems; if its use is considered, initially and the total amount of free propylene glycol that may form during the shelf life is 0.10% (w / w) It is analytically shown that it does not exceed its limit. Chelating agent and transition metal control Transition metal ions, particularly iron and copper, cause homolytic cleavage of the peroxide bond. It can catalyze. High water content and low molecular weight hydroxylated solvent content. Since ionic mobility is relatively high in a confined system, the transition metal Limiting catalyzed degradation is preferred. For this purpose, the composition and pharmaceutical... It may contain an acceptable chelating agent. Suitable chelating agents include disodium. This includes edetate, calcium disodium edetate, sodium phytate, and combinations thereof. The amount of chelating agent should preferably be 0.005-0.50% (w / w), or even more preferably 0.01-0.10% (w / w). It is within the range. The chelating agent is preferably added to the water phase before the addition of benzoyl peroxide. In addition, there is a low-pass metal residue specification for raw materials and production equipment. Applicable; low-additive materials such as stainless steel for product contact surfaces. Materials containing copper and copper alloys are preferred, and contact surfaces containing copper are avoided. Final Iron and copper levels in the product can be monitored using an appropriate elemental analysis method. Wetting and dispersion aids In some applications of the invention, the dispersion of the aqueous polymer network of benzoyl peroxide is used only. This is achieved with controlled mixing or high shear. Adapalene is distinctly hydrophobic. Therefore, wetting in the absence of a low molecular weight hydroxylated solvent and Deagglomeration may be difficult. Therefore, a low molecular weight hydroxylated solvent should be used. pharmaceutical that does not fall under the definition but has been shown to be chemically compatible with benzoyl peroxide An acceptable wetting or dispersion aid can be used in low quantities. 17Preferred wetting / dispersion aids include low peroxide / hydroperoxide. impurities such as hippopoloxamers (especially poloxamer 124 and poloxamer 188; if required) Poloxamer 407), polysorbate 20 and sodium docusate are included. Poloxamers and sodium Docusate is used for wetting / dispersion purposes in topical systems containing benzoyl peroxide. It is known that surfactant gradients containing unsaturated fatty acid chains are used. Because they may be more susceptible to oxidative degradation, these grades are only formulation-specific. Used with compatibility data. Poloxamers and polysorbates are polyether-based. It may form hydroperoxide during storage; therefore, it is included in the raw material specifications. The upper limit for peroxide / hydroperoxide is determined, and the raw material is cooked under inert gas and at low temperature. It is stored. If a grad containing antioxidants is to be used, the antioxidant should be mixed with benzoyl peroxide. chemical compatibility and its contribution to the total limits defined in Claim 1, Claim 2 and Claim 3 It is also verified. When used, the total amount of excipients is preferably 0.01-1.0% (w / w). preferably in the range of 0.02-0.5% (w / w). The commercial grades of the aforementioned excipients are free polyethylene glycol, free polyol or similar residues or low molecular weight auxiliary components containing free hydroxyl groups because they may contain, regardless of whether they are called residues or not, the relevant totalaccounts(fornamecompounds in Request1, for functional subclass in Request1) The total in Request 3 is included for the entire class defined in 2. The composition... total low molecular weight hydroxylated compound content below 0.10% (w / w) limit To ensure this, suitable low-residue grades are selected and specified in the raw material specification. Necessary upper limits are defined. Protective system and microbial quality A limited content of high water content and low molecular weight hydroxyl compounds. Since the water activity in the system may be relatively high, the composition is pharmaceutically acceptable. It may contain a preservative or a preservative system. The preservative has a low total molecular weight. will not disrupt the predominantly hydroxylated compound limit and benzoyl peroxide / clindamycin phosphate It is selected to be chemically compatible with the system; carrying free hydroxyl groups and Preservatives that can significantly dissolve benzoyl peroxide are not preferred. A suitable preservative is needed. Examples include potassium sorbate. Potassium sorbate is characterized by its conjugated structure. Because it may be susceptible to radical oxidation conditions, potassium sorbate-containing preservative content, color / appearance and preservative efficacy during storage in applications Its protective efficacy is monitored according to European Pharmacopoeia 5.1.3 or an equivalent method. This is verified. In an alternative application, a preservative-free composition is used with suitable water. With its 18% activity and one-way flow packaging, it will ensure microbial quality. devisable. Moisture retention and tolerability compensation Removal of low molecular weight hydroxylated solvents, moisture retention, water activity or If it has a negative effect on skin sensation, compatibility with benzoyl peroxide has been demonstrated and Auxiliary substances that do not belong to the solvent class in question can be used. For example, sodium. PCA, betaine, sodium hyaluronate, urea, or suitable combinations thereof. assessable. The following points are taken into consideration when selecting these components: Urea hydrolyzes slowly in an aqueous environment. It can release ammonia and raise the pH of the composition throughout storage. This can lead to the hydrolytic decomposition of benzoyl peroxide and clindamycin phosphate. Long-term pH in urea-containing applications can negatively affect stability. The shift is also monitored and an appropriate buffering system is used if necessary. Sodium Since hyaluronate is a polysaccharide, it can be reacted with benzoyl peroxide through radical reactions. The chain may break; therefore, it is expected to assume a rheological function. In applications, viscosity is monitored throughout storage. Sodium PCA and betaine are important in this respect. These are the relatively preferred candidates. The level of these components; rheology, water activity, active ingredient. Stability, in vitro uptake / permeation, and local tolerability are considered together when selecting the product. pHvereology The pH value of the composition; topical use, stability and distribution of clindamycin phosphate, The hydrolytic stability of benzoyl peroxide, the ionization state of adapalene, and its gel structure are considered together. Taking into consideration, preferably in the range of 4.8-6.2, even more preferably 5.0-6.0, and most preferably 5.2-5.9. Adapalene is a naphthoic acid derivative, therefore it is ionized at lower pH values. The proportion of the non-existent form increases and the active substance is retained in the form of solid particles. It can become easier; therefore, a range of 4.8-5.5 is also foreseen as an application method. In other applications, the pH value may be in the range of 4.0-6.5; pH values ​​below 4.8 The physical stability (tendency to precipitate) and local tolerability of clindamycin phosphate are 6.2%. chemical stability of clindamycin phosphate and benzoyl peroxide at pH values ​​above This is also confirmed. Potassium hydroxide, sodium hydroxide, and citric acid can be used to adjust the pH. Phosphoric acid or another pharmaceutically acceptable pH regulator can be used. In the accelerated study in document US5733886, pH was measured using clindamycin / benzoyl peroxide. It has been shown that a known formulation is a leverage for stability. The document in question... Table 7 shows the loss of clindamycin pH after one month of aging at 40 °C. 43.3% at 6.96;25.5% at pH5.99;21.6% at pH5.32;20.5% at pH4.85and15.9% at pH4.03 This has been reported. The physical stability data for clindamycin solution in the same document indicates that the pH... that it cannot be reduced indefinitely downwards; precipitation may occur under low pH conditions. This shows that, therefore, the current invention does not propose pH control as a new element; In addition to pH optimization, limiting the dissolved benzoyl peroxide pool. It aims to be used as a secondary and independent formulation lever. Rheology refers to the ability of a product to spread during application and to release particles during storage. limiting sedimentation and enabling the filling / packaging process It is selected in a way that will provide. In preferred applications, the composition can be measured at 25°C. It has a yield stress; yield stress preferably less than 0.5 Pa, The polymer type and quantity are experimentally determined for this purpose. The yield stress and viscosity can be adjusted and accelerated under stability conditions. Protection is monitored. Particle and microstructure Benzoyl peroxide and adapalene particle size distributions are determined by laser diffraction, microscopy, or... It can be determined by an equivalent method. Benzoyl peroxide is preferred in applications. particles with D90 value below 100µm, preferably below 50µm, preferably 25µm Adapalene particles are kept below a D90 value of 50µm, preferably 20µm. It is kept below, preferably below 10µm, preferably below 5µm. Reducing the particle size of adapalene using a low molecular weight hydroxylated solvent. In its absence, it can support the dissolution rate of the active ingredient and thus its penetration into the skin. In contrast, excessive reduction in benzoyl peroxide particle size increases the specific surface area. It can accelerate dissolution and surface reactions by increasing them; therefore, for benzoyl peroxide Particle size is selected by considering both homogeneity and stability. Particle size selection. Chemical stability is evaluated together with in vitro uptake and permeation performance. It is done. PACKAGING The composition is packaged in a way that supports the stability of benzoyl peroxide. Preference The packaging materials used are light-impermeable, low-pass metallic-coated, laminated tubes or airtight. These are (airless) pump systems. They limit the air gap inside the packaging and are one-way. A flow-through distribution system is preferred. The packaging material should not contain benzene. 20. Sorption / desorption behavior and product interaction suitability studies. It is evaluated. Benzene degradation assessment Benzene analysis in compositions containing benzoyl peroxide, using the method's own thermal conditions. Low-temperature headspace GC-MS method to reduce the risk of benzene production This can be done. In the preferred method, approximately 500 mg of product is mixed with 4.5 mL of headspace-class dimethyl. It is prepared with sulfoxide, benzene-13C6 is used as the internal standard, and headspace balancing is approximately... It is performed at 37°C for 20 minutes. The suitability of the method for the formulation matrix depends on parallel formulations prepared from the same formula. Measurement of samples at 37°C for 10, 20, 40 and 60 minutes of equilibration times, diluent blank, benzoyl peroxide raw material, blank, benzoic acid, blank, benzoyl peroxide-free Comparison of carrier blank and full formulation starting sample, matrix-specific Spike / recovery studies, control of heating during sample weighing and sample collection. This is confirmed by checking for the delay between the analysis and the data. In preferred applications, the benzene content of the composition starts post-production. at the point 2 ppm, preferably 1 ppm, preferably 0.5 ppm, preferably The composition is less than 0.1 ppm. Preferred application conditions: 40°C and 75% relative humidity. After being stored for three months under these conditions, the benzene level should be less than 2 ppm, preferably less than 1 ppm. It contains. In preferred applications, the composition is best suited for use at 25°C and 60% relative humidity. Contains less than 2ppm of benzene after storage for at least two months, preferably at least twenty-four months and benzoyl peroxide determination value from 90% of the initial value; clindamycin phosphate determination Its value shall not be less than 95% of the initial value, and 90% in other applications. The aim is to preserve it in this form. In preferred applications, the composition uses the same amounts of active ingredients and 5% (w / w). under the same conditions and with the same analytical method as the comparison composition containing propylene glycol. When compared in sequence, it is measurably less than the comparison composition. Contains benzene; preferably less than half the benzene level of the comparison composition. It preferably contains less than one-fifth, or even less than one-tenth, of benzene. These values ​​are the performance that the invention aims for and form part of its technical teaching. These are the levels. As a result obtained experimentally from these values ​​on the application date. not suggested; these values ​​are based on comparative stability and benzene analyses. These are described as target ranges to be verified. 21Clindamycin phosphate stability Clindamycinphosphate undergoes oxidative degradation in the presence of benzoyl peroxide and phosphate in aqueous media. It may be susceptible to hydrolysis of the ester. Increasing the water content and using a lower molecular weight compound. Since removing the hydroxylated solvent can increase the water activity of clindamycin phosphate. Determination value and degradation products are primary monitoring parameters in the development of the invention. It is located between them. To support the stability of clindamycin phosphate; pH is within the optimum range. retention, a suitable buffer system, use of chelating agents, dissolved benzoyl peroxide keeping the pool small and limiting the production and storage temperatures together The pH-stability profile for clindamycin phosphate is applied as defined in the development of the invention. The area is experimentally mapped within a certain range, and the final H is selected based on this map. Analytical methods The total low molecular weight free hydroxylated compound content of the composition is the target. It is determined by validated methods appropriate to the physicochemical properties of the analyte. Ethanol, isopropanol, propyleneglycol, ethyleneglycol, diethyleneglycol, ethoxydiglycol and similar volatile or semi-volatile compounds directly or, if necessary, after appropriate derivatization. GC-FID / GC-MS with glycerol, sorbitol, mannitol, xylitol and low molecular weight PEG The fractions are then subjected to GC-FID / GC-MS and / or target analyte after derivatization as needed. It can be determined using suitable, validated methods such as HPLC or LC-MS. The method depends on the formulation. For the target compounds that can be found, the reliability limit is below 0.10% (w / w) individually and collectively. Appropriate LOQ / LOD is developed to ensure determination. Gelling agent, surfactant and other Each supplier of auxiliary materials must release CoA and, if necessary, additional tests for Gradvelotu. Glycol / polyol and other components included in the calculation are evaluated; supplier or grade change. The total limit of the final product is re-evaluated. Active substance determination and degradation product determination were performed using high-performance liquid chromatography; particle size distribution by laser diffraction; rheology by rotational rheometry; water activity Microbial quality is assessed using appropriate water activity meters and pharmacopoeia methods. Suspended fraction and dissolved pool, according to the method specified in the Definitions section. It is determined. Expected technical effects The invention, compared to the known state of the art of ternary compositions containing polyhydric alcohol, It is expected to provide the following technical effects: (i) benzoyl peroxide during storage (ii) a decrease in benzene formation due to decomposition; (ii) a lower benzoyl peroxide determination value 22. good preservation; (iii) reduction of the dissolved benzoyl peroxide pool in the continuous phase (iv) room ensuring storage at the specified temperature and eliminating the need for a cold chain. or reduction;(v)removal of propylene glycol in three active ingredient compositions Accordingly, improvement in local tolerability, especially in individuals sensitive to this excipient. and the likelihood of reduced application site reactions. These effects are described as part of the initial technical teaching of the application. A specific benzene reduction percentage, extended shelf life, and tolerability difference as of the application date. or the coefficient of superiority is not experimentally proven; the effects in question This will be determined quantitatively through comparative studies. Preparation Method The composition that is the subject of the invention can be prepared using the following general steps: a) By controlled mixing of the gelling / suspension polymer in a portion of pure water hydration or dispersion and, if necessary, the addition of a chelating agent to this phase. dissolution; b) Clindamycin phosphate should be dissolved in a separate section of pure water and, if necessary... Adjusting the pH value of this phase; c) Wetting of hydrous benzoyl peroxide with a low molecular weight hydroxylated solvent, unless added as a dissolving or dispersing solvent, water and / or controlled mixing or high pressure into a portion of the pre-prepared aqueous polymer phase Suspension of solid particles by direct addition under shear; d) Adapalene, when dissolved in a low molecular weight hydroxylated solvent, by wetting or dissolving. Unless a dispersion solvent is added, the water and / or aqueous polymer phase in one section, in the presence of a wetting / dispersion aid when necessary, in a controlled manner. dispersion by means of mixing or high shear; e) Addition of benzoyl peroxide and adapalene dispersions to the main gel / suspension phase; f) Addition of clindamycin phosphate solution; g) Adjusting the final H value to the range of 4.8-6.2 and completing it to the final weight with water; h) Homogenization of the composition, deaeration, and packaging into a single primary pack. filling. 23The product temperature throughout the process is adjusted as much as possible, taking into account the stability of benzoyl peroxide. The product temperature is kept as low as possible; preferably during the mixing and combining steps. It does not exceed 35°C, more preferably 30°C, preferably 25°C. Dry benzoyl peroxide is unnecessary. Heat, friction, or high energy are not applied. Process and filling stages are used as needed. It can be carried out under a nitrogen or other inert gas cover. For surfaces in contact with the product. Materials providing low-transition metallic additives are used. Application Examples The following examples are intended to illustrate the technical forms in which the invention can be implemented. These examples do not present any experimental performance results; compositions for formulation development and comparative stability studies can be prepared. In all samples, the total molecular weight in the final composition is low. suitable low- to ensure that the amount of free hydroxyl compound remains less than 0.10%(w / w) Pharmaceutical grades with residues are selected, and the limit in question is validated using an analytical method. It is verified. Example1-Carbomer based composition Component Quantity (%a / a) Function Clindamycinphosphate 1.20 Active ingredient Benzoyl peroxide (added as hydrosol) 3,10 Active ingredient, suspension phase Adapalene 0.15 Active ingredient, suspension phase Carbomer homopolymer (benzene-free grade) 1.0-2.0 Gelling agent / suspension system Poloxamer188(low peroxide, low 0.05-0.20 Wetting / dispersing aid free polygrade) Disodium edetate 0.02-0.05 Chelating agent Potassium hydroxide ym pH 5.2-5.9 Pure water is completed to 100%. Continuous phase. Example 2 - Cellulose / gum-based composition Component Quantity (%a / a) Function Clindamycinphosphate 1.20 Active ingredient 24Component Quantity (%a / a) Function Benzoyl peroxide (added as hydrosol) 3,10 Active ingredient, suspension phase Adapalene 0.15 Active ingredient, suspension phase Hydroxyethylcellulose 0.8-2.5 Primary hydrophilic polymer Xanthan gum 0.05-0.50 Suspension / yield strength support Poloxamer188 0.05-0.30 Wetting / dispersion aid Disodium edetate 0.02-0.05 Chelating agent pH regulator ym pH5.2-5.9 Pure water is completed to 100%. Continuous phase. Example3- HPMC / scale based composition Component Quantity (%a / a) Function Clindamycinphosphate 1.20 Active ingredient Benzoyl peroxide (added as hydrosol) 3,10 Active ingredient, suspension phase Adapalene 0.15 Active ingredient, suspension phase Hydroxypropylmethylcellulose 0.5-2.0 Primary hydrophilic polymer Xanthan gum 0.05-0.30 Suspension / yield strength support Poloxamer188(low peroxide, low 0.05-0.25 Wetting / dispersing aid free polygrade) Disodium edetate 0.02-0.05 Chelating agent pH regulator ym pH5.2-5.9 Pure water is completed to 100%. Continuous phase. Example 4 - Preservative-containing, low pH application. Component Quantity (%a / a) Function Clindamycinphosphate 1.20 Active ingredient Benzoyl peroxide (added as hydrosol) 3,10 Active ingredient, suspension phase Adapalene (D90 <10 µm) 0.15 Active ingredient, suspension phase 25Component Quantity (%a / a) Function Hydroxyethylcellulose 1,0-2,0 Primary hydrophilic polymer Xanthan gum 0.10-0.40 Suspension / yield strength support Poloxamer188 0.10 Wetting / dispersing aid Disodium edetate 0.05 Chelating agent Potassium sorbate 0.10-0.30 Preservative pH regulator ym pH4.8-5.4 Pure water is completed to 100%. Continuous phase. Example 5 - pH-independent acrylamide copolymer-based composition Component Quantity (%a / a) Function Clindamycinphosphate 1.20 Active ingredient Benzoyl peroxide (added as hydrosol) 3,10 Active ingredient, suspension phase Adapalene (D90 <10 µm) 0.15 Active ingredient, suspension phase Acrylamide / sodium acryloyldimethyltaurate is pH independent of 1.0-4.0. copolymer (via supply form; gelling / suspension system) sorbitanester-free, low free polyolgrad Sodium tissue 0.05-0.20 Wetting / dispersing aid Poloxamer124 0.05-0.20 Wetting / dispersion aid Disodium edetate 0.02-0.10 Chelating agent Sodium PCA 0.20-1.00 Moisture retention / tolerability pH regulator ym pH5.0-5.9 Pure water is completed to 100%. Continuous phase. Comparative Composition - Prior Art Trademark / Patent a reference derived from their statements, containing polyol which is not within the scope of the invention Component Quantity (%a / a) Function Clindamycinphosphate 1.20 Active ingredient 26Component Quantity (%a / a) Function Benzoyl peroxide (added as hydrosol) 3,10 Active ingredient, suspension phase Adapalene 0.15 Active ingredient, suspension phase Propylene glycol 5.00 Polyol / comparison variable Carbomer homopolymer approximately 1.75 Gelling agent Potassium hydroxide ym pH 5-6 Pure water is completed to 100%. Continuous phase. Comparative Development Program The effect of a low molecular weight hydroxylated solvent is preferable to that of the same active substance. propylene glycol in its composition and, where possible, in the same gelling system It is examined with a series in which the amount is varied as 0%, 0.5%, 2% and 5% (w / w). This series; hydroxyl solvent level and benzoyl peroxide dissolved pool and suspension sefraction, chemical stability, benzene formation, clindamycin phosphate stability, physical suspension To quantitatively determine the relationship between behavior, water activity, and microbial quality. It is used for the purpose of understanding the mechanism and formulation behavior at 0.5% to 5%. These are comparative tools and do not create the assumption of independent freedom of use. Monitored parameters: appearance; pH and storage length; pH shift; viscosity and flow tension; content homogeneity; benzoyl peroxide and adapalene particle size distribution; benzoyl Peroxide dissolved pool and suspension refraction; clindamycin phosphate, adapalene and benzoyl Decomposition products related to peroxide determinations; benzoic acid; benzene level; water activity; Sedimentation and phase separation; microbial limits and preservative efficacy; in vitro release. (IVRT) and invitropermeation (IVPT) when necessary. In benzoate-containing preservative systems, benzoic acid exhibits specific degradation properties compared to benzoyl peroxide. It is not used as an indicator; degradation assessment of benzoyl peroxide in these applications. Determination is carried out using relevant degradation products and other orthogonal analytical indicators. Stability conditions: 25°C / 60% relative humidity long-term; 40°C / 75% relative humidity accelerated; 50°C short-term stress is only for the purpose of quickly sequencing the formulations. Commercial room temperature. The stability claim is based on 25°C long-term data. Time points are preferably 0, 1, 3, 6, 9 and 12 months. Removal of low molecular weight hydroxylated solvent prevents the transfer of active ingredients into the water. because it can affect, in vitro release (IVRT) from the initial formulation screening set onwards 27. It is carried out in parallel with stability. Reference at the starting or early time point. Significant and uncorrectable emission loss according to comparator, Go / No-Go for formulation. is the criterion; in this case, long-term stability and patent topification cannot be continued. First, the adapalene particle size, wetting aid level, and polymer system are revised. If necessary, IVPT is used to confirm dermal permeation and tension. Lower benzene formation, conserved active substance amounts, acceptable impurities. profile, preserved rheology, acceptable microbial quality and acceptable in vitro uptake. Applications that display profiles are preferred. Application Method to Industry The compositions in question are mixing compounds used in the production of pharmaceutical semi-solid products. It can be produced with dispersion, hydration, pH adjustment, deaeration and filling equipment. Since the excipients used can be selected from among commonly available pharmaceutical raw materials. Expensive encapsulation, nano-carrier, or dual-compartment packaging technology is not required. The production method can be scaled up to suit both pilot and commercial scales. Cold chain distribution and storage costs if the need is eliminated or reduced An additional industrial advantage is provided. 28

Claims

1. It is a pharmaceutical composition suitable for topical application to acne; 1.0-1.5% (w / w) clindamycin phosphate, 2.5-3.5% (w / w) according to total composition weight. benzoylperoxide and 0.10-0.20% (w / w) adapalene; an aqueous continuous phase and a minimal hydrophilic It has a polymer network containing a gelling and / or suspension polymer; benzoyl peroxide and adapalene are suspended mainly as undissolved solid particles. in this case, clindamycin phosphate is dissolved in the aqueous continuous phase or is molecularly present. its presence in a dispersed state; and raw materials that exist as free molecules in the composition. and residues from auxiliary materials, regardless of their function or use The substances taken into account are propylene glycol, glycerol, ethylene glycol, diethylene glycol, dipropylene glycol, 1,3- butylene glycol, pentylene glycol, hexylene glycol, ethoxydiglycol, molecular weight greater than 1000 Da total of low polyethylene glycols, sorbitol, mannitol, xylitol, ethanol and isopropanol the amount should be less than 0.10%(w / w).

2. According to Claim 1, it is a pharmaceutical composition with the characteristic of; additionally, it contains free particles in its composition. including residues in molecular form, originating from raw materials or auxiliary materials, polymers that are not ecovalently bonded, have a molecular weight less than 1000 Da, and react with water. miscible, containing at least one free hydroxyl group and having a defined equilibrium at 25°C. In the solubility method, organic benzoyl peroxide has a solubility higher than 1 mg / g. the total amount of compounds not exceeding 0.10%(w / w), preferably 0.05%(w / w), preferably less than 0.02%(w / w).

3. According to Claim 1, it is a pharmaceutical composition and its characteristic is; additionally, it contains free particles in the composition. including residues in molecular form, originating from raw materials or auxiliary materials, polymers that are not recovalently bonded, have a molecular weight less than 1000 Da and contain at least one total amount of organic compounds containing free hydroxyl groups not exceeding 0.10% (w / w), preferably less than 0.05%(w / w), even more preferably less than 0.02%(w / w); as long as this total the amount of clindamycin phosphate, benzoyl peroxide and adapalene and their decomposition products, disodium edetate, calcium disodium edetate and sodium phytate, potassium hydroxide, Sodium hydroxide, citric acid, phosphoric acid, and potassium sorbate are not considered in Claim 1. the total amount in question, regardless of the function of use of the listed compounds It will be added to your account.

294. A pharmaceutical composition according to any of Claims 1-3, and its characteristics are as follows: In Claim 1 less than 0.05%(w / w) of the total amount of the listed compounds, preferably less than 0.02%(w / w). It is the fact that.

5. A pharmaceutical composition with the characteristics of any of the previous requirements; approximately 1.2% (w / w) clindamycin phosphate, approximately 3.1% (w / w) benzoyl peroxide and It contains approximately 0.15% (w / w) adapalene.

6. A pharmaceutical composition with the characteristic of propylene according to any of the previous requirements. water-soluble and free hydroxyl groups, including carbonate and dimethylisosorbit. total amount of non-organic cosolvanes not exceeding 0.10%(w / w), preferably 0.05% It is less than (a / a).

7. Pharmaceutical composition according to any of the previous requirements; its characteristic is production. it is prepared as a single composition that has been mixed beforehand and is a single In the primary packaging, separate active substance phases at the time of administration or use to the patient. It is the presence of elements without requiring combination.

8. A pharmaceutical composition with the characteristic of being water, according to any of the previous requirements. the amount should be in the range of 80-95% (w / w) of the total composition weight, preferably 85-93% (w / w). It is the fact that.

9. A pharmaceutical composition with a characteristic according to any of the preceding requirements; word the subject is gelling and / or suspension polymer hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose and pharmaceutically acceptable salts, xanthangam, sclerotiumgam, gellangam, carrageenans, pharmaceutically acceptable carbomers, cross-linked acrylic acid polymers, acrylate copolymers, polyacrylamide gelators, sulfonated acrylamide copolymers, acrylic polymers bonded to hydrophobic chains, modified new stars and It is the selection of combinations of these.

10. According to claim 9, the pharmaceutical composition has the characteristic of being; total gelling agent and / or suspension polymer content in the range of 0.20-6.0%(w / w), preferably 0.5-4.0%(w / w). It is the fact that. 3011. A pharmaceutical composition according to claim 9 or 10, and its characteristic is; hydroxyethylcellulose in the range of 0.8-2.5%(w / w) and xanthan gum in the range of 0.05-0.50%(w / w) together It is the presence of.

12. A pharmaceutical composition according to claim 9 or 10, and its characteristic is; hydroxypropylmethylcellulose in the range of 0.5-2.0%(w / w) and xanthan gum in the range of 0.05-0.30%(w / w). It is their being together.

13. A pharmaceutical composition according to claim 9 or 10, and having the characteristic of being accepted as a pharmaceutical. The available carbomer should be in the range of 0.5-2.5% (w / w).

14. According to claim 13, it is a pharmaceutical composition and its characteristic is the carbomer in question. It is a pharmaceutical grade in which benzene was not used in polymerization.

15. Pharmaceutical composition according to claim 9 or 10, and its characteristic is; the polymer in question. the network contains a pH-independent gelling system and this system is polyacrylamide gelling agents, sulfonated acrylamide copolymers, acrylics bonded to hydrophobic chains. It is the selection of polymers and modified starches.

16. According to claim 15, the pharmaceutical composition is characterized by being independent of the aforementioned H. gelling system is acrylamide / sodium acryloyldimethyltaurate copolymer and supply Calculated according to the form, 0.5-6.0%(a / a), preferably 1.0-4.0%(a / a) It is located within a certain range.

17. A pharmaceutical composition with the characteristics of any of the preceding requirements; additionally, at least one of the following selected from disodium edetate, calcium disodium edetate and sodium phytate. The chelating agent should be in the range of 0.005-0.50% (w / w), preferably 0.01-0.10% (w / w).

18. A pharmaceutical composition with the characteristics of any of the preceding requirements; additionally poloxamer124, poloxamer188, poloxamer407, polysorbate20 and sodium a selected wetting or dispersion aid of 0.01-1.0% (w / w), Ideally, it should contain between 0.02% and 0.5% (w / w).

19. According to claim 18, it is a pharmaceutical composition and its characteristic is; the wetting or dispersion aid free polyol and low molecular weight polyethylene glycol 31 residues, the total 0.10%(a / a) limit specified in Claim 1 in the final composition It is the selection of a pharmaceutical grade that will ensure it is not exceeded.

20. A pharmaceutical composition with the characteristics of any of the preceding requirements; Additionally, it contains potassium sorbate as a pharmaceutical preservative.

21. A pharmaceutical composition with the characteristics of any of the preceding requirements; Additionally, sodium PCA, betaine, sodium hyaluronate and urea are selected, with a molecular weight of 1000. At least one moisture-retaining compound that does not fall into the class of low-free hydroxyl compounds. It contains a tolerability aid.

22. Pharmaceutical composition according to any of the previous requirements and its characteristic is; pH The value should be in the range of 4.8-6.2, preferably 5.0-6.0, and even more preferably 5.2-5.

9.

23. Pharmaceutical composition according to any of claims 1-21, and its characteristic is; pH Its value should be in the range of 4.8-5.

5.

24. A pharmaceutical composition with the characteristic of being benzoyl according to any of the previous requirements. Peroxide suspension fraction should be at least 95%(w / w), preferably at least 98%(w / w), even more preferably It must be at least 99%(a / a).

25. According to claim 24, it is a pharmaceutical composition with the characteristic of being benzoyl peroxide suspension. fraction at least 99.5%(w / w), preferably at least 99.7%(w / w), even more preferably at least 99.9% It is (a / a).

26. A pharmaceutical composition with the characteristics of any of the preceding requirements; Keeping the sample at 25±2°C, dissolved in micelles or other colloidal structures. benzoyl peroxide fraction with a nominal molecular weight of 3 kDa has a cutoff value. Separation of benzoyl peroxide in the filtrate by a validated ultrafiltration membrane Adsorption and recovery confirmed by matrix-specific spike / recovery study. free dissolved benzoyl determined by a validated HPLC method The peroxide content should be less than 0.01% (w / w) of the total composition weight. 3227. A pharmaceutical composition according to any of the previous requirements, and its characteristic is benzoyl. The D90 value of peroxide particles is 100µm, preferably 50µm, and even more preferably 25µm. It should be smaller than µm.

28. A pharmaceutical composition with the characteristics of any of the preceding requirements; The D90 value of adapalene particles should be less than 50µm, preferably 20µm, and even more preferably 10µm. The size should be smaller than µm, preferably 5µm.

29. A pharmaceutical composition according to any of claims 1-28, with the characteristic of acne. It is intended for use in the treatment of vulgaris.

30. Regarding the preparation of a pharmaceutical composition according to any of the requirements 1-28. a method with the characteristic of; (a) at least one hydrophilic gelling agent and / or suspension aqueous polymer phase by dehydration or dispersion of polymer in water preparation, (b)hydrous benzoyl peroxide low molecular weight free hydroxyl groups compounds not added as wetting, dissolving or dispersing solvents by being added directly to the aqueous polymer phase or a part thereof under the conditions (c) wetting of the compounds in question by adapalene, suspension in the form of solid particles, unless added as a dissolving or dispersing solvent, water and / or aqueous solution (d) dispersion of clindamycin phosphate in the aqueous phase as solid particles in the polymer phase dissolution, (e) combining of phases and adjustment of pH value to the range of 4.8-6.2, (f) homogenization of the resulting composition, removal of air and a single primer including the packaging and filling steps and the final composition listed in Claim 1. the total amount of compounds is less than 0.10% (w / w).

31. The method according to claim 30 has the following characteristic; (a) step a chelating agent into the aqueous phase It is dissolved before the addition of benzoyl peroxide.

32. Method characteristic according to claim 30 or 31; benzoyl peroxide and adapalene Product temperature during the preparation of dispersions and the combining of phases The temperature should not exceed 35°C, preferably 30°C, or even better, 25°C.

33. Method characteristic according to any of the claims 30-32; starting benzoyl peroxide its raw material being hydrozoster benzoyl peroxide and the amount of raw material weighed, Final active benzoyl peroxide equivalent based on the active benzoyl peroxide content of 33 raw materials. It is about correcting it in a way that will achieve its goal.

34. Method characteristic according to any of the claims 30-33; benzoyl peroxide and / or Adapalene perfusion of low molecular weight free hydroxyl compounds, controlled conditions when not added as a dissolving or dispersing solvent It is prepared by high-shear mixing.

35. Method with a characteristic according to any of the 30-34 points; mixing, homogenization and / or the filling stages are carried out under a ert gas cover and come into contact with the product. Copper and copper alloys should not be used on surfaces. 34