JPH0627068B2 - Transdermal drug - Google Patents

Description

The present invention relates to transdermal drugs, and in particular to drugs containing nicorandil or N- (2-hydroxyethyl) nicotinamide nitrate ester.

Nicorandil has significant anti-angina properties and can therefore be used in the treatment of heart defects, myocardial infarction or pulmonary oedema.

Nicorandil, which is active at relatively low dosages, requires gradual release into the organism for maximum effect. Generally, these agents are used in tablet form, which can be administered orally or sublingually. When used in this form, the drug has a relatively short duration of action, in some cases up to one hour. Sequential treatments require the drug to be taken at precisely defined intervals, but it is not possible to obtain a uniform effect. Here, in order to have as constant an effect as possible over a limited period of time, reaching hours or even days, it is possible to release the active ingredient continuously and in a controlled manner into the organism. It is particularly important to have the usual galenic morphology that

It is known to use compositions which function by transdermal absorption, whose dosage is easily monitored and which releases the active ingredient in a uniform manner into the organism. Such galenic forms facilitate administration of the active ingredient. It can enter the systemic circulation directly without passing through the gastrointestinal tract and avoid first-path effects.

Various systems in this regard are described, for example, in US Pat.
7,494 and 4,336,243, European Patent No. 13,606 and French Patent No. 2,497,45.
As described in No. 7, they either contain technical difficulties in use or give results depending on the sensitivity of the patient as the skin acts as a regulating membrane.

It has now been discovered that a uniform membrane with variable hydrophilicity and controlled release kinetics of the active ingredient can advantageously replace the above mentioned microporous membranes. This is the purpose of the invention.

The novel transdermal forms of the present invention differ from known systems by the nature of the ingredients and by the ability to control the kinetics of release of the active ingredient in a microporous membrane-free manner.

In the novel transdermal drug, the active ingredient is in crystalline form and / or
Alternatively, preferably in dissolved form, dispersed in a homogeneous elastic matrix containing a nonionic emulsifier. By changing the hydrophilic properties of the mixture it is possible to define and regulate the release rate of the active ingredient.

One of the sequences or one of the graft chains is incompatible with the matrix and has a low surface energy (30 erg / cm
It is further possible to add to the mixture a random or graft copolymer having a value of ² or less or equivalent. These sequences or grafted chains increase the concentration of the copolymer at the surface and may supplementally control the release, and form a uniform film that favors the achievement of zero order kinetics of release. These compounds are, for example, random or graft copolymers based on polydimethylsiloxane.

To provide the transdermal drug of the present invention, a polymer which is insoluble in water but is miscible with water and forms a thermoreversible, non-crosslinked film capable of changing hydrophilic properties is used. This is particularly advantageous. The films obtained from these polymers swell in the presence of water (in liquid or steam form), the degree of swelling can be controlled by the hydrophilic-lipophilic balance of the matrix, additives and active ingredients. .

More particularly, polyurethane-polyoxyethylene glycol (POEG) -polyoxypropylene glycol (P
OPG) copolymers are very suitable for this purpose. Polyethers or polyesters such as polytetramethylene glycol, polycaprolactam or polyadipate-based polyurethanes such as Pellethane, Estane or Qu
It is also advantageous to use the products marketed under the tradename inn. Other thermoreversible elastic bodies such as polyamide,
Polyesters, polyethers or polyolefins can also be used.

Generally, the hydrophilic (or hydrophobic) properties of a polymer can be determined by the degree of swelling in a humid atmosphere, according to the following method: First weighed sample at least overnight at about 20 ° C. Place in an atmosphere of saturated steam at temperature. The degree of hydration is calculated from the weight of the swollen sample. This is directly related to the hydrophilicity of the polymer. For example, polyurethane-POEG-POP
In the case of G copolymer, its hydrophilic property is POEG-POP.
It is a function of the ratio of G. In this case, the copolymer is POEG
-When the POPG ratio is greater than 1, it is hydrophilic and POE
When the G-POPG ratio is less than 1, it is hydrophobic. It is clear that this hydrophilic or hydrophobic property depends more or less on the exact value of the above mentioned ratio.

Dispersion of the active ingredient in the polymer matrix is carried out using a non-ionic emulsifier which is compatible with the polymer matrix and the active ingredient. These emulsifiers are generally those used in cosmetics and in medicine as an ingredient for creams, milks or ointments or as a gel or dispersant or as an excipient for suppositories.
These nonionic emulsifiers based on glycol or glycerol polymers are generally polycondensates of ethylene oxide with fatty acids or fatty alcohols, sorbitan esters, triglycerides with free hydroxyl groups, polyethylene glycol monoglycerides or polyglycerol esters. It is a thing. Nonionic emulsifiers of this type which can be used are in particular the products manufactured and marketed, for example by the company Gattefosse, for example stearin Plurol.
(Polyglycerol palmitostearate), isostearine Plurol (polyglycerol isostearate),
Sucroester WE15 (sucrose monopalmitate), Lab
rafil CS 2735 or 1944CS (polyoxyethylene me glycerides), including Transcutol (diethylene glycol monoethyl ether) or Labrasol (polyoxyethylene C ₈ -C ₁₀ glycerides). These nonionic emulsifiers can also be used as excipients for transdermal administration.

These nonionic emulsifiers differ essentially in their hydrophilic / lipophilic balance (HLB) and in their melting points.

The kinetics of release of the active ingredient are described by S. Borodkin and E. F.
Tucker, J .; Pharm. Sci. , 64 (8) 1289-94
According to the method of (1975), it can be determined by measuring as a function of time the amount of release compound accumulated in a volume of liquid from a film attached to a support immersed in the liquid. . The active ingredient depends essentially on the nature of the polymer and additives used, but also on other factors,
For example, if it is a crystal, it diffuses through the matrix at a rate that may be a function of the rate of dissolution of the active ingredient or the swelling of the matrix.

According to Fick's law, the amount of accumulated release component as a function of time can be expressed as: In this equation, Q is the amount of separated product accumulated per unit surface area (mg
/ Cm ² ); A represents the amount of product (mg / cc) in the polymer matrix per unit volume; Cs and Cp represent the solubility of the product in liquid and matrix; and D is It represents the diffusion coefficient of the product in the matrix.

This function is represented by a straight line, the slope (kr) of which is proportional to the initial release rate of the active ingredient.

By studying the effect of various variables on the value of kr, the composition of the transdermal drug suitable for the desired effect can be determined.

In order to improve the release kinetics of the active ingredient, polyurethane-containing hydrophobic compounds that migrate to the surface and form a uniform film.
It is particularly advantageous to add it to the POEG-POPG matrix. It is particularly advantageous to use polydimethylsiloxane-polyoxyethylene glycol copolymers. In this case, the polydimethylsiloxane block is hydrophobic and migrates to the surface to form a uniform film, while the polyoxyethylene glycol block provides matrix compatibility.

According to the invention, the novel transdermal agents add active ingredients and nonionic emulsifiers in limited amounts to a mixture of elastic copolymers and organic solvents such as dimethylformamide, methylethylketone, dioxane or methylisobutylketone. It can be obtained. The mixture is then poured onto a suitable support, such as a glass plate or a controlled-adhesion support, such as silicone coated paper, according to known techniques, following some removal of the solvent by evaporation under reduced pressure. The film obtained is dried under reduced pressure and all solvents are removed, especially if high boiling solvents are used.

Mixtures of copolymers and organic solvents may include elastic copolymers and, where relevant, hydrophobic copolymers of dimethylformamide at temperatures above 50 ° C. to obtain a uniform mixture, generally in the form of collodion. It is prepared by stirring in an organic solvent such as The mixtures obtained generally contain 5 to 30% by weight of copolymer or copolymer mixture.

The mixture of active ingredient and nonionic emulsifier is prepared from a solution of the active ingredient in a suitable organic solvent such as alcohol or ethyl ether with addition of nonionic emulsifier. A mixture of active ingredient and nonionic in the desired proportions is obtained by evaporation of the solvent, if necessary under reduced pressure.

For example, nicorandil 5-20 based on the polymer used.
It is advantageous to produce a film based on polyurethane which contains by weight, 5 to 30% by weight of nonionic emulsifiers and, if appropriate, 1 to 30% by weight of hydrophobic additives.

For the use of the transdermal drug product according to the invention, the film thus produced needs to be in as complete contact with the skin as possible. For this purpose, an adhesive which may have uniform film properties, such as a silicone adhesive, can be applied to the surface of the film by crosslinking in the presence of a suitable catalyst.

Other adhesives such as those described in U.S. Pat. No. 3,797,494 can also be used. If appropriate, the adhesive may contain active ingredients. The adhesive can also be applied by coating or by transfer.

Further, the film containing the active ingredient is coated with a material that is impermeable to the release of the active ingredient on the surface that does not come into contact with the skin and can help maintain the device on the skin. Good.

The following example illustrates the invention.

Example 1 Labrasol (Labrasol: polyoxyethylene C ₈ -C ₁₀
Glyceride) (500 mg) and Nicorandil (500 m
g) with methyl ethyl ketone (82%) and Estane 57
02 (polyurethane based on polycaprolactam) (1
It was dissolved in collodion (8.3 g) consisting of 7%).

After homogenization, a transparent, colorless collodion was obtained. The composition was as follows: Methyl ethyl ketone 73.1% Estane 5702 polymer 16.1% Nicorandil 5.4% Labrasol (hydrophilic emulsifier) 5.4% This collodion was cast on a silicone coated paper in the form of a film. . This initial thickness was 0.8 mm. Depressurize methyl ethyl ketone at 65 ℃ for 3 hours (100 mmH
g; 13 kPa).

This resulted in a dry, uniform and transparent film containing 20% nicorandil, from which discs with a diameter of 45 mm were cut.

The kinetics of release were determined in aqueous medium and the released nicorandil was evaluated by UV spectroscopy at 261 nm. 75% of the nicorandil originally present in the film was released after 7 hours.

Example 2 The procedure of Example 1 was followed except that Labrasol was replaced with Labrafil 1944CS (polyoxyethylene oleyl glyceride).

A uniform and transparent collodion having the following composition was obtained: Methyl ethyl ketone 73.1% Estane 5702 polymer 16.1% Nicorandil 5.4% Laprafil 1944CS (hydrophilic emulsifier) 5.4% Described in Example 1 from this collodion. The film was produced under the conditions described above. Release kinetics were determined in aqueous medium.
50% of nicorandil originally present in the film is 94
Released after hours.

The following is an experimental example that demonstrates that the nicorandil-containing transdermal drug obtained by the present invention has excellent release properties.

(Experimental Example) For the same preparation as in Example 1 except that the formulation of the present invention described in Example 1 and a nonionic emulsifier (Labrasol) were not added as a comparative example, Japanese Pharmacopoeia Manual (12th
Revised) General test method Dissolution test Method 2 Dissolution test was conducted according to the paddle method. The results are shown in the table below.

As is clear from the table, the production of the present invention containing an emulsifier has extremely preferable characteristics as a nicorandil preparation in which a large amount is temporarily released and then gradually released, as compared with a preparation without an emulsifier. .

Claims (12)

[Claims] 1. Nicorandil in crystalline form or in dissolved form, dispersed in a water-insoluble, non-crosslinked, film-forming homogeneous thermoreversible elastic polymer and a nonionic emulsifier. A transdermal drug consisting of. 2. A homogeneous thermoreversible elastomeric polymer is polyurethane-polyethylene glycol-polyoxypropylene glycol copolymer, polyester of polyether or polytetramethylene glycol, polyurethane, polyamide, polyester based on polycaprolactone or polyadipate, The drug according to claim 1, which is a polyether or a polyolefin. 3. The nonionic emulsifier is a polycondensation product of ethylene oxide and a fatty acid or an aliphatic alcohol, sorbitan ester, triglyceride having a free hydroxyl group, polypropyrin glycol monoglyceride, or polyglycerol ester. The drug according to item 1 or 2. 4. A nonionic emulsifier is polyglycerol palmitostearate, polyglycerol isostearate, sucrose monopalmitate, polyoxymethylene oleyl glyceride, diethylene glycol monoethyl ether, or ethylene oxide and a C _{8 to} C ₁₀ glyceride. The drug according to claim 1 or 2, which is a condensate. 5. A copolymer comprising a hydrophobic sequence which migrates to the surface and forms a uniform film which aids in the regulation of the release of the active ingredient.
The drug according to any of paragraphs. 6. The drug according to claim 5, wherein the hydrophobic copolymer is a polydimethylsiloxane polyoxyethylene glycol copolymer. 7. Tens based on the elastic matrix used.
7. A drug as claimed in any one of claims 1 to 6 containing -20 wt% nicorandil and 10-20 wt% nonionic emulsifier. 8. From 5 to 5 based on the polymer matrix used.
7. A drug as claimed in any of claims 1 to 6 containing 20% by weight nicorandil, 5 to 30% by weight nonionic emulsifier and 1 to 30% by weight hydrophobic copolymer. 9. The drug according to any one of claims 1 to 8, which is coated with an adhesive. 10. The drug according to any one of claims 1 to 9, which is packaged in a unit dosage form. 11. Addition of a limited proportion of a mixture of nicorandil and a nonionic emulsifier to an elastic copolymer, if appropriate in an organic solvent, and the mixture obtained, if appropriate, to partial evaporation of the solvent. A process for the preparation of a transdermal drug product which comprises subsequently pouring onto a support, drying the resulting film to remove any solvent and, if appropriate, coating the drug with an adhesive. 12. Nicorandil and a nonionic emulsifier,
A limited proportion of emulsifier, if appropriate in organic solvent,
Added to the mixture of elastic copolymer and hydrophobic copolymer,
The method of claim 11 comprising: