Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents

Definitions

• the invention described here relates to the use of a substance belonging to the class of atypical retinoids for the topical treatment of acne.
• Acne is a multifunctional disorder which commonly occurs during adolescence and which sometimes heals spontaneously but more often takes a long time and requires specific topical or systemic treatments with chemical substances such as benzoyl peroxide, retinoids, antibiotics and anti-androgens.
• chemical substances such as benzoyl peroxide, retinoids, antibiotics and anti-androgens.
• benzoyl peroxide retinoids
• antibiotics and anti-androgens antibiotics and anti-androgens.
• side-effects such as reddening, dryness of the skin and allergic reactions.
• one of the fundamental problems in treating acne and other skin diseases is crossing the epidermal layer, which represents the natural physiological barrier to the ingress of the drugs. Indeed to obtain a local pharmacological effect, topical application is used by administering the active principle formulated in ointments, creams or gels, used as vehicles.
• Lecithin a phospholipid of natural origin, is used in certain cosmetic or pharmaceutical preparations as the principal component or as an emulsifier. Its function, apart from being structural, can be functional in terms of carrying the active principle into the skin. Indeed the chemical similarity between lecithin (phosphatidyl choline) and the lipid components of the cell membranes suggests that vehicles based on lecithin can be well tolerated by the body and at the same time increase the pharmacological action (Scartazzini and Luisi, 1988 J. Physiol. Chem. 91 , 823-833).
• acne (from the Greek akni: efflorescence) describes the follicular lesions which appear during adolescence and which are linked with seborrhoea and the formation of comedones. It is an extremely common disease which, to a variable degree, affects approximately 90% of adolescents, but only 10% of these require medical intervention and only 1% of the latter pose clinical problems which are difficult to solve.
• Acne is a chronic inflammation of the pilosebaceous apparatus which presents in various ways, as comedones, pustules, nodules, cysts and scars.
• comedones pustules
• nodules cysts and scars.
• the most common form is juvenile acne which appears at puberty and resolves itself spontaneously around the age of 25, even though it can appear later, recur and regress after 30 years of age (Kraning et al. 1979 J.
• comedones are follicles swollen with sebum, commonly called “whiteheads", when the follicular orifice is
• the papules are the inflammatory complication of the comedo and appear as reddened raised areas of various sizes. They last a few days and disappear without trace.
• Pustules are yellowish- coloured lesions, hemispherical in shape and pus-filled, which surmount the papules. They last two to three days and voided to the outside with scab formation.
• Nodules are large solid formations, often painful to pressure, produced by an inflammatory infiltrate. Cysts are large raised areas filled with pus, very painful to the touch, which remain unchanged for weeks and unlike the other acne lesions can easily turn into scars, these being the permanent consequences of acne which are unaesthetic and sometimes disfiguring.
• the main pathogenic factors involved in the etiopathogenesis of acne are: 1 ) sebaceous hypersecretion; 2) follicular hyperkeratosis; 3) bacterial colonisation of the follicles; 4) the onset of an inflammatory process.
• Follicular hyperkeratosis is a fundamental event for the development of the acne lesions and is due in part to the increased proliferation of the epidermis and partly to the delayed detachment of the comeocytes. The result is a thickening of the follicular wall obstructing the exit of the sebum, which then stagnates and forms comedones. Under these conditions Propionibacterium Acnes, an anaerobic bacterium, tends to develop and to proliferate (Strauss et al., 1974 J. Invest. Dermatol. 62, 321-325; Harris et al., 1983 J. Am. Acad. Dermatol. 8, 200-203), producing free fatty acids with irritant and comedogenic capability stimulating the immune response.
• inflammation is due to the passage of biologically active substances from the pilosebaceous duct to the dermis.
• the treatments available can be divided into keratolytic and bacteriostatic treatments if they relate to cell reconstruction and antibacterial action respectively.
• the therapeutic strategies depend on the severity of the disorder.
• Medicines for topical use are preferred for medium or moderate forms of acne.
• the most common creams are those based on benzoyl peroxide, which dries out the spots and blocks infection.
• retinoids comedolytic agents, which slow down the process of desquamation in order to reduce the number of comedones and microcomedones
• antibiotics with bactericidal activity which act by directly killing the forms of P. acnes, also having a slight indirect effect on comedogenesis
• combined therapy using both retinoids and topical antibiotics, for patients who suffer from severe forms of acne, with comedonic and inflammatory lesions at the same time.
• Retin-A also known as tretinoin
• tretinoin is an anticomedonic agent which is applied directly to the skin. Its action, in the form of a lotion or cream, is keratolytic, i.e. it restores the normal process of keratin formation and prevents the formation of comedones (blackheads).
• Tazarotene a synthetic product which interacts specifically with the receptors of vitamin A. As well as on acne, it is effective in the treatment of psoriasis; 2. Azelaic acid has produced alternative results in European studies and is characterised by a broad spectrum of dual action, both antimicrobial and keratinising; it is in fact also used in cases of cutaneous hyperpigmentation
• Adapalene a derivative of naphthoic acid with retinoidal activity. This is a modulator of cell differentiation with a keratinising effect, which is effective
• Differin ® is used for the topical treatment of acne vulgaris, where comedones, papules and pustules predominate.
• the international patent application WO03/011808 describes a new class of compounds defined as atypical retinoid acids which are described as having anti-tumoral use.
• the compounds described in this application include adamantyl methoxydiphenyl propenoic acid (ST1898). DESCRIPTION OF THE INVENTION
• the main object of the present invention relates to the discovery that adamantyl methoxydiphenyl propenoic acid has anti-acne activity in the animal model used as a reference for this disease.
• the main object of the present invention is therefore the use of adamantyl methoxydiphenyl propenoic acid for the preparation of a
• Another object of the present invention is also a pharmaceutical or cosmetic composition for topical treatment of acne containing adamantyl methoxydiphenyl propenoic acid, as the active ingredient, together with other excipients and/or pharmaceutically acceptable vehicles.
• pharmaceutically acceptable means approved by the pharmacopoeia (European, British or United States) for animal use and more particularly human use.
• excipients examples include glucose, lactose, sucrose, gelatin, amide, stearates, monostearates, palmitates, glycerol, water, ethanol, lipids, phospholipids, buffered agents such as sodium dehydrogenate phosphate, or ammonium salts, mixtures of these, etc.
• excipients or vehicles are described in "Remington's
• composition of the present invention can be formulated in the form of cream, ointment, gel, foam, spray solution or sustained-release patches.
• the composition of the present invention is preferably in gel form. More preferably the composition of the present invention is a lecithin gel, such as for example Epikuron 200TM, which is a purified soya lecithin, i.e. a waxy phosphatidyl choline purified from soya seeds by column chromatography for use in the pharmaceutical industry (purity greater than 92%).
• composition of the present invention preferably contains 0.1 mg of active principle per 100 mg of lecithin gel.
• the invention is illustrated by the following examples which are not limitative of the scope of the invention. DESCRIPTION OF THE DRAWING
• Figure 1 shows the effects topical treatment with ST1898 (Formulation 1 ) on the skin of rhino mice.
• This treatment had a very marked effect on the reduction in the number, dimensions and horny content of the utriculi/pseudocomedones, as well as on the morphology of the sebaceous glands, which became more atrophic (arrows in figure).
• the hyperplasia of the epidermis (B) compared with the untreated mice was also particularly clear (A).
• lecithin soya seed extract (Epikuron 200 TM)
• isopropyl palmitate ascorbic acid
• ammonium molybdate iodine crystals
• tetramethylammonium phosphate decolourising carbon and sodium dehydrogen phosphate.
• chloroform methylene chloride, methanol, ethanol, dimethylsulphoxide (DMSO) and an aqueous solution of ammonia (30%).
• the reference lipid POPC i-palmitoyl-Z-oleoyl-sn-glycero-S-phosphatidyl choline
• Avanti Polar Lipids Canada
• the active principle adamantyl methoxydiphenyl propenoic acid (ST1898) was synthesised and purified by Sigma-Tau (Pomezia, Rome). Gel preparation method The lecithin solution was prepared by dissolving lecithin in isopropyl palmitate (IPP), by magnetic agitation at 40-50 0 C, in a few minutes or a few hours depending on the percentage weight of lecithin. Every solvent-lecithin
• the gel was formed when the water was completely dispersed in the organic phase, a phenomenon generally dependent on the concentration of lecithin, on the magnetic agitation and of the nature of the solvent used. Under the conditions used in this study, the gelification of the lecithin/IPP solution took
• V H O (mL) mEP20o (g) X lSx W 0 _ _ ⁇ o V ' 760 ° Eq. 2
• V ⁇ 0 represents the volume of water to be added (in ml)
• m E p2oo is the
• UV-Vis spectrophotometry was used to characterise the retinoid ST1898 quantitatively both dissolved in the solvent DMSO and incorporated in the lecithin/IPP gel phase, using a diode array spectrophotometer (Agilent HP8452A), with a resolution of 2 nm, using 1 cm quartz cuvettes. Transferring
• the organogel containing the retinoid ST1898 to the cuvette required raising the temperature (approx. 6O 0 C), given the high viscosity of the material, followed by cooling to carry out the analysis.
• HPLC analysis
• HPLC analysis of retinoid ST1898 both dissolved in DMSO and incorporated in the gel phase was carried out with HPLC HP1050 apparatus (Agilent), provided with a UV-Vis diode array detector and HP ChemStation software.
• the procedure for the quantitative analysis of the drug involves isocratic elution (methanol/water, in the volume ratio 80/20, with 0.2% of TFA) on a Reverse Phase Nucleosyl C18 column, 3 ⁇ m (particle dimensions), 125 x 4 mm; flow 1.5 ml/min; injected volume equal to 5 ⁇ ⁇ (under these conditions a
• the rhino mouse (hr ⁇ hr ⁇ 1 ) is an allele of the hairless mouse and is an experimental animal model for non-inflammatory acne.
• a fault in the catagen phase results in a premature and irreversible hair loss at the age of 4 weeks.
• the follicle fails to reconstruct itself. Instead, the lower part of the original follicular unit develops into horn-producing cysts which become permanently situated in the deep dermis and enlarge as the animal ages. Meanwhile, the original pilary canals (upper part of the original follicular unit) transform into ampulliform cavities or utriculi.
• utriculi are filled with horny cells and sebum and progressively enlarge due to the production and accumulation of horny material. Histologically, they resemble typical retentional acneic lesions or comedones. However, they are not visible to the naked eye and can not be squeezed out between the fingers. As in human acne, the sebaceous glands progressively shrink as the utriculi form and enlarge. Finally, the skin of the rhino mouse appears sagging and redundant, due to a paucity of elastic fibers. Therefore, the skin of adult rhino mice is characterized by the utricoli that are derived from the infundibular zone of the original follicular units. These are histologically similar to retentional acne lesions, i. e.
• Rhino mice have, therefore, been used over the last 30 years in in vivo protocols aimed at testing the comedolytic activity of new drugs, topically and to a lesser extent istically administered, for the treatment of acne.
• Comedolytic effects of various anti-acne agents, in particular retinoids administered topically, on the rhino mouse skin were first reported in the 70 using qualitative histological methods which showed: 1) the transformation of part of the utriculi/comedones in short, narrow, non-hyperplastic pilary canals with well-developed sebaceous glands, 2) the complete involution of part of the utriculi, leaving long stretches of normal appearing epidermis, 3) an increase in epidermal thickness, 4) no effect on the deep dermal cysts.
• retinoids e. g. a ⁇ -trans- retinoic acid or adpalene
• the most widely used technique in the screening of topical comedolytic agents for evaluation and measurement of their comedolytic activity is quantitative histological image analysis of rhino mouse skin sections from a skin biopsy obtained at the end of a three week treatment period.
• Several microscopic measurements allow to calculate the following parameters: the total number of epidermal utriculi (comedones) per centimetre of stratum corneum length, the comedo profile which gives a measure of the morphological aspect of the comedo (i. e. ampulliform versus narrow), and the epidermal thickness.
• the parameters of the animal room were set as follows: temperature 22 ⁇ 2 0 C, relative humidity equal to 55 ⁇ 15%, air filters changed every 15-20 hours. The environmental conditions were monitored and the data were kept in the Animal Housing Archives.
• mice transferred the mice from the boxes to the cages at random. Each cage was then labelled with a card identifying the type of treatment (substance used, dose, route of administration and identification number of the animal).
• the animals were treated by the topical application to the back for 45 sec. of the compounds examined dosed using a 50 ⁇ l volume micropipette, once a day for 5 consecutive days per week, for a period of 3 weeks (at the Sigma-Tau laboratories).
• Biopsies were taken using 6 mm punches of the area treated, fixed in 10% buffered formalin and included in paraffin (fixing and passing through 70% ethanol at the
• the in vivo model used in this research project is the rhino mouse (hr rh hr rh ), which is allelic to the mouse without hair ( ⁇ /"/7/”) and represents an experimental animal model for non-inflammatory acne.
• This model has been used for over twenty years to evaluate the therapeutic efficacy, in particular comedolytic efficacy, of anti-acne compounds applied topically and also administered systemically.
• the rhino mice manifested various skin changes, including a defect in the catagenic phase of the hair follicle which involved the complete loss of the hair by the sixth week of life and the development of the so-called utriculi/pseudocomedones (C in Fig.
• ST1898 (Formulation 1 ) applied topically, had pharmacologically useful characteristics for treating acne, with a comedolytic and anti-inflammatory effect and leading to a reduction in the number of comedones. ST1898 therefore acted as a modulator of the cell differentiation processes of keratinisation and
• Example 5 Preparation of the Composition of ST1898 - Formulation 2 - Preparation of The ST1898 Formulate in the Gel Phase Formulations: ST1898 0.1 and 0.05 % in the vehicle.
• Vehicle carbomer 980, propylene glycol, poloxamer, disodium edentate, methyl hydroxybenzoate, phenoxyethanol, sodium hydroxide and purified water).
• Adapalene Differin gel ® was used as reference compound (0.1%).
• Example 6 Comedolvtic Action of ST1898 (Formulation 2) on Epidermal
• mice Charles River Italy S.p.A. for the Jackson Laboratory.
• Drinking water was supplied ad libitum. Each mouse was offered daily a complete pellet diet (GLP 4RF21 , Mucedola) throughout the study. The analytical certificates of animal food and water were retained at Sigma-Tau premises.
• mice 30 rhino (RHJ/LeJ) mice (Jackson Laboratory), 15 male and 15 female (6- 8 weeks of age) were subdivided in 6 mice/group.
• Two groups were treated with ST1898 (Formulation 2) (0.1% and 0.05% in the vehicle), a group with adapalene (Differin ® gel), used as reference compound (0.1%), a group with the vehicle (the same of the formulation of Differin ® gel: carbomer 980, propylene glycol, poloxamer, disodium edentate, methyl hydroxybenzoate, phenoxyethanol, sodium hydroxide and purified water).
• mice were sacrificed by cervical dislocation. Two skin punch biopsies (6 mm) were taken immediately after death from all sacrificed animals. The biopsies were formalin-fixed (10% buffered formalin solution) and paraffin-embedded. Post mortem examination
• Quantitative histological image analysis was evaluated as the total number of epidermal utriculi (comedones) per centimetre of stratum corneum length, the comedo profile, and the epidermal thickness. From one biopsy, three
• 3- ⁇ m thick skin sections were obtained at 150 ⁇ m intervals and were stained with hematoxylin-eosin. The second biopsy was kept stored for records.
• Assisted computer morphometric analysis of the stained skin sections was performed using a Zeiss KS300.3 system (parameters n. 1 , 3 and 4). For total length of the stratum corneum measurement a micrometric equipment was used. The following microscopic parameters were measured: 1) on each open epidermal utriculum/comedo the largest diameter or diameter taken at half depth (D) and diameter of the surface orifice (d), 2) length of the three sections, taken as total length of the stratum corneum,
• test item 3 epidermal thickness, calculated as S/L in Dm.
• mice During the treatment, the body weight of mice was recorded to control the healthy status of mice. No significative variation in body weight was found (table 2).
• the scant interfollicular epidermis of untreated and vehicle-treated mice comprised a single layer of basal cells, two to three layers of spinous cells and one layer of granular cells containing keratohyaline granules.
• the stratum corneum appeared thick and loosely organized, with a characteristic "basket wave" appearance.
• interfollicular epidermis comprised a single layer of basal cells, 3-6 layers of spinous cells and 3-5 layers of granular cells containing numerous, large keratohyaline granules. The stratum corneum was more compact, in particular in its lower portion.
• epidermal hyperplasia appeared more marked in the skin of adapalene-treated mice as compared to ST1898-treated mice.
• a mild dermal lymphocyte infiltrate was observed in all active compound-treated animals.
• ST1898 exerted a similar effect to that elicited by the reference compound, adapalene, on both comedo number and profile, when administered at the same concentration (0.1%).
• the effect of ST1898 was dose-related, being 0.05% ST1898 less effective than 0.1% ST1898 in reducing the number of comedones and in inducing epidermal hyperplasia.
• epidermal hyperplasia was significantly reduced following ST1898 0.1% topical treatment as compared with reference compound treatment, showing a possible advantage in using ST1898 over presently
• ST1898 (Formulation 2) was the same of Differin gel (carbomer 980, propylene glycol, poloxamer, disodium edentate, methyl hydroxybenzoate, phenoxyethanol, sodium hydroxide and purified water). *One mouse was excluded from the study before starting the treatment for the low body weight.

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