PL234378B1 - Emulsion composition of cefazolin with anti-psoriasis effect - Google Patents

Abstract

The subject of the application is an emulsion composition, in particular in the form of a cream with antipsoriasis activity, containing a therapeutically effective amount of cefazolin, oil phase ingredients and water phase ingredients, characterized by the fact that it contains: oil phase ingredients including: - liquid paraffin or white petrolatum, - stearyl ether polyoxyethylene (21) and - cetylstearyl alcohol; aqueous phase components including a buffering system providing the starting pH of the composition in the range of 6.1 to 8.7, optionally an additional amphiphilic non-ionic emulsifier and other water-soluble/miscible excipients, with water constituting from 50 to 80% by weight of the composition. The subject of the application is also a method of producing an emulsion composition.

Description

Description of the invention

Field of the Invention

The invention relates to an anti-psoriatic emulsion composition containing cefazolin. The cefazolin emulsion composition is in the form of a cream for use on the skin with excessive exfoliation and keratosis, especially on the skin with lesions characteristic of psoriasis, eczema and atopic dermatitis.

Background of the invention

Psoriasis is a chronic, inflammatory skin disease of unknown etiology, where genetic and immunological factors play an important role in the pathogenesis of which. Plaque psoriasis is characterized by neutrophil and lymphocyte infiltration and abnormal epidermal proliferation (M. Abe, Journal of Dermatology 2006, 2: 108-111). The disease is manifested by the appearance of extensive skin lesions in the form of lumps or raised lesions, peeling of the epidermis, and often accompanying itching.

Currently available treatments for psoriasis include external treatments, general treatments, physical treatments, and mixed treatments. The classic methods of external treatment include the use of exfoliating drugs, such as salicylic ointments or urea ointments and creams, as well as drugs that reduce the division of the epidermis - primarily anthralin (Cygnolina) and tar, and cytostatics. Corticosteroids, retinoids, and vitamin D3 analogues are a newer generation of topical anti-psoriasis medications. Systemic treatments include oral administration of retinoids, immunomodulatory drugs such as cyclosporin A or tacrolimus, and cytostatics such as methotrexate and hydroxyurea. A new approach to treating this disease and its complications offers the use of immunosuppressive biological drugs such as the monoclonal antibodies efalizumab and infliximab, alefacept and the recombinant etanercept receptor protein, indicated in psoriatic arthritis.

Some treatments prove ineffective or burdensome for patients. The administration of systemic drugs poses a risk of serious side effects. They cannot always be used due to comorbidities. These problems necessitate the use of the so-called classic methods of treating psoriasis in an alternating or intermittent manner, which may result in frequent relapses and a significant deterioration in the quality of life of patients with psoriasis (J. Szepietowski, Dermatologia Kliniczna 2009, 11 (3)).

Over the past decade, topical use of vitamin D3 analogues has become the first-line therapy in the routine treatment of psoriasis. Clinical trials have confirmed the efficacy and safety of tacalcitol in the treatment of psoriasis and the lack of systemic effect on calcium homeostasis at therapeutic doses (P.C.M. van de Kerkhof, British Journal of Dermatology 2002: 146, 414-422).

Since psoriasis is a persistent and recurrent disease, patients often require long-term treatment, preferably with a low cumulative toxicity potential. Optimal therapy should be effective over the long term without long-term side effects, and must be well tolerated and accepted by patients to ensure proper adherence to physicians' recommendations.

There is therefore still a need to find improved anti-psoriasis therapies that meet the above requirements.

In the patent application WO 2015/044762, screening studies have been described, which led to the identification of a substance that by specific binding and blocking the IL-15 specific receptor IL-15Ra and simultaneously blocking the common IL-15 and IL-2 subunits of the IL-2R3 receptor and IL-2R- / can effectively inhibit the biological activity of both of these cytokines.

Interleukin 15 (IL-15) is a pleiotropic cytokine that acts on cells of the immune system as well as a number of other cell types. Due to the broad spectrum of activity of IL-15, it is increasingly placed at the top of the pro-inflammatory cytokine cascade. Disruption of the mechanisms regulating the expression of IL-15 leading to its overproduction directly contributes to the development of inflammatory, autoimmune, infectious and neoplastic processes. IL-15 plays a key role in the etiology of psoriasis, inter alia (Villadsen L.S. et al., J. Clin. Invest. 112, 1571-80 (2003).

The significant role of IL-15 in the pathogenesis of this disorder suggests the possibility of a therapeutic intervention consisting in blocking the biological activity of this cytokine. The validity of this concept is confirmed by the tests carried out so far. Inhibition of the biological effects of IL-15 by the use of the soluble IL-15Ra receptor (Liew FY, McInnes IB, Ann. Rheum. Dis. 61 Supl. 2, ii100-2 (2002); Ruchatz H. et al., J Immunol. 160, 5664-60 (1998); Smith XG et al., J. Immunol. 165, 3444-50 (2000); Wei X. et al., J. Immunol. 167, 277-82 (2001). ), IL-2 / IL-15R3 receptor blocking antibodies (Morris JC, Proc. Natl. Acad. Sci. USA 103, 401-6 (2001); Tinubu SA et al., J. Immunol. 153, 4330-8 ( 1994), IL-15 blocking antibodies (Villadsen LS et al. J. Clin.

Invest. 112, 1571-80 (2003) or a mutant IL-15 molecule with competitive antagonist properties (Ferrari-Lacraz S. et al., J. Immunol. 173, 5818-26 (2004); Kim YS et al., J. Immunol 160, 5742-8 (1998)) resulted in an amelioration of the course of cytokine-dependent diseases. As a result of these experimental treatments, an amelioration of the course of psoriasis was observed in a mouse model of this disease (Villadsen L.S. et al. J. Clin. Invest. 112, 1571-80 (2003)). All the IL-15 blocking strategies used so far appear to be equally effective, but to date most of them are used only under experimental conditions.

As confirmed by in vitro studies, a substance that, in addition to a broad spectrum of bactericidal activity, is effective in blocking the biological response induced by both IL-15 and IL-2 is cefazolin (acid (6R, 7R) -7 - [[- 2-amino- 2-phenylacetyl] amino] -3-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic) - first generation cephalosporin with an established therapeutic position.

Cefazolin's biological activity has been demonstrated by in vitro studies that confirm its efficacy in inhibiting IL-15-induced cell proliferation and blocking IL-15-induced TNF-α and IL-17 production. The same effect was seen when the cells were stimulated by IL-2.

As a result, cefazolin can be used to inhibit the excessive cellular response induced by the action of both IL-15 and IL-2, by blocking the IL-15 specific receptor IL-15Ra and the common IL-2R3 and IL-2Ry receptors for both cytokines.

Despite its beneficial effects, the effective use of cefazolin in therapy is limited by the disadvantages of the poor absorption of cefazolin from the gastrointestinal tract. It penetrates well into the pleural cavity, the peritoneal cavity, synovial fluid, bile, bones, urine; does not penetrate into the cerebrospinal fluid. Currently available cefazolin preparations are intended for parenteral administration, i.m. or i.v.

For skin diseases such as psoriasis, topical administration of therapeutic formulations is usually more effective than oral administration, injection and other systemic modes of administration both in terms of bioavailability and avoiding side effects such as penetration of the active ingredient into the bloodstream.

The forms of medicaments used for topical application to the skin include ointments, creams, lotions, patches, compresses, powders, sprays and others. Ointments and creams are the most convenient dosage form for skin diseases such as psoriasis.

In connection with the above, attempts were made to develop cefazolin preparations with local action on the skin, which, apart from their therapeutic properties, would be characterized by high utility values.

Topical cefazolin preparations are the subject of only a few applications and patents which do not provide any specific data on the stability of the preparations. The small number of reports on this type of preparation is probably due to the difficulties in obtaining medicinal products that remain stable for longer periods of time required for pharmaceutical preparations, which results from the nature of cefazolin itself, namely the instability of substances in a water-containing environment, even at a temperature of about 4-5 ° C.

Studies on the stability of cefazolin in aqueous solutions of eye drops have been the subject of works published, among others, in J. Clin. Pharm. and Therapy (1998), 23, 41-47 and Acta Pol. Pharm., Vol. 69, No. 1.95-105 (2012).

J. Clin. Pharm. and Therapy, the concentrations of cefazoline sodium, pH and osmolarity of preparations of 1% aqueous eye drops solutions containing a preservative and no preservative, stored at 4 ° C and room temperature, were tested. The drops stored at 4 ° C were stable for 42 days, while the drops stored at room temperature were only stable for a few days, an increase in pH and osmolarity was observed.

Authors of Acta Pol. Pharm. tested the stability of 1% and 5% aqueous solutions of eye drops with cefazolin at temperatures of 4 ° C and 20 ° C, depending on the type of buffer used. Acetate buffers pH 4.5 and 4.7, phosphate buffer pH 7.5, sodium chloride solutions and glycerol were used. The stability of cefazolin in aqueous solutions depended mainly on pH and temperature, and was highest in acidic solutions.

PL 234 378 B1

The low stability of cefazolin in aqueous solutions means that eye drops are not commercially available, but can only be prepared immediately before administration by pharmacists in hospital ophthalmic departments.

Application CA 502542 A describes a method for producing an ointment with a broad-spectrum antibiotic comprising mixing a dispersant, lanolin, petroleum jelly, wax, mineral oil and an antibiotic in proportions such that the melting point of the ointment is from 33 to 44 ° C. The composition of an ointment comprising 1 to 10% dispersing agent, glycerol monoester and long chain fatty acid or cholesterol ester, 5 to 20% lanolin, 10 to 30% petroleum jelly, 5 to 20% wax selected from cerein, paraffin and bee waxes, 30 to 60% liquid paraffin and 0.1-10% antibiotic.

Patent description EP 0043 738 B1 relates to a topical composition with increased skin penetration, containing a) 0.01% to 35% of an active substance selected from among antibiotics, b) 0 to 70% ethanol or isopropanol, c) 0.01 to 99% a skin penetration enhancer composed of a suitable diol and a cell envelope disruptor selected from esters of myristic and lauric acids.

EP 0103911 A1 discloses a topical composition containing an emollient. The claims include an emulsion composition containing 9-89% petroleum jelly, 0.25-10% emulsifier (glyceryl monooleate, glyceryl monolinoleate or mixtures thereof), 10-90% water and 0.01-25% drug substance, e.g. an antibiotic. Example IV discloses that the composition may include cefazolin.

Patent EP 0 455 396 B1 relates to a method of obtaining an aqueous composition with balanced osmolarity, which is liquid at or below room temperature and takes the form of a gel at the temperature of the human body, intended for topical application, containing i.a. polyoxyalkylene block copolymer, surfactant, polyether and drug substance. The specification discloses that the drug substance is cefazolin.

US 5,409,917 A describes acne treatment compositions in the form of a cream containing a cephalosporin antibiotic, including cefazoline, and ethoxylated cetyl stearyl alcohol, alcohol and fatty acid ester, and an aqueous phase containing a water-miscible alcohol, e.g., ethanol, isopropanol, propylene glycol.

WO 01/01960 A1 discloses a composition in the form of e.g. an ointment containing a triglyceride, two surfactants, including one hydrophilic, and a triglyceride-soluble drug substance, the amounts of triglyceride and surfactants being selected such that a clear dispersion is formed when mixed with water.

The application WO 01/12155 A1 relates to a composition with increased absorption of a hydrophilic drug substance, e.g. cefazoline sodium, containing two surfactants, one of which is hydrophilic.

The application WO 2007/103555 relates to a composition with a pH of 3.0 to 7.4 intended for topical application to the skin, containing two penetrants acting synergistically, selected from, for example, short chain alkyl diols, C 10 -C 20 fatty acids and their esters, substituted and unsubstituted C4-C20 alcohols and the like, and a drug substance, e.g. cefazolin.

The application US 2013184242 A1 relates to a pharmaceutical composition intended, inter alia, to for topical application, with rheological properties which render it semi-solid at rest and liquid when applied under the action of shear forces. The composition comprises a pharmaceutical base containing 75 to 99% of a hydrophobic solvent, e.g. olive oil, rapeseed oil, soybean oil and the like and 1 to 25% fatty alcohol as a solidifying agent, and a biologically active substance, e.g. an antibiotic.

Application publication WO 2013/163734 A1 describes a non-aqueous, non-exfoliating topical formulation containing an organic solvent that readily penetrates into tissues, e.g. C1-C10 alkyl sulfoxide, an organic cosolvent, e.g. glycol, polyglycol, alcohol, a film former and a drug substance, e.g. . an antibiotic, incl. cefazolin.

For the preparation of creams, water-in-oil or oil-in-water emulsion bases are most often used, consisting of a hydrocarbon or fat part, water and an emulsifier, enabling the preparation of a suitable type of emulsion and its stabilization. Typical vehicles contain fat phase ingredients such as petroleum jelly, liquid paraffin and / or liquid triglyceride mixture oils emulsified in an aqueous phase containing water-soluble substances with buffering, chelating and preservative functions. Emulsions, as a rule, also contain

These substances provide skin moisturization, facilitate penetration and absorption, have skin softening properties and antioxidants, as well as provide the emulsion with the proper viscosity and stabilize the emulsion system.

Topical preparations for the treatment of psoriasis, in addition to the appropriate proven pharmacological activity and safe application to the skin, for example the scalp of the patient, should also be sufficiently stable under the usual conditions of storage and use of the drug. It is also important that the preparations, especially in the form of a liquid emulsion or a semi-solid cream, have the appropriate appearance and handling properties, are easy to apply, do not stick to the hair and have an optimal consistency that does not allow them to flow easily.

A significant problem in the preparation of this type of preparation is physical and chemical stability, because emulsions are systems sensitive to temperature and mechanical factors. Even slight changes in the mutual proportions of ingredients or the addition of an ingredient not compatible with the others may cause destruction of the emulsion structure, manifested by its delamination or change in consistency at the stage of preparation of the formulation or its storage.

Attempts to prepare a stable cefazoline emulsion by the inventors of the present invention confirmed the above-described formulation problems related to the instability of substances in an aqueous environment. Despite attempts to use the various buffering systems described in Example 1, it has been found that most systems show a rapid yellowing of the aqueous phase containing cefazolin, indicative of degradation of the substance.

The problems with the instability of cefazolin prompted the present inventors to attempt to modify the composition of the emulsion base by appropriate selection of oil components, emulsifier and buffering system. One of the directions of pre-formulation work was the development of emulsions containing a non-ionic emulsifier - polyoxyethylene stearyl alcohol ether containing 21 ethylene oxide units (INCI Steareth-21), often used in the production of cosmetic oil-in-water emulsions. Although emulsions with this component were physically stable, they did not meet the basic criterion required from medicinal products, which is stability over longer periods of storage at room temperature.

When the inventors of the present invention have obtained promising results by combining a suitable buffering system with a simple oil phase composition including liquid paraffin or petroleum jelly, a hydrocarbon alcohol and a non-ionic emulsifier, it may be considered unexpected in the light of the prior art.

The use of a new approach in technological work on the combination of these known ingredients allows for the production of a stable emulsion of appropriate consistency and utility values, maintaining stability at least at temperatures of 4-5 ° C.

Disclosure of the Invention

The present invention is based on an emulsion composition with anti-psoriatic action comprising a therapeutically effective amount of cefazolin, oil phase ingredients and water phase ingredients, characterized in that (i) the oil phase ingredients include:

- liquid paraffin or white petroleum jelly,

- polyoxyethylene (21) stearyl ether, i

- cetyl stearyl alcohol;

(ii) water phase ingredients including a buffering system that provides a starting pH of the composition in the range of 5 to 9, particularly preferably 6-8;

(iii) optionally an additional amphiphilic non-ionic emulsifier;

and other water-soluble / miscible excipients, with water constituting from 50 to 80% by weight of the composition.

In a preferred embodiment, the composition comprises an additional non-ionic emulsifier which is a polyoxypropylene glycol-polyoxyethylene glycol condensation polymer.

The water phase ingredients of the composition include buffering substances, disodium phosphate dodecahydrate and sodium hydrogen phosphate dihydrate, or trometamol (TRIS) and boric acid.

The remaining ingredients of the composition include an organic solvent selected from the group of alcohols, diols and triols, preferably ethanol, isopropanol, propylene glycol or glycerin; phenoxyethanol and urea.

The emulsion composition is a cream containing more than 50% by weight of water, preferably about 55 to 65% by weight of water.

Alternatively, the composition is in the form of a lotion containing about 70 to 75% water.

PL 234 378 B1

Detailed description of the invention

During the pre-formulation work on the development of cefazolin emulsions, it was found that the factors significantly affecting the physicochemical stability of the emulsion are not only the composition of the emulsion base, affecting the dispersion of the oil phase in water, i.e. the size of the oil phase particles, but also the pH of the water phase and the method of emulsion preparation.

In the solution according to the invention, obtaining physically stable emulsions of appropriate consistency is possible thanks to the use of an oil phase containing liquid paraffin or petroleum jelly, cetyl stearyl alcohol and polyoxyethylene (21) stearyl ether as a non-ionic emulsifier.

Liquid paraffin, which is a mixture of liquid hydrocarbons, is a typical component of emulsion preparations used in pharmacy and cosmetics, due to the property of creating an occlusive barrier on the skin surface, which inhibits the loss of water to the environment, preventing its excessive drying. According to the invention, the liquid paraffin or white petroleum jelly constitutes from 4.0 to 20.0% by weight. the total weight of the composition.

Stearyl alcohol etherified with 21 moles of ethylene oxide obtained by condensing a mixture of stearyl alcohol with 20 moles of ethylene oxide (INCI: Steareth-21) is available, for example, under the trademark Brij ™ S721. It has the characteristics of a non-ionic emulsifier with a high hydrophilic-lipophilic balance (HLB 16), resulting from the combination of the lipophilic properties of stearyl alcohol with a unique distribution of ethylene oxide blocks of different chain lengths. It can be used in combinations with other ingredients over a wide pH range as a liquid surface tension reducing, dispersing and emulsifying substance.

The optimal amount of nonionic surfactant in the composition according to the invention is from 3 to 10% by weight, preferably from 7 to 9% by weight, based on the total weight of the composition.

Cetyl stearyl alcohol is a mixture of solid aliphatic alcohols consisting mainly of stearyl (C18H38O) and cetyl (C16H34O) alcohol, possibly with a minor addition of other alcohols, for example myristyl, and has the properties of an emollient, emulsifier and viscosity enhancing agent. According to the invention, it is from 2.0 to 10.0 wt.%. the total weight of the composition.

The selection of an appropriate buffering system plays a key role in cefazolin emulsion compositions. It has been found that the best results for the stability of the compositions according to the invention are obtained when using a phosphate buffer (approx. PH 6.15) and TRIS (trometamol) / boric acid (approx. PH 8.7) buffer.

The amounts of the remaining ingredients of the composition can be selected on the basis of the knowledge and experience of a skilled pharmacy. Suitable excipients are described, for example, in the Handbook of Pharmaceutical Excipients, edited by R.C. Rowe, P.J. Sheskey, S.C. Owen, pub. 5th, 2006, American Pharmaceutical Association Washington and The Pharmaceutical Press London.

In addition to the buffering substances, the aqueous phase may also contain other water-soluble auxiliaries known from pharmaceutical practice, such as phenoxyethanol and urea.

Phenoxyethanol preservative provides effective microbiological protection to the emulsion composition of the invention. Due to the high water content in the composition, it can be used in an amount of at least 0.75%, preferably 1.0% by weight. the total weight of the composition. This quantity meets the criteria of monograph 5.1.3 Ph Eur in the declared content range. The effectiveness of the amount of preservative used is confirmed by tests carried out in accordance with the methodology recommended in the European Pharmacopoeia (Ph Eur.). The selected amount of preservative does not affect the stability of the emulsion.

Urea, carbonic acid diamide, a component of the skin's natural moisturizing factor, is known for its antibacterial and antipruritic properties. It has anti-inflammatory effects resulting from antiproliferative and anti-granulating activity. Urea is traditionally used in cosmetic preparations as a humectant and has antiseptic and exfoliating properties. In higher concentrations, urea softens the skin and increases its permeability, which allows other active ingredients to penetrate deep into the skin. It is also used as an exfoliating ingredient. Due to the fact that urea binds water, it becomes less accessible to microorganisms, and therefore cosmetic preparations with urea may contain less preservatives. The amount of urea in the emulsion composition is from 3.0 to 7.0% by weight, preferably 5% by weight, based on the total weight of the composition.

The emulsion composition according to the invention preferably also comprises a water-miscible organic solvent selected from the group of alcohols, diols and triols, which is preferably ethanol, isopropanol, propylene glycol or glycerin. Especially preferred is propylene glycol, the role of which in the emulsion composition is to retain moisture and moisturize as well as to facilitate the absorption of the active ingredient. Its content in the composition may vary from 2.0 to 10.0%.

PL 234 378 Β1

Content (wt%)

4.0-20.0

3.0-10.0

2.0-10.0

2.0-10.0

0.0-1.0

3.0-7.0 to pH 5.0-9.0 100%

In one embodiment of the invention, the anti-psoriatic emulsion composition comprises 2 g or 5 g of cefazoline sodium, and the following excipients, by weight percent, per 100 g of the composition:

Ingredient

Liquid paraffin

Polyoxyethylene Stearyl Ether (21)

Cetyl stearyl alcohol Organic solvent Phenoxyethanol Urea

Buffering system

Water in addition to

The emulsion composition in this embodiment is prepared in a manner known from pharmaceutical practice by preparing an aqueous phase containing water-soluble excipients (preservative, buffering substances) and heating it to a temperature of 70-80 ° C. Then, after thorough mixing and heating to 65-75 ° C, the previously prepared oil phase is added. The resulting system is mixed, cooled, and then homogenized to form the correct emulsion structure, followed by continued cooling and successively introducing an organic solvent selected from the group of alcohols, diols and triols, and finally the active ingredient cefazoline sodium dissolved in a second part of water. The system is homogenized to obtain a homogeneous distribution of the active ingredient. After cooling down to room temperature, the product is dispensed and packed into individual packages.

Surprisingly, however, it turned out that the addition of an additional non-ionic emulsifier with an amphiphilic structure to the emulsion composition and the use of a different technology for the production of the emulsion not only allows obtaining physically stable emulsions, but also prevents too rapid decomposition of cefazoline, which is naturally unstable during the storage of preparations.

This additional emulsifier in the composition according to the invention is a polyoxypropylene glycol-polyoxyethylene glycol condensation polymer, preferably a polymer under the trade name Poloxamer 188. Due to its amphiphilic structure, this polymer is well soluble in water, increases the miscibility of substances with different hydrophobicity and has good properties. surfactants.

In this embodiment of the invention, the anti-psoriatic emulsion composition comprises 2 g or 5 g of cefazoline sodium, and the following excipients, by weight percent, per 100 g of the composition:

Ingredient Phase Content (wt%) Liquid paraffin 10.0-20.0 Polyoxyethylene Stearyl Ether (21) (ABOUT 5.0-10.0 Cetyl stearyl alcohol 2.0-6.0 Cefazolin 2.0-5.0 Organic solvent (2) 4.0-7.0 Buffering system to pH 5.0-9.0 Polymer of polyoxypropylene glycol with polyoxyethylene glycol (3) 1.0-2.0 Urea 3.0-7.0 Phenoxyethanol 0.0-1.0 Water, in addition to 100%

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The addition of an additional emulsifier makes it possible to use a different method of preparing emulsions, in which the active substance is introduced into the composition not at the end of the emulsification process, but by emulsifying the first aqueous phase containing it, containing the buffer system (2) and the oil phase (1), and then bringing the active ingredient to the formulation. emulsifying therewith the second aqueous phase containing the additional emulsifier (3) and optionally the remaining water-soluble / miscible excipients.

The emulsion composition in this embodiment is prepared as follows:

the first aqueous phase (2) containing water-soluble auxiliaries (organic solvent selected from the group of alcohols, diols and triols, components of the buffer system) is heated with stirring to a temperature of 70-80 ° C, at a temperature of about 70 ° C, the prepared oil phase (1) is mixed and cooled to 50-60 ° C, the second aqueous phase (3) is added with stirring, containing additional amphiphilic non-ionic emulsifier and optionally other auxiliary substances soluble / miscible with water, system the product is homogenized while maintaining the temperature of about 50 ° C until the active ingredient is uniformly dispersed, the product is cooled to room temperature, dispensed and packed in unit packages.

The emulsification process in this embodiment of the invention gives it a "double" emulsion structure. Thanks to the use of an appropriate buffering system and modified emulsion production technology, the pH-sensitive active substance is protected against degradation by water by the presence of buffering substances and the surrounding oil phase.

The cefazoline emulsion composition of the invention may be in the form of a lotion or cream. The developed composition of the emulsion composition allows to obtain the desired form of preparation, from liquid to semi-solid, without excessive interference in the composition and proportions of the components of the composition, and consists in the use of various amounts of water, which is compensated by the components of the oil phase, without compromising the stability and physicochemical properties of the emulsion.

The lotion emulsion composition contains about 70 to 75% by weight of water.

The cream emulsion composition comprises about 55 to 65% by weight of water.

A particularly preferred cream composition is as follows: Ingredient

Liquid paraffin

Polyoxyethylene Stearyl Ether (21)

Cetyl stearyl alcohol

Propylene glycol

TRIS buffer / boric acid

Trometamol

Boric acid

Water I.

Poloxamer 188

Urea

Water

Content (wt%)

14.0

8.0

8.0

2.4

0.042

0.02

5.6

1.5

5.0

Ad. 100%

The stability of the emulsion compositions of the invention was tested at 5 ° C and 25 ° C / 60% RH. Emulsions show good stability at 5 ° C, while at higher temperatures decomposition of the active ingredient by up to 50% is observed already 5 one month after preparation of the emulsion.

The combination of the therapeutic activity of the pharmacologically active substance of cefazolin with the soothing, moisturizing and exfoliating action provided by the base composition of a cream or lotion applied to the lesions affected by the disease provides the beneficial anti-psoriatic effect of the compositions of the invention.

The emulsion composition according to the invention can be effectively used in the treatment of skin diseases caused by excessive cell proliferation, such as psoriasis vulgaris, guttate psoriasis, erythrodermic psoriasis, arthritic psoriasis, chronic psoriasis and other forms of the disease.

The following examples illustrate the invention.

Examples

Example 1. Selection of the buffering system

In order to determine the optimal pH of the emulsion preparation, standard aqueous solutions of cefazolin sodium (2% by weight) were prepared with the following buffering systems:

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l. TRIS / boric acid

Composition mg / rn! pH Trometamol 0.42 8.7 Boric acid 0.2

2. Phosphate-citrate

Composition mg / ml pH At ₂ HPO ₄ 7 HzO 22.08 7.19 ¹⁰ Citric acid 1,855

3. Phosphate

Composition mg / ml pH NaH _with PO ₄ HzO 1.6 6.15 twenty On ₂ HPO ₄ 0.25 4. HEPES Composition mg / ml PH HEPES 238 25 7.43 NaOH until the pH is about 7.4

Due to the rapidly progressing degradation of the active ingredient in the citrate-phosphate buffer and the HEPES buffer, visually observed as a yellowing of the solution, TRIS / boric acid and phosphate acid buffers were selected for further pre-formulation work.

Example 2. Emulsion with phosphate buffer

Emulsion preparations containing 2% (CF 2%) or 5% (CF 5%) of cefazolin sodium with phosphate buffer for stability tests were prepared, with the following compositions:

CF 2%

No. Ingredient Amount per 100 g [g] 1 White petroleum jelly 4 2 Cetostearyl alcohol 3 3 BRIJ S721 3 4 Urea 5 5 NaH ₂ PO ₄ H ₂ O 0.16

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6 On ₂ HPO ₄ 0.025 7 Phenoxyethanol 1 8 Water I + II 71.815 (56.815 + 15) 9 Propylene glycol 10 10 Cefazolin 2 SUM 100

CF 5%

No. Ingredient Amount per 100 g [g] 1 White petroleum jelly 4 2 Cetostearyl alcohol 3 3 BRD S721 3 4 Urea 5 5 NaH ₂ PO ₄ H ₂ O 0.16 6 On ₂ HPO ₄ 0.025 7 Phenoxyethanol 1 8 Water I + II 68.815 (53.815 + 15) 9 Propylene glycol 10 10 Cefazolin 5 SUM 100

Manufacturing process

Preparation of the water phase

Ingredients 4, 5, 6, 7, 9 and water 8 (batch I) were charged to the reactor and stirred until dissolved while heating the entire solution. It was stirred with an anchor stirrer at a rotation speed of 40 rpm until a temperature of 70 ° C was obtained.

Preparation of the oil phase

Ingredients 1, 2, 3 are added to a glass beaker and mixed until dissolved while heating the entire solution. Stirred periodically until a temperature of 70 ° C was reached.

Preparation of cefazolin solution

Water 8 (portion II) was introduced into a glass beaker placed on a magnetic stirrer, and then cefazoline sodium (10) was added with stirring and stirred at a rotation speed of 500 ± 100 rpm until complete dissolution.

Connecting phases

The oil phase was introduced into the water phase reactor with the agitator running. The contents of the reactor were stirred at 70 ° C for 20 minutes at a rotation speed of 40 rpm.

After the two phases were mixed, the mixture was cooled at low speed. At a temperature of about 60 ° C, the rotational speed of the agitator was reduced and the substrate homogenization was started at the rotational speed of the homogenizer 13,500 rpm and the anchor agitator 30 rpm for 15 minutes. After the allotted homogenization time had elapsed, cooling of the mixture was continued

PL 234 378 Β1 until the temperature is 40 ° C. Then propylene glycol (9) was introduced to the substrate and mixed for 5 minutes at the rotational speed of 40 rpm.

Introducing the active substance solution

A solution of cefazoline sodium (10) was added to the medium. Stirring was carried out for 10 minutes at a rotation speed of the homogenizer of 13,500 rpm and an anchor stirrer of 30 rpm, maintaining the temperature at about 40 ° C.

Dosage

After the required time of homogenization, the homogenizer was turned off and the emulsion was cooled to the temperature of approx. 30 ° C. Cream for aluminum tubes was dispensed.

Emulsion stability studies

The emulsion compositions of Example 1 were selected for stability studies.

Stability test method

The stability of the emulsion was assessed by determining the content of the active ingredient of cefazolin in the cream at two temperatures, 5 ° C and 25 ° C / 60% RH, and the pH of the emulsion after 1 month of storage at the same temperatures.

Content marking:

The content was determined by high performance liquid chromatography (HPLC) using the mixture of acetonitrile / 0.1% formic acid (45:55 v / v) as the mobile phase and a Waters chromatographic column with a length of 250 mm and an internal diameter of 4.6 mm and filling granulation 5 μΠΊ. In order to isolate the active ingredient, the emulsion samples were extracted using a mixture of acetonitrile and water in a volume ratio of 3: 2 (v / v) as the extractant, with an extraction time of 30 min (sonication).

Despite the repeatability of the method, the cefazolin content in the initial emulsion was not achieved at the declared level, i.e. 20 mg / g and 50 mg / g. In the chromatogram of the test sample, an increase in the additional peak (impurity) was observed in relation to the additional peak in the chromatogram of the standard solution. There was also observed a decrease of the cefazolin surface area in the standard solution stored in the refrigerator (temperature + 5 ° C) for 48 hours by 30% and in the autosampler at the temperature of 25 ° C within 48 hours by 60%.

Test results for two series of emulsions (2% and 5%): immediately after making the emulsion and after 1, 3 and 6 (7) months of storage at 5 ° C / 60% RH and 1 month of storage at 25 ° C / 60% RH are shown in the tables.

Temp. 5 ° C

Cefazolin content [mg / g] 1 2 3 4 5 SERIES Theoretical compactness Time "0" 1 month 3 month 7 months CF-2 twenty 15.88 - 15.83 13.13 CF-5 50 39.29 43.6 38.76 27.95

Temp. 25 ° C

Cefazolin content [mg / g] 1 2 3 SERIES Theoretical compactness Time "0" 1 month CF-2 twenty 15.88 7.15 CF-5 50 39.29 17.18

PL 234 378 Β1

The content of active substance immediately after the preparation of the emulsion composition, determined by HPLC, is within the range of 75-80% of the declared content. After a month of storing the emulsion at 25 ° C, very clear drops in the content of the active substance are observed (to the level below 50% of the initial value). This is accompanied by a clear yellowing of the cream.

The samples stored at 5 ° C are stable for 3-6 months.

Example 3. Emulsion with TRIS / boric acid buffer

In order to verify the suitability of the TRIS / boric acid buffer for the preparation of the emulsion, 5 test A-E preparations with modified composition and technological process were made. A ready-made buffer solution was used, added in appropriate proportions to the composition:

BUFFER mg / ml Trometamol (TRIS) 0.42 Boric acid 0.2

CREAM A

Ingredient Amount per 100 g [g] Phase Liquid paraffin 14 Cetostearyl alcohol 8 (1) Brij S721 8 Propylene glycol 2.4 TRIS buffer solution / boric acid 5.6 (2) Cefazolin 2 Water 55 Urea 5 Gu

KREMB

Ingredient Amount per 100 g [g] Phase Liquid paraffin 14 (1) Cetostearyl alcohol 8 Brij S721 8 TRIS buffer solution / boric acid 8 (2) Cefazolin 2 Water 55 (3) Urea 5

PL 234 378 Β1

KREMC

Ingredient Amount per 100 g [g] Phase Liquid paraffin 14 (1) Cetostearyl alcohol 8 Brij S721 8 Propylene glycol 8 (2) Cefazolin 2 Water 55 (3) Urea 5

KREMD

Ingredient Amount per 100 g [g] Phase Liquid paraffin 14 Cetostearyl alcohol 8 (1) Brij S721 8 Propylene glycol 2.4 TRIS buffer solution / boric acid 5.6 (2) Cefazolin 2 Water 53.5 Poloxamer 188 1.5 (3) Urea 5

PL 234 378 Β1

CREAM E

Ingredient Amount per 100 g [g] Phase Liquid paraffin 14 (1) Cetostearyl alcohol 8 Brij S721 8 Propylene glycol 8 (2) Cefazolin 2 Water 55 (3) Poloxamer 188 1.5 Urea 5

In series A, B and C, the influence of the buffer solution, glycol and buffer with propylene glycol on the stability of the active ingredient of cefazolin was investigated. In series D and E, an additional emulsifier Poloxamer 188 was introduced into the water phase (3). The composition of emulsion preparations is presented in the summary table.

Ingredient AND B c D E. Liquid paraffin X X X X X Cetyl stearyl alcohol X X X X X Brij S721 X X X X X Propylene glycol X —- X X X Cefazolin X X X X X TRIS buffer solution / boric acid X X X --- Water X X X X X Polosamer 188 X X Urea X X X X X

Manufacturing process

Preparation of the oil phase (1)

The ingredients of phase (1), liquid paraffin, Brij S721 and cetyl stearyl alcohol, were melted by mixing with an anchor mechanical stirrer and heating to 70-75 ° C.

Preparation of the water phase (2)

Components of phase (2), cefazolin and propylene glycol, were dissolved in an aqueous buffer solution by heating in a beaker on a magnetic stirrer to 70 ° C. In series C and E, the buffer solution was replaced with propylene glycol.

PL 234 378 Β1

Preparation of the water phase (3)

Ingredients of phase (3), urea and Poloxamer 188 (if present), were dissolved in water in a beaker on a magnetic stirrer by heating to 50 ° C.

Connecting phases

Phases (1) and (2) were mixed with an anchor mechanical stirrer and homogenized for 10 minutes at the rotational speed of the homogenizer in the range of approx. 13,500 rpm, maintaining the temperature at approx. 70 ° C. It was cooled to 50-60 ° C and phase (3) was introduced, agitated with an anchor mechanical stirrer and homogenized for 10 min at a rotation speed of the homogenizer of approx. 9500 rpm, keeping the temperature approx. 50 ° C. It was cooled to 30-40 ° C and dispensed into PE containers.

The cefazolin content and the pH of the emulsion after 1 month of storage are presented in the tables.

Cefazolin content [mg / g] 1 2 SERIES 1 month at 5 ° C 1 month at 25 ° C AND 14.35 5.43 B 11.72 5.08 C. 15.44 5.15 D 19.56 5.63 E. 13.68 4.82

Claims (11)

Patent claims CLAIMS 1. An anti-psoriatic emulsion composition comprising a therapeutically effective amount of cefazolin, oil phase ingredients and water phase ingredients, characterized in that (i) the oil phase ingredients include: - liquid paraffin or white petroleum jelly, - polyoxyethylene (21) stearyl ether, i - cetyl stearyl alcohol; (ii) water phase ingredients including a buffering system that provides a starting pH of the composition in the range of 5.0 to 9.0, preferably 6.0-8.0; (iii) optionally an additional amphiphilic non-ionic emulsifier; and other water-soluble / miscible excipients, with water constituting from 50 to 80% by weight of the composition. 2. The emulsion composition according to claim 1 The method of claim 1, wherein the buffering system comprises disodium phosphate dodecahydrate and sodium hydrogen phosphate dihydrate. 3. The emulsion composition according to claim 1 The method of claim 1, wherein the buffering system comprises trometamol (TRIS) and boric acid. 4. The emulsion composition according to claim 1 The water-soluble / miscible excipients of claim 1, wherein the water-soluble / miscible excipients include an organic solvent selected from the group of alcohols, diols and triols and / or phenoxyethanol and / or urea. 5. The emulsion composition according to claim 1 The method of claim 4, wherein the organic solvent is ethanol, isopropanol, propylene glycol or glycerin. 6. The emulsion composition according to claim 1 5. The process of claim 5, wherein the organic solvent is propylene glycol. PL 234 378 Β1 7. An emulsion composition according to any one of claims 1-6, characterized in that it is in the form of a cream containing from about 55 to 65 wt. water. 8. The emulsion composition according to claim 1 A cream according to claim 7, characterized in that it is in the form of a cream containing the following excipients in% by weight, based on the total weight of the composition: Ingredient Content (wt%) Liquid paraffin 4.0-20.0 Polyoxyethylene Stearyl Ether (21) Cetyl stearyl alcohol 3.0-10.0 2.0-10.0 Organic solvent 2.0-10.0 Phenoxyethanol Urea 0.0-1.0 3.0-7.0 Buffering system to pH 6.0-8.0 Water in addition to 100 9. The emulsion composition according to claim 1 A cream according to claim 7, characterized in that it is in the form of a cream containing the following excipients in% by weight, based on the total weight of the composition: Ingredient Phase Content (wt%) Liquid paraffin Polyoxyethylene Stearyl Ether (21) Cetyl stearyl alcohol (1) 10.0-20.0 5.0-10.0 2.0-6.0 Cefazolin Organic solvent Buffering system (2) 2.0-5.0 4.0-7.0 to pH 6.0 - 8.0 Polymer of polyoxypropylene glycol with polyoxyethylene glycol Urea Phenoxyethanol Water, in addition to (3) 1.0-2.0 3.0-7.0 0.0-1.0 100% Process for the preparation of an emulsion composition according to claim 9, characterized in that the first aqueous phase (2) containing the water-soluble auxiliaries (an organic solvent selected from the group of alcohols, diols and triols, components of the buffer system) is heated to 70 ° C with stirring. -80 ° C, at a temperature of about 70 ° C, the previously prepared oil phase (1) is added, the whole is mixed and cooled to 50-60 ° C, PL 234 378 Β1, while stirring, the second aqueous phase (3) containing additional amphiphilic non-ionic emulsifier and optionally other water-soluble / miscible excipients is introduced, the system is homogenized while maintaining the temperature of about 50 ° C until the active ingredient is homogeneously dispersed, the product cooled to room temperature, dispensed and packed in unit packages. 11. An emulsion composition obtained by the method of claim 1 The composition of claim 10, characterized in that it contains the following excipients in% by weight, based on the total weight of the composition: Ingredient The content (wt.%) Liquid paraffin 14.0 Polyoxyethylene Stearyl Ether (21) 8.0 Cetyl stearyl alcohol 8.0 Propylene glycol 2.4 TRIS buffer / boric acid Trometamol 0.042 Boric acid 0.02 Wodal 5.6 Poloxamer 188 1.5 Urea 5.0 Water Ad. 100%