CA2146607A1 - Pharmaceutical composition for treatment of epidermis profilerative disease - Google Patents

Abstract

Abstract:
A pharmaceutical composition for the treatment of epidermis proliferative diseases comprising a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof.

Description

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Pharmaceutical Composition for Treatment of Epidermis Proliferative Diseases `

This invention relates to a useful pharmaceutical composition for the treatment of skin diseases. More particularly, this invention relates to a useful ;~
pharmaceutical composition -Eor the treatment of epidermis proliferative diseases, such as psoriasis, ichthyosis, palmoplantar keratoderma and pityriasis rubra pilaris, `
comprising an ascorbyl tocopheryl phosphate compound or a pharmacologically acceptable salt thereof. ~;

The epidermis or outermost layer of the skin plays the role of protecting the internal environment of the dermis from the external environment. In the event this epidermis ~ ;~ . .
is damaged for whatever cause, it undergoes vigorous ~rowth, thus causing psoriasis which is a proliferative disease of the epidermis. Psoriasis, also known as inflammatory keratosis, is one of the typical diseases of the skin. It forms a singular to numerous lesions varying in size and ~
shape, with intense redness (erythema~, slightly raised from - `
the normal skin surface (infiltration), and frequently accompanied by thick scalin~. Once psoriasis develops, it 25 i9 refractory and in most cases persists ~or the rest of `~ one's life repeating remission and exacerbation. ;

For~ the pharmacotherapy of psoriasis steroidal antiinflammatory drugs and immunosuppessive drugs have hereto-~ore been used. Among them, steroidal antiinflammatory drugs are efficacious in psoriasis but induce or aggravate fungal and bacterial infections and a `
variety of adverse reactions such as purpula and ~: . :' ~ ~'`: ,' ' ' : '';',''',' '. ,~':"';' " ~

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peristomatous dermatitis. Therefore, massive or long-term administration of such a steroidal antiinflammatory drug calls for caution with constant attention to the posslble onset o-f such side effects. On the other hand, ~p~
immunosuppresent drugs have the disadvantage of inducing renal disorder, hypertension and other side effects, too. ~ i More recently, vitamin D preparations have also come into clinical use but are not satisfactory enough in ef-Eicacy.

Therefore, in the field of dermatological therapeutics, , ~, much research and development work is going on in search Or improved drugs for the treatment o-f epidermis proliferatlve ~ ~
diseases. Under the circumstances, the inventors of this ~ ;
invention who had been investigating the pharmacological profile of ascorbyl tocopheryl phosphate compounds in detail discovered that these compounds are of use as a drug for the treatment of epidermis proliferative diseases. This invention has been developed on the basis of the above - i flnding.

Thls invention provides a useful pharmaceutical ~`
compositlon for the treatment of epidermis proliferative diseases comprlsing a phosphoric diester compound. -~

This invention, therefore, is directed to~
(1) a pharmaceut~cal composition for the treatment of epidermis proliferatlve diseases comprising a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof (hereinafter rèferred to as the present compound).

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' Co0 0 R~ ~ ~0 CH3 CH3 Or ll ~0 -P -O ~ (C~2CH2CH~CH)3-CH3 C~ Rl ~H-OH

: [wherein Rl and R2 are the same or different and each represents a hydrogen atom or a methyl group]-; - :~
(2) a pharmaceutical composition of (1) which is ~or ~:
topical application;

(3) a pharmaceutical composition ~or topical application o~
(Z) which is an ointment, an aqueous liquid, or a gel; ;

(4) a pharmaceutical composition of (3) wherein the concentration of said compound or pharmacologically acceptable salt in said ointment or gel is 0.01-5 (w/w) %;
and : ,:. ~ . : ::
~ (5) a pharmaceutical composition of (3) wherein the ;~ ~ concentration o~ said compound or pharmacologically : ~ ~ :
acceptable~ salt ln said aqueous liquid is 0.01-5 (w/v) %.
(6) a method for~treating epidermis proliferative diseases 15 ~ in à patien~ ln need thereofi comprising administering to : said patient an effective amount o~ the pharmaceutical `;~
composition of (1).
(7) The use of the~composition of (1) in the manufacture of~
a medicament for the treatmenl; of epidermis proliferative ~:diseases.

The present compound can be synthesized by, inter alia, ~ ;

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the processes described in JP Publication H2-44478 and JP
Kokai Publication S62-205091. :~

For the present compound, a variety of uses are already known, among which are an anticataract drug, a prophylactic and therapeutic drug for climacteric disturbance, a skin care cosmetic ingredient (JP Publication H2-4447i8), an :~
antiin~lammatory drug (JP Publlcation H1-27044), an .~: ., ; antlulcer drug (JP Kokai Publication S63-270626), a :~
10~ prophylactic and therapeutic drug ~or ischemic organ : dlseases (JP Kokai Publication H2-111722), and a Maillard reactlon inhibitor (JP Kokai Publication H3-161444), among others.

The present compound can be either the free compound or : a pharmacologically acceptable salt. The pharmacologicallY
acceptable salt includes not only alkali metal salts such as ~; sodium:salt, potassium salt, etc and alkaline earth metal `~
salts such as calcium salt, magneslum salt, etc. but also other salts which are pharmacologically acceptable.

According to the intended use and need, the pharmaceutical composition of this invention may comprise~s ~',"'`'t,'''"'.,'.''either one species or a pIura:lity of species, in a suitable . ``.-`~`.
25 combination, of the present compound. - `

The present compound for use as an active ingredient in the pharmaceutical composition of this invention is very ;.~....... ~
~ safe with an extremely low to~ic potential and can, :l 30 ~ therefore, be used with advantage for the purposes of this : invention [LD~o of L-ascorbyl DL-a -tocopheryl phosphate ;~
potassium (abbreviation: EPC-K): 2 5 g/kg p.o. (rats), 2 100 :mg/kg i.v. (rats)]. ~-. .~ . .. ~ . . .',.
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The pharmaceutical composition of this invention can be administered either orally (e.g. tablets etc.) or otherwise (e.g. ointments, aqueous liquids, gels, etc.). The dosage form in which the therapeutic composition of this invention :-can be provided includes ointments, aqueous liquids, gels~
tablets, granules, powders and so on. These dosage forms ~;
can be respectively manufactured by established pharmaceutical procedures. In these dosage forms, a variety of additives such as excipients, binders, disintegrators, dispersants, reabsorption promoters, buffers, surfactants, solubilizers, preservatlves, emulsi-fiers, lsotonizing agents, stabilizers and pH control agents can be included in appropriate amounts. ;~

In appllcation of the present compound as an ~ ~
pharmaceutical composition for the treatment of epidermis ~ ;
proliferative diseases, its dosage depends on the disease, species of compound, the patient's age and body weight, clinical manifestations that must be controlled, and the dosage form. In the case of an ointment or gel for topical application, a preparation containing about 0.01-5 (w/w) %, - ~-preferably about 0.05-2 (w/w) %, o~ the present compound can -~
be applied to the affected skin area a few times a day for the average adult. In the case of an aqueous liquid for topical application, a preparation of about 0.01-5 (w/v) %
concentration, preferably about 0.05-2 (w/v) %
concentration, i8 applied to the affected skin area a few `
~ times daily -for the average adult. In the case of an oral ,~ preparation, about lO mg-lO00 mg per dose can be administered a few times a day for the average adult.

Unless contrary to the spirit and ob~ect of this .. .
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invention, the pharmaceutical composition oE this invention may further contain other agents for the treatment of epidermis proliferative~diseases and/or other kinds of medicinal substances. ~ ~ ;
The following examples and Eormulation examples are intended to describe this invention in fur-ther detail.

Example 1: Assay of eEficaey of the present compound in the mouse model of psoriasis vulgaris The e-Eficacy of the present compound was assayed in the mouse model of psoriasi~ vulgaris constructed usin~ 12-o~
tetradecanoylphorbol-13-acetate (briefly TPA).

Test substances: ~' (1) Methanol (control drug) 20 ~ l/auricle (2) L-ascorbyl DL-a -tocopheryl phosphate potassium ~ --(briefly EPC-K) 500 ~ g/20 ~ l/auricle i~ ;~
(3) EPC-K 1000 ~ g/20 ~ l/auricle `;
(4) Betamethasone valerate 25 ~ g/20 ~ l/auricle ~

Method: ~, r' ' ',''''`ln' Male 6-week-old ddY mice purchased from SLC Japan were ``~
u9ed-~; The entire external surface of the right auricle of -~
each mouse was coated with 20 nmol/40 ~ l of TPA/methanol, ~ ;
and after 6, 24, 4~ and 72 hours, the thickness of the I ~ -'~ 30 auricle was measured with a dial thickness gauge. The ear , ~ swelling rate (%) was then calculated. At 72 hours after ;~ application of TPA, the mouse was sacrificed and the right -~
and left auricles were respectively punched out with a 8 mm ''''",''',','':'''',''','''' `','.''' .~, ' . ','~ .''"

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(dla.) punch. The epidermis of each aurlcle was peeled of~
and the epidermal weight was determined. Then, the % gain ' in epidermal weight of the right auricle relative to the ~:
left auricle was calculated.
Each test substance was extemporaneously blended with , TPA-methanol and 40 ~ 1 of the mixture was applied to the e~ternal surface of the right auricle o-f each mouse. Then, a methanolic solution of the corresponding test substance, 10 40 ~ 1, was applied once daily ~or 2 days. --, . ., ~ ~:
Dunnet's test was used ~or statistical efficacy ~
evaluation o~ the test substance. ;
, . . ,~ . .
Results:
The results are shown ln Table 1 and Fig. 1, in which Table 1 shows inhibitory effect o~ EPC-K on ear epidermal ~.
weight gain in the mouse model of psoriasis vulgaris and Fig l is a graph showing the time course of ear swelling rate in :
~20 the mouse model of psoriasis vulgaris. The abscissa `
; represents time (hrs) and the ordinate represents the swelling rate (%).
" . : : ;:
Table 1 ~
~25~ Inhibltory e~fect of EPC-K on ear epidermal weight gain in - ;
the mouse model o~ psoriasis vulgaris ":
Group Control EPC-K Betamethasone valerate 1~ 30 ~
'~:~ ~ : ' , ~ Dose/auricle - 500 ~ g 1000 ~ g 25 ~ g ~: .
~ Epidermal - . , ! 2 1 4 6 6 ~ 7 weight % galn 110.9+ 68.~ 52.4+ 40.1* 21.8+ 17.4** 21.0+ 19.9** -~
.. _ ... _ . . . . . _ ...................... . .. . _ Each figure ln the table represents mean+ SD (n=6-9).;~
Significant difference from control: ** p<O.O1, * p~O.05.
. - ~ ~ . . .,;
It is apparent -from Table 1 that 500 and 1000 ~ g of` ~
the present compound inhibited the epidermal weight gain :
significantly, by 52.8% and 80.3%, respectlvely. On the other hand, 25 ~ g betamethasone valerate inhibited the ,~
10 epidermal weight gain slgnificantly by 81.1%, or ~ ;
equipotently as 1000 ~ g of the present compound, but it induced body weight loss as a side ef-fect.

In the ear swelllng rate, too, the present compound ; ' 15 showed dose-dependent lnhibltory effects at all polnts of ~, time as shown in Fig. 1. On the other hand, 25 ~ g betamethasone valerate also showed fairly potent e-fficacy but its effect had been attenuated by 24 and 48 hours after application. Thus, a more potent inhlbitory effect was 20 obtained in the group treated with 1000 ~ g of the present ~` ;
compound. l ~
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It is, therefore, clear that the composltion o~ this ` ~`
invention is useful for the treatment of psorlasis which is 25 a proliferatlve disease of the epidermis. --~
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Formulation Example 1: Ointment ; `

EPC-K 1.0 g ! 1 30 i i Hydrophilic ointment base to make 100 g The above components are mixed in the routine manner to provide an ointment. ;~

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., , ~, Formulation Example 2: ~gLueous liquid , EPC-K 0.5 g : :~
Glycerin 1.0 g : . ~
Propylene glycol 1.5 g ' :
Ethanol 30 ml ::
Sterilized puri~ied waterto make 100 ml The above components are mixed in the routine manner to :.
10 provide an aqueous liquid. :' ., .
Formulation Example 3: Gel "
EPC-K 0.5 g Carboxyvinyl polymer 1.0 g :~ Triethanolamine q.s. -;~ ~ Ethanol 30 ml Sterilized puri~ied waterto make lOQ ml pH=7.0 ~ .
.
The above components are mixed in the routine manner to ~ .
provide a gel. : - :

;;25 Formulation Example 4: Oral tablet EPC-K 100 mg Lactose 75 mg Starch 20 mg 30~; Polyethylene glycol 6000 5 mg `~; :

The above components per tablet are mixed in the ~.. :.

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routine manner to provide tablets. Where necessary, the tablets may be sugar-coated.

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Claims (6)

1. A pharmaceutical composition for the treatment of epidermis proliferative diseases comprising a phosphoric diester compound of the following formula or a pharmacologically acceptable salt thereof.

[wherein R1 and R2 are the same or different and each represents a hydrogen atom or a methyl group]

2. A pharmaceutical composition according to Claim 1 which is for topical application.

3. A pharmaceutical composition for topical application as claimed in Claim 2 which is an ointment, an aqueous liquid, or a gel.

4. A pharmaceutical composition according to Claim 3 wherein the concentration of said compound or pharmacologically acceptable salt in said ointment or gel is 0.01-5 (w/w) %.

5. A pharmaceutical composition according to Claim 3 wherein the concentration of said compound or pharmacologically acceptable salt in said aqueous liquid is 0.01-5 (w/v) %.

6. A method for treating epidermis proliferative diseases in a patient in need thereof, comprising administering to said patient an effective amount of the pharmaceutical composition of the following formula or a pharmacologically acceptable salt thereof.
[wherein R1 and R2 are the same or different and each represents a hydrogen atom or a methyl group]