FI56931B - FOERFARANDE FOER FRAMSTAELLNING AV ETT THERAPEUTIC ACTIVE STABILT TRETINOINGELPREPARAT UR VILKET TRETINOINET LAETT FRIGOERES OCH ABSORBERAS I HUDEN - Google Patents

Description

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Ma lJ ^ 'UTLÄGGN I NGSSKRIFT · • AÄS (45) ^ ^ (51) K ».ik. * / Int.a. · A 61 K 31/20 A 61 El 9/06 A 61 K 31/07 ENGLISH —Fl N LAN D (21) F «Mnttlh» lMrou · - i> u «ntamefcn (n (700089 (22) Hakamhpilvi —Amekabipdag l6.01.j6 ^ ^ (13) Alkupilvl — ClMghtttdif l6.01. J6 (41) ) Tullut | ulklnk «l - Bllvlt offuntllg lB.0J.j6

National Board of Patents and Registration (44) Nlhtlvik, .p ™ n j. date * * * * *. -

Patent * och registerstyreisen An * ek * n utiagd och uti.ikrtft * n pubiic «rad 31.01.80 (32) (33) (31) Fyj ^ sttjr« cuoikms —Begird prlorltet. 01.75 USA 5 ^ 1906 (71) Johnson & Johnson, 501 George Street, Nev Brunswick, New Jersey, USA (72) Alan Marks, East Brunswick, New Jersey, USA (7 * 0 Oy Kolster Ab (5 ^) A process for the preparation of a therapeutically active stable trethiionin gel preparation from which tretinoin is easily released and absorbed into the skin - For the preparation of a therapeutically active, stable tretinoin preparation

The invention relates to a process for the preparation of a therapeutically active, stable tretinoin gel preparation from which vitamin A acid is easily released and absorbed into the skin.

The process according to the invention is characterized in that 0.001-0.025 wt. vitamin A acid (tretinoin) is added to a carrier gel comprising a mixture of an organic solvent, namely ethanol, isopropanol or propylene glycol, or a solvent mixture of two or all three of the above solvents, an antioxidant further soluble in said solvent or solvent mixture a pharmaceutically acceptable gelling agent solvated in a solvent or solvent mixture, wherein said organic solvent or solvent mixture is 8U to 99% by weight? kantja material.

2 56931

Acne vulgaris is a skin disease that is common in adolescence. It most commonly occurs on the patient's face and body. The starting point for acne is a black spot on the hair follicle, or "skin worm." In its mildest form, there are only a few pimples, but in its more serious form, there are masses of persistent black pimples. Permanent scarring is often the result of a severe form of acne.

Acne occurs when sebaceous blisters fill with a fairly tough cornea, and a "skin worm" forms. As a result of bacterial growth in these filled sebaceous vesicles, the skin ruptures, initiating the inflammatory phase of the disease with pimples, pustules, lumps and nodules.

Several different methods have been used to treat acne, cosmetics, hormone therapies for female patients, antibiotics and even surgical skin smoothing.

Although systematic administration of hormones and antibiotics has been used with some success, to date none of the external treatments have been particularly effective.

Vitamin A acid (tretinoin) has been used topically, (Beer, Von P., "Untersuchungen uber die Wirkung der Vitamin A-Säure", Dermatologica, 12k: 192-195, March, 1962 and Stuttgen, G., "Zur Lokalbehandlung von Keratosen mit Vitamin A-Säure ", Dermatologica, 12k: 65-80, February 1962), in those patients with hyperthyroidism who are sensitive to high doses of vitamin A when administered orally. There have been cases of acne among patients treated by Beer and Stuttgen; however, these researchers have not shown effective results with vitamin A for pimples. British Patent 906,000 discloses a cosmetic preparation containing vitamin A acid which is used to regulate the corneal processes in human skin, but nothing is mentioned about the use of such a preparation for the treatment of acne. This known preparation is in the form of a cream; it is essentially a thick emulsion prepared at high temperature without a gelling agent.

Recently, long-term topical use of vitamin A acid has been shown to be effective in the treatment of pimples, (Kligman, AM, "Topical Vitamin Avacid in Acne Vulgaris" Arch Derm., 99: b69 ~ hrf6, April 1969) - Kligman uses a combination in which vitamin A acid is dispersed in a water-miscible (mainly oil-free and fat-free) liquid carrier with high solubility. However, this vitamin A acid preparation is irritating to the skin (U.S. Patent No. 3,729,568).

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A creamy tretinoin preparation is known from Finnish application 2960/7 **. However, this preparation has less activity. In addition, tretinoin-containing creams have harmful properties. One of these detrimental properties is the difficulty of applying the product evenly and in sufficiently effective amounts to the puncture site of pimples while avoiding local overdoses, when applied or distributed to facial wrinkles, nasal folds and palate, where the ointment may cause redness, stinging and itching. Another detrimental feature of previous tretinoin ointment preparations is their poor stability, which often makes it necessary to use cooling or antibacterial antiseptics, as well as special additives to maintain physical stability.

In Arzneimittel-Forsch. No. 8 (197 * 0 ΙΙ8Π-ΙΙ87 is described as a gel containing 0.05% vitamin A acid. This known gel contains, among other things, preservatives and solubilizing additives which are not required in the process according to the invention. The preparation according to the invention is very effective, nevertheless that its vitamin A acid content is very low, only 0.001-0.025% · In addition, the new product has very few side effects, as well as good physical and chemical stability, for more than 18 months at 37 ° C and is cosmetically pleasant. also a significant drying effect and thus does not increase the oiliness of the skin of an acne patient.

Unexpectedly, it has been found that new tretinoin gel formulations are more effective in treating acne conditions than known tretinoin creams with the same tretinoin concentration. It has also been found that creams with low tretinoin concentrations have very little or no effect against pimples compared to the same carrier without tretinoin, while gel formulations with the same low tretinoin concentrations have a strong effect against pimples. the degree of efficacy is often almost the same as for gels with higher tretinoin concentrations. This is a surprising and unexpected finding and the reason for it is not fully understood.

For example, the composition of the new preparation is as follows:

Weight-#

Tretinoin 0.001-0.0025

Antioxidant (k) 0.010-0.100

Gel (k) 0.5 -5,000 Dye (s) and / or perfume oil (s) 0.0 -, 750

Sunscreen (k) 0.0 -2,500

External corticosteroid 0.0 -2,000

Antimicrobial (k) 0.0 -3,000

Organic solvent g.s. 100,000, respectively.

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Butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid (vitamin C), propyl ligate or οί-tocopherol (vitamin E) can be used as said antioxidant. The gelling agent is (1) an acidic carboxy polymer such as Carbopol 93 and Carbopol 90 neutralized with an organic amine, (2) hydroxyethylcellulose or (3) hydroxypropylcellulose. Other commonly used ingredients may be added if desired, such as colorants, perfumes, sunscreens, antibiotics, and corticosteroids.

Example 1 Weight #

Tretinoin 0.001

Butylated hydroxytoluene 0.01

Hydroxypropylcellulose 2.0

Propylene glycol q.s. 100.0, respectively.

Example 2 Weight #

Tretinoin 0.005

Butylated hydroxytoluene 0.05

Carbopol 9 * + 0 (carboxyvinyl polymer, manufactured by B.F. Goodrich 3.0

Company, USA)? -Alanine 3.0

Ethanol q.s. 100.0, respectively.

Example 3 Weight #

Tretinoin 0.025

Butylated hydroxytoluene 0.05

Hydroxypropylcellulose 3.0

Ethanol q.s. 100.0, respectively.

Example k Weight #

Tretinoin 0.025

Butylated hydroxytoluene 0.05

Carbopol 9 ^ 0 3.00

Diisopropanolamine 3.00

Isopropanol q.s. 100.0, respectively.

Example 5 Weight #

Tretinoin 0.02

Butylated hydroxytoluene 0.05

Carbopol 93 ^ (caroxyvinyl polymer; manufactured by B.F. Goodrich 1.5

Company, USA)

Diisopropanolamine 1.5

Propylene glycol / i sopropanol 50/50 mixture by weight q.s. 100.0, respectively.

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Therapeutic experiments

The new tretinoin gel combination is usually used daily until the desired assistance is obtained. The number of daily smears depends on the severity of the patient's pimple condition and can range from one to three smears. Normally, treatment requires at least 8-12 weeks. However, in its mildest form, pimples can be mainly treated off in k-6 weeks. More serious cases may require 2-3 months or more.

In use, it has been found that the new gel preparations are easy to apply and remain in the treated areas with very little tendency to run and distribute or cause disturbing irritation in the mouth or nasal folds. In addition, and quite unexpectedly, only momentary stinging has been observed rather than prolonged discomfort after application compared to previously used dosage forms.

Various investigators have conducted clinical trials with new gel formulations containing tretinoin in combination with butylated hydroxytoluene, hydroxypropylcellulose, and ethanol, comparing their relative efficacy to ointment formulations containing tretinoin in combination with stearic acid, stearic acid, isopropyl myristate, polyoxy , sorbic acid and butylated hydroxytoluene. The studies have been double-blind, parallel clinical trials comparing gels and ointments with the same tretinoin concentrations and the corresponding reference solvent or active substance without tretinoin. The combined results of these studies are summarized in Tables I-III. ......

Table I compares the overall efficacy of known ointments and new gel formulations in the treatment of acne. Table II compares the efficacy values of creams and gels in reducing blackheads. Table III compares the effectiveness of creams and gels in reducing pimples.

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The following preparations were used in the studies (table):

The composition of the preparations was used in the studies

Tretinoin 0.01 0.01 0.002 0.025 0.025 0.02 0.025

Butylated hydroxytoluene 0.05

Butylated hydroxyanisole 0.05

Vitamin C 0.05

Vitamin E 0.05 0.05 0.05

Propyl gallate 0.05

Propylene glycol 97.1 + 1 +

Ethanol 1 * 8.72 97.93 95.93 95.93

Isopropyl alcohol 97.1 * 1 + 1 * 8.72 99.18

Carbopol 93 * + 2.0

Carbopol 9l * 0 2.0

Hydroxyethylcellulose 2.0 2.0 0.75

Hydroxy propylcellulose 2.0 2.0 / 3-alanine 2.0

Diisopropanolamine 2.0 Dye 0.25 0.25

Scent 0.25 0.25

Hydrocortisone 0.25 0.25 X) · *,

carboxyvinyl; manufactured by B.F. Goodrich Company, USA.

Table 1% of patients with good or excellent clinical evaluation

«..., X

Tretinoin- Number of patients Percentage concentration_Cream_Gel_Cream_Gel 0.000% 121 66 28 39 0.010% 59 1 * 1 31 83 0.025% 65 67 1 * 6 83 0.050% 125 6H 62 80

Table II

Black button reduction%

X

Tretinoin- Number of patients Percentage concentration_Cream_Gel_Cream Gel 0.000% 122 60 35 1 + 8 0.010% 62 38 1 * 1 + 67 0.025 1 67 65 1 * 1 + 77 0.050% 126 62 61 78 S6931

Table III Acne reduction- $

Tretinoin- Number of patients * Percentage concentration_Cream_Gel_Cream_Gel 0.000% 122 60 23 3 ^ 0.010% 62 38 HU 67 0.025% 67 65 UU 77 0.050% 126 62 61 78

Some patients in the studies had only blackheads and some only had pimples, although most patients had both. Therefore, Table I, which summarizes the investigators' review of overall efficacy, could be expected to show a somewhat higher total number of patients than either of Tables II and III, and this is the case for "gel" patients. However, one of the researchers ignored the overall review for “cream” patients, giving only a separate review for blackheads and pustules. This results in a lower total number of patients in the ointment column of Table I compared to Tables II and III.

Tables I, II and III show that the percentage improvement in acne conditions is greater when patients are treated with a zero-strength or ineffective gel than with a zero-strength or ineffective cream. The reason for this difference is undoubtedly the cleansing or disinfecting nature of these carriers; both carriers cause a reduction in acne conditions due to the cleansing ability of some of their components, and a gel carrier containing alcohol has a stronger bactericidal effect. .

It is also apparent from Tables I, II and III that, with a low tretinoin content, gel preparations unexpectedly provide a greater improvement in the reduction of acne conditions than cream preparations. In fact, an increase of about ten times the tretinoin content in ointment formulations of 0.01- $ gel is required to achieve the efficacy of the gel formulation, both in reducing blackheads and lumps and in overall clinical healing. * R- · - »- *“ * - · - * · *.

Claims (1)

56931 Patents: Process for the preparation of a therapeutically active, stable tretinoin gel preparation from which tretinoin is easily released and absorbed into the skin, characterized in that 0.001-0.025% by weight of vitamin A acid (tretinoin) is added to the carrier gel, which mixture is organic. a solvent, namely ethanol, isopropanol or propylene glycol, or a solvent mixture comprising two or all three of the above solvents, a further antioxidant soluble in said solvent or solvent mixture and a pharmaceutically acceptable gelling agent solvated in said solvent or solvent mixture, -99 weight- # of carrier a.