OA12322A

OA12322A - Topical pharmaceutical preparation.

Info

Publication number: OA12322A
Application number: OA1200200286A
Authority: OA
Inventors: Zoltan Dardai
Original assignee: Diabetic Trust Ag
Priority date: 2002-09-12
Filing date: 2002-09-12
Publication date: 2006-05-12

Description

ι 012322

TOPICAL PHARMACEUTICAL PREPARATION

FIELD OF INVENTION

The invention relates to topically applicable pharmaceutical préparations whichenable one to introduce peptidaceous pharmacons in living organisme bytransdermal résorption. The topically applicable pharmaceutical préparationsaccording to the invention may be e.g. ointments, creams, gels, lotions, solutions,suspensions and similar formulations routinely utilized in topical treatments, whichcan be applied onto the skin surface optionally in supported forms. Particularlypreferred représentatives of them are those wherein the topically applicableformulation is applied onto a support capable adhering to skin, i.e. plasters(patches), which enable safe dosing and easy handling.

BACKGROUND TO INVENTION

Topically applicable pharmaceutical préparations are outstandingly preferredformulations with respect to the treatment comfort of the patient. In contrast toparentéral formulations, like injections, the introduction of which is painful or atleast unpleasant and requires either assistance of a doctor or of a nurse, or, whenself-administered, requires practice and skill from the patient, a topical formulationcan be applied to the place of treatment easily and painless even by the patient.Topical formulations are also more preferred than oral ones for patients who sufferfrom dysphagia or are averse to the taste of the medicine. A spécifie advantage oftopical formulations is that the patient can, either at first sight or by touching hisskin, easily ascertain whether he has applied the medicine or not, thereby the risk ofinadvertent overdosing or underdosing considerably decreases.

Despite of these advantages topically applicable formulations are utilized in medicalpractice in a rather narrow range, generally only for the treatment of externalinjuries and local inflammations. The reasons of this fact lie primarily on thephysiological features of active agent résorption. In order to enable a topicallyapplied active agent to reach the target organ in an appropriate concentration the 2 012322 active agent should penetrate not only through the skin but also through the wallsof the subdermal blood vessels. Even skin and vessel walls are of highly restrictedpermeability owing to their physical structures (porosity and semipermeablemembrane structure). Further significant hindrance arises from the so-called 5 barrier fonction of the horny layer, which latter serves essentially to protect livingorganisms from foreign substances contacting the skin. There hâve already beenelaborated some topical formulations which can successfolly replace oral ones forthe introduction of the active agent concerned. One of them is an antirheumaticpatch marketed in Hungary since about 15 years under the name ΜΟΊΤΟ®, 10 which comprises formic acid (as an antirheumatic agent), salicylic acid andoptionally a pain-relieving agent in an émulsion formed with Unguentumemulsificans (a cream comprising nonionic tensides, Ph.Hg.V.), which is applied ona support capable of adhering to skin. NITRODERM®, a composition sold byCiba-Geigy Co. (German Fédéral Republic), comprises nitroglycerol (as a cardiac 15 agent) in a gel formed with methyl or carboxymethyl cellulose, which is applied onsmall polyuréthane sponges capable of adhering to skin. SALONPAS®, acomposition sold by Hisamitsu Pharmaceutical Co. Inc. (Japan), comprises methylsalicylate (as an anti-inflammatory agent) and a methol in a thick mass formd withpolyvinyl alcohol, which is applied on small polyuréthane sponges capable of 20 adhering to skin. The active agents in these known compositions are strongly polarsubstances of relatively low molecular weights, thus they hâve much more chancefor résorption than les s polar substances with higher molecular weights.

Peptidaceous compounds form an important group of pharmaceutically activesubstances. In the spécification and daims the term “peptidaceous compound” or 25 “peptidaceous pharmacon” refers generally to any pharmaceutically activesubstance the molécule of which comprises at least two amino acids boundtogether by a peptide bond. A narrower group of them with outstandingpharmaceutical importance is the group of polypeptides, of which naturalhormones and artificial analogues and dérivatives thereof are of particular interest. 30 A member of this latter group with outstanding importance from the aspects of 3 012322 public health is insuline. Hormones and hormone analogues which regulate finebalances of the organism are hazardous substances, thus with these substances it isparticularly necessary to decrease the risks of inadvertent overdosing orunderdosing. Some représentatives of hormones and hormone analogues, in 5 particular insuline, can be introduced only parenterally. Thus it would be highlydésirable to introduce these active agents topically in the living organism.However, topical préparations applicable for introducing peptidaceous pharmaconsin living organisms hâve not been disclosed before.

SUMMAR Y OF INVENTION 10 Based on studies, it has been found that, upon utilizing spécifie auxiliary agents,peptidaceous pharmacons can be brought to a form capable of transdermalrésorption. This récognition enables one to produce topically applicablepharmaceutical preparaions comprising pharmacons.

Thus, the invention relates to a topically applicable préparation for introducing a 15 peptidaceous pharmacon in a living organism. The préparation according to theinvention comprises in admixture with carriers and/or diluents conventionallyapplied in topical pharmaceutical préparations, optionally applied onto a supportcapable of adhering to skin: (i) at least one peptidaceous pharmacon; 20 (ii) one or more constituents selected from the groupo comprisingcapsaicine, histamine and cantharis extract; and (iii) at least one epithelizing agent.

The préparations according to the invention may comprise as peptidaceouspharmacon preferably a natural hormone or a synthetic analogue or dérivative 25 thereof, particularly preferably insuline. The amounts of peptidaceous pharmaconscontained in a unit dose (i.e. in a dose for a single treatment) of the préparationsaccording to the invention (such as in a single plaster) may be about the same as 4 012322 présent in the conventional oral or parentéral unit dose forms. Thus, as anexample, plasters according to the invention applicable in the treatment of diabètesmellitus may comprise 0.1-50 IU of insuline for one plaster or for a unit plasterfragment (e.g. for 1 cm2 of plaster surface).

Capsaicine, histamine and cantharîs extract (the active agent of Tincturacantharidis), which form component (ii) of the préparations according to theinvention, are rubefacient local vasodilators. These substances hâve been appliedfor a long time in the therapy as external rubs for stimulating subdermal circulation e.g. for the treatment of chilblains, extremital pains, rheuma and the like [Kirây,Râcz, Tôrôk: Bor- es nemibetegségek (Skin and Venereal Diseases, in Hungarian);1927 and subséquent pages (Medicina Kônyvkiado, Budapest, 1986)]. AsepitheEzing agent, which is component (iii) of the préparation according to theinvention, any agent known to be appEed in the therapy to loosen the upperepitheEal layer of skin can be utilized. Characteristic représentatives of such agentsare Ested e.g. in the textbook cited above. SaEcyEc acid, sodium chloride, urea andresorcinol are examples of epitheEzing agents which can be utiEzed with goodresults in the préparations according to the invention.

Although, as it appears from the textbook cited above, components (ü) and (iii) ofthe préparation according to the invention hâve already been utiEzed beforeseparately in compositions for topical treatment, no data can be found in theEterature on their combined use and on their prospective combined effects. Nodata can be found in the Eterature, either, that component (ü) or component (iii)would hâve been utilized before in combination with a peptidaceous pharmaconfor the purpose of topical treatments.

In the préparations according to the invention components (i) and (ii) interact with one another, which is verified e.g. by the observation that when capsaicine is added to an insuEne suspension (such as to a préparation sold by Novo Nordisk under the name InsuEn lente MC), a transparent solution forms. The accurate nature of this interaction has not yet been elucidated, however, most probably hydrogen 5 012322 bonds are formed between the loose hydrogen-bearing groups and the localhydrogen acceptor centers of the two components (such as between the HO- andHOOC- groups of capsaicine and the -NH2 groups of insuline). The transdermalrésorption ability of peptidaceous pharmacons from the préparations according tothe invention can be attributed basically to this interaction.

The préparations according to the invention must contain component (ii) at least inan amount enabling the above interaction to take place, it is preferred, however,when the préparations contain more component (ii) than this minimum. For anyindividual peptidaceous pharmacon/component (ii) pairs the minimum andsuitable ratios can be determined easily by tests belonging to the routine knowledgeof one skilled in pharmacotechnology. As a guidance, e.g. insuline-containingpréparations according to the invention may contain 0.001-0.3 g, preferably 0.003-0.1 g, particularly preferably 0.005-0.05 g of component (ii) for 10IU of insuline.

The préparations according to the invention may contain components (ii) and (iii)in a weight ratio of 1:(0.01-10), preferably in a weight ratio of 1:(0.03-3), particularlypreferably in a weight ratio of 1:(0.05-2).

It is observed that the higher is the amount of components (ii) and (iii) in thepréparation according to the invention, the faster is the résorption of the activeagent.

The préparations according to the invention comprise components (i)-(iii) inadmixture with conventional carriers and/or diluents for topical préparations, ofwhich the following are listed as examples: water, alcohols (also comprisingglycerol), glycols, gellifying agents (such as methyl cellulose, carboxymethylcellulose, polyvinyl alcohol and polyvinyl acetate), ointment bases (such aslanoline), ionic and nonionic tenzides and the like.

The préparations according to the invention may also comprise the peptidaceouspharmacon in enveloped form (such as closed into a cyclic starch formicroencapsulated). Use of such an envelope may be necessary from 6 012322 pharmacotechnological considérations, for instance when the peptidaceouspharmacon concemed is incompatible with the selected carriers or diluents. Forinstance, hydrophilic pharmacons, when closed into an envelope of hydrophobiesurface, can be rendered compatible with oily carriers. In such instances the 5 interaction between components (i) and (ii) proceeds at the rate of libération ofcomponent (i) from the envelope.

If desired, the préparations according to the invention may also comprise otherpharmaceutically active or activity-increasing agents to be introduced together withthe peptidaceous pharmacon. Examples of such components are zinc compounds 10 which are sometimes added together with insuline.

If desired, the préparations according to the invention may also comprise anindicator suitable to detect the presence of the peptidaceous pharmacon.Substances which react with a visually observable change (most suitably with acolour reaction) to the presence or absence of the pharmacon concerned can be 15 utilized as indicators. Ninhydrine, which indicates the presence of a peptidaceoussubstance by blue colouration, is a very suitable indicator to show the presence ofpeptidaceous substances. A great advantage of such indicator-containingpréparations is that the patient can easily conclude from the colour change of theapplied composition (e.g. from the dissapearance of the blue colour of ninhydrine) 20 whether résorption has taken place or not, and, if necessary, can change the alreadyexhausted plasters at due intervals. The préparations according to the inventionmay comprise the indicator in amounts which provide good observability. Theseamounts are well known to one skilled in analytics or can be determined easily byroutine tests. 25 7 012322

EXAMPLES

The following examples serve to demonstrate the composition and manufacture ofthe préparations according to the invention.

Example 1 5 0.28 ml of Tinctura capsaicini (Ph. Hg. V., capsaicine-containing 70 % alcohol solution) and 0.05g of salicylic acid were added to 10 ml of an intramuscularlyadministerable acqueous suspension comprising 40 IU/ml of insuline (sold byNovo Nordisk under the trade name Insulin rapitard). Upon adding the capsaicine,a transparent solution formed from the" insuline suspension. 0.01 % by weight of 10 ninhydrine were added to the solution, whereupon the colour of the solutionturned blue. The resulting solution was gellified by adding 15 % by weight ofmethyl cellulose, and the resulting gel was applied onto a polyuréthane spongeplaster with an active surface of 20 cm2. The gel applied was covered withaluminium foil. 15 Example 2 10g of Unguentum nonionicum emulsificans (Ph.Hg.V., an oily gel formednonionic tenzides) was admixed with 10 g (400 IU) of crystalline insuline, 0.05 g ofcrystalline salicylic acid and 0.28 ml of Tinctura capsaicini. The resulting oilyointment was applied onto a polyuréthane sponge plaster with an active surface of 20 20 cm2, and the ointment applied was covered with aluminium foil.

Claims

8 012322 PATENT CLAIMS 2, 10 3. 4. 15 5. 6. 20 7. 8. A topical pharmaceutical préparation, which comprises, in an admixture withcarriers and/or diluents conventionally applicable in topical pharmaceuticalpréparations, (a) at least one peptidaceous pharmacon; (b) one or more constituents selected from the groupocomprising capsaicine, histamine and cantharis extract; and (c) at least one epithelizing agent. A préparation as claimed in claim 1, which is applied onto a suitable supportcapable of adhering to skin. A préparation as claimed in claim 1 or claim 2, which comprises an indicatorwhich is adapted to react to the presence or absence of the peptidaceouspharmacon by a visually observable change. A préparation as claimed in claim 3, in which the indicator is ninhydrine. A préparation as claimed in any of the preceding daims, which comprisessalicylic acid, sodium chloride, resorcinol or urea as the epithelizing agent. A préparation as claimed in any one of the preceding daims, in which thepeptidaceous pharmacon is a natural hormone or a synthetic analogue ordérivative thereof. A préparation as claimed in any one of the preceding daims, in which thepepdaceous pharmacon is insuline. A préparation as claimed in any one of the preceding daims, whichcomprises 0.01-0.3 g of the capsaicine, histamine and/or cantharis extractfor 10 IU of pepdaceous pharmacon being insulin. 9 012322
9. A préparation as claimed in any one of the preceding daims, whichcomprises 0.003-0.1 g of the capsaicine, histamine and/or cantharis extractfor 10 IU pepdaceous pharmacon being insulin.
10. A préparation as claimed in any one of the preceding daims, which 5 comprises 0.005-0.05 g of the capsaicine, histamine and/or cantharis extract for 10 IU of pepdaceous pharmacon being insulin.
11. A préparation as claimed in any of the preceding daims, which comprisesthe capsaicine, histamine and/or cantharis extract and the epithelizingagent(s) in a weight ratio of 1:(0.01-10). io 12. A préparation as claimed in any one of the preceding daims, whichcomprises the capsaicine, histamine and/or cantharis extract and theepithelizing agent(s) in a weight ratio of 1:(0.03-3).
13. A préparation as claimed in any one of the preceding daims, whichcomprises the capsaicine, histamine and/or cantharis extract and the 15 epithelizing agent(s) in a weight ratio of 1:(0.05-2).
14. A topical pharmaceutical préparation substantially as hereinbefore described.