JP4807974B2 - Transdermal absorption enhancing composition - Google Patents

Description

  The present invention relates to a composition for promoting percutaneous absorption. More specifically, the composition contains a pyrrolidone derivative and a higher fatty acid having 10 to 18 carbon atoms as essential components, and is excellent in transdermal absorbability of morphine and has few side effects. Accelerating composition.

  Opioid analgesics act as agonists on opioid receptors that are abundant in the central nervous system and exert a strong analgesic effect. There are various types of opioid analgesics, and each pharmacological property is derived from the affinity for opioid receptors and the difference in individual activity.

  By the way, as an analgesic prescription for the treatment of cancer pain, it is difficult to obtain patient satisfaction only with an analgesic for suppressing pain that lasts all day, and it is necessary to cope with sudden pain that suddenly attacks It is very important to bring a fast-acting analgesic so that it can be taken at the patient's discretion. In other words, cancer pain treatment, especially opioid therapy for cancer pain, which is nociceptive pain, requires a combination of taking an opioid formulation that exhibits stable analgesic effects over a long period of time and taking a rapid-acting opioid formulation. If neither of these is present, opioid therapy is not possible.

In addition, the World Health Organization (WHO) stated that the first goal in the treatment of cancer pain was to ensure a good night's sleep without being interrupted by the pain, and then to eliminate the pain at rest during the day. It is advocated that it is to eliminate the pain during body movement. Therefore, in general, analgesics are basically administered orally, and efforts are made to maintain effective blood concentrations that exert analgesic effects. If oral administration is not possible, rectal administration, subcutaneous administration, or intravenous administration is performed. ing. In order to maintain the effective blood concentration, analgesics are repeatedly administered. However, in this administration method, the maximum blood concentration (C _max ) appears repeatedly, resulting in severe nausea and vomiting, which are side effects, particularly in the case of morphine preparations. Often, continuous administration of the formulation becomes difficult.

  In the case of digestive cancer and terminal cancer, oral administration is often difficult, and parenteral administration is performed. However, many patients are resistant to rectal administration (suppository), and the injection during subcutaneous or intravenous administration is painful and causes muscle atrophy at the administration site by repeated injections. There are also problems, and there is a high demand for the development of opioid analgesics that do not have these problems.

  Furthermore, cancer pain is the chief complaint of about 70% of end-stage cancer patients, and morphine hydrochloride, a narcotic analgesic, has long been administered among opioid analgesics to effectively remove this pain. Recently, pain control of cancer patients has been systematically implemented, and in recent years, oral sustained-release preparations have become common as medical morphine preparations.

  Therefore, an oral sustained release agent of morphine sulfate that can maintain the plasma concentration of morphine for 12 hours or more in a single administration has been developed. As these oral sustained-release preparations, morphine sulfate sustained-release preparations (market name: MS Contin (registered trademark)) by oral administration twice a day, or morphine sulfate sustained-release preparations (sale) by oral administration once a day Name: Kadian (registered trademark)). In such a sustained-release preparation, morphine sulfate was gradually released from the preparation in the digestive tract, and the effective blood concentration was maintained, thereby making it possible to reduce the number of repeated administrations. Therefore, the burden on the patient is reduced, and not only a good night sleep can be obtained, but also compliance is improved, and there is an advantage that the burden on the medical staff can be reduced.

  However, these oral sustained-release preparations are not completely free of problems. Both MS Contin and Kadian have side effects, such as digestive constipation, nausea, vomiting, dry mouth, loss of appetite, and the central system. Side effects such as sleepiness and confusion are observed. The incidence of side effects is high and is said to have reached about 50% or more.

  In addition, these sustained-release oral morphine agents have a duration of only 12 hours and have a drawback that they cannot be used in patients who cannot take them orally. Thus, the present inventors have been studying a route of administration of a drug that is difficult to be administered orally, and as one of the methods, studies by transdermal administration have been added.

  However, the skin permeability of the drug is remarkably deteriorated due to the presence of the stratum corneum located in the outermost skin layer. For this reason, the development of techniques for promoting the percutaneous absorption of drugs using chemical, physical and biological methods has been developed, and among these, research using percutaneous absorption enhancers has been actively conducted. It has been broken.

  For example, Patent Literature 1 discloses a technique for enhancing the effect of promoting absorption of a drug by using a fatty alcohol in combination with a lower alcohol. However, this method does not always provide a sufficient absorption promoting effect. Patent Document 2 discloses a technique for enhancing percutaneous absorption by combining a plurality of percutaneous absorption accelerators in percutaneous absorption of morphine hydrochloride. For example, it is intended to enhance narcotic and non-narcotic analgesic drugs such as morphine hydrochloride by combining absorption enhancers. Specifically, hydrochloric acid is prepared using an absorption enhancing composition composed of ethanol, l-menthol and water. It is intended to improve the effect of promoting transdermal absorption of morphine. However, this method promotes the transdermal absorption of morphine hydrochloride, but also promotes the skin permeability of ethanol and l-menthol at the same time, resulting in strong skin irritation.

Accordingly, the present situation is that development of a transdermal absorption composition with improved percutaneous absorption of morphine that eliminates these drawbacks is desired.
JP-A 61-249934 Japanese Patent Laid-Open No. 6-48962

  In view of the above-mentioned present situation, the present invention provides a composition for promoting percutaneous absorption, which reduces the occurrence of side effects, has a good transdermal absorbability of morphine, and is less irritating to the skin upon administration. Let it be an issue.

  As a result of intensive investigations by the present inventors to solve such problems, pyrrolidone derivatives and higher fatty acids having 10 to 18 carbon atoms are essential components, and organic acids, fatty acid esters, aromatic esters, etc. are added thereto as necessary. When the composition containing morphine is percutaneously absorbed, the in vivo absorbability of morphine is easily improved from the skin stratum corneum to the capillaries of the dermis layer and its deep blood vessels to the systemic circulatory system. As a result, the present invention has been completed.

  Therefore, the present invention for solving the above-mentioned problems is characterized in that, as a basic aspect thereof, a pyrrolidone derivative and a higher fatty acid having 10 to 18 carbon atoms are blended as essential components, and morphine is contained as a drug. It is a skin absorption promoting composition.

  More specifically, the present invention relates to the composition for promoting percutaneous absorption described above, wherein the blending ratio of the pyrrolidone derivative and the higher fatty acid having 10 to 18 carbon atoms is 1: 9 to 9: 1. is there.

  More specifically, the present invention provides the composition for promoting percutaneous absorption, wherein the pyrrolidone derivative is N-methyl-2-pyrrolidone and the higher fatty acid is oleic acid.

  Moreover, this invention is the said transdermal absorption promotion composition characterized by further including 1 type chosen from an organic acid, a fatty acid ester, and an aromatic ester as the specific aspect.

  That is, in the present invention, both pyrrolidone derivatives and higher fatty acids having 10 to 18 carbon atoms are selected as essential components constituting the transdermal absorption composition, and organic acids, fatty acid esters, aromatic esters, etc. are selected there as necessary. Morphine-containing percutaneous absorption composition with added morphine increases the permeability of morphine to the skin stratum corneum, and as a result, facilitates in vivo absorption from capillaries of the dermis layer and its deep blood vessels into the systemic circulatory system It has one feature at a point.

The composition for promoting percutaneous absorption provided by the present invention is a composition excellent in transdermal absorbability of morphine. By using this composition for promoting percutaneous absorption, the effective blood concentration of morphine can be increased over a long period of time. Can be maintained. Therefore, it has the advantage that it can be effectively applied to a patient who presents pain symptoms, and an extremely high analgesic effect can be expected.
In addition, side effects such as digestive constipation, nausea, vomiting, dry mouth, loss of appetite and side effects such as central sleepiness and confusion observed in oral administration are also reduced. Moreover, it has the advantage that an excellent composition is provided.

  The basic aspect of the present invention, as described above, is a composition for promoting percutaneous absorption, comprising a pyrrolidone derivative and a higher fatty acid having 10 to 18 carbon atoms as essential components, and containing morphine as a drug. The transdermal absorption promoting composition is characterized in that the blending ratio of the pyrrolidone derivative and the higher fatty acid having 10 to 18 carbon atoms is 1: 9 to 9: 1.

Hereinafter, each element constituting the transdermal absorption composition provided by the present invention will be described in detail below.
Examples of pyrrolidone derivatives used in the composition of the present invention include 2-pyrrolidone, N-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2- Examples include pyrrolidone and 1-dodecyl-2-pyrrolidone. Among these, N-methyl-2-pyrrolidone (hereinafter referred to as NMP) is preferably used. The blending amount is 5 to 90% by weight, preferably 30 to 90% by weight.
If the blending amount is less than 5% by weight, the intended percutaneous absorption effect cannot be increased, and even if the blending amount exceeds 90% by weight, no further effect is observed, which is wasted.

On the other hand, examples of the higher fatty acid having 10 to 18 carbon atoms used in the composition of the present invention include higher fatty acids such as lauric acid, myristic acid, palmitic acid, and oleic acid. Among them, oleic acid is preferable. used. The blending amount is 5 to 90% by weight, preferably 5 to 50% by weight.
If the blending amount is less than 5% by weight, the intended percutaneous absorption effect cannot be increased, and even if the blending exceeds 50% by weight, no further effect is observed, which is wasted.

  In the composition of the present invention, the blending amount of the pyrrolidone derivative and the higher fatty acid having 10 to 18 carbon atoms is maintained, and the blending ratio of the pyrrolidone derivative and the higher fatty acid having 10 to 18 carbon atoms is 1: 9. It was found to be ˜9: 1, but preferably 1: 1 to 9: 1. That is, it is preferable to use the pyrrolidone derivative in an equivalent amount (% by weight) to about 9 times the equivalent amount (% by weight) with respect to the blended amount of the higher fatty acid.

  Further, the percutaneous absorption enhancing composition of the present invention can further contain a percutaneous absorption enhancing agent, and examples of such absorption enhancing agents include organic acids, fatty acid esters and aromatic esters, By further containing one of them, the transdermal absorbability of morphine is further improved.

  Examples of such organic acids include monocarboxylic acids such as lactic acid, propionic acid, capric acid, sorbic acid, salicylic acid, gallic acid, acetic acid, butyric acid, and valeric acid; adipic acid, maleic acid, oxalic acid, malonic acid, and succinic acid. Examples thereof include dicarboxylic acids such as acid, glutaric acid, fumaric acid, phthalic acid, isophthalic acid, terephthalic acid, and malic acid; and tricarboxylic acids such as citric acid. In addition, any pharmaceutically acceptable organic acid may be used. Of these, sorbic acid, succinic acid and adipic acid are particularly preferred. The amount of these applied is 1 to 10% by weight, preferably 1 to 5% by weight.

  Examples of fatty acid esters include diisopropyl sebacate, diethyl sebacate, dioctyl sebacate, methyl oleate, ethyl oleate, n-butyl oleate, decyl oleate, oleyl oleate, isopropyl myristate, octyl myristate Examples thereof include decyl and diisopropyl adipate. In addition, a pharmaceutically acceptable fatty acid ester may be used. Of these, ethyl oleate and isopropyl myristate are particularly preferable. The amount of these applied is 1 to 30% by weight, preferably 1 to 5% by weight.

  Furthermore, examples of the aromatic ester include ethyl aminobenzoate, benzyl benzoate, and phenyl salicylate. Any other pharmaceutically acceptable aromatic ester may be used. The amount of these applied is 1 to 10% by weight, preferably 1 to 5% by weight.

On the other hand, the blending amount of morphine is preferably used so as to be within the range of 0.001 to 25% by weight as the content in the intended transdermal absorption composition.
If it is less than 0.01% by weight, the intended analgesic effect cannot be obtained, and even if it exceeds 25% by weight, no further analgesic effect is observed, which is wasted.

In the composition of the present invention, an appropriate amount of an ultraviolet absorber, an antioxidant or other excipients can be blended as required.
Examples of these ultraviolet absorbers, antioxidants, and other excipients include pharmaceutically acceptable components used for transdermal administration.

  The absorbent composition of the present invention can be applied transdermally as it is or as an external preparation in various dosage forms. Examples of such dosage forms for external use according to the present invention include gels, ointments, creams, lotions, liniments, patches, reservoir-type patches, and the like. In general, it can be carried out by adopting widely used means.

  Hereinafter, the present invention will be described more specifically based on examples and test examples, but the present invention is not limited thereto.

Test Example 1:
Using 6-week-old Wistar rats, euthanized with ether, the abdomen was removed with a clipper, and the abdominal skin was removed. The abdominal skin was sandwiched between vertical diffusion cells (effective diffusion area: 1.77 cm ² ), the mixed compositions of Examples and Comparative Examples described in Table 1 below were placed on the stratum corneum side, and pH 7 was placed on the dermis layer side. .4 phosphate buffer was applied. The experiment temperature was 32 ° C., and 300 μL of phosphate buffer was sampled at 2, 4, 6 and 8 hours after the start of the experiment, and the concentration of morphine that permeated through the skin and eluted in the buffer was measured by HPLC. The cumulative amount of morphine permeated in was measured. The results are shown in FIG. In the drawing, numbers corresponding to the examples and comparative examples are indicated by circled numbers (the same applies hereinafter).

Test example 2:
In the same manner as in Test Example 1, a mixture composition of each example described in Table 2 below was applied to the stratum corneum side, and a phosphate buffer solution having a pH of 7.4 was applied to the dermis layer side. The experiment temperature was 32 ° C., and 300 μL of phosphate buffer was sampled at 2, 4, 6 and 8 hours after the start of the experiment, and the concentration of morphine that permeated through the skin and eluted in the buffer was measured by HPLC. The cumulative amount of morphine permeated in was measured. The results are shown in FIG.

Test Example 3:
In the same manner as in Test Example 1, a mixture composition of each example described in Table 3 below was applied to the stratum corneum side, and a phosphate buffer solution having a pH of 7.4 was applied to the dermis layer side. The experiment temperature was 32 ° C., and 300 μL of phosphate buffer was sampled at 2, 4, 6 and 8 hours after the start of the experiment, and the concentration of morphine that permeated through the skin and eluted in the buffer was measured by HPLC. The cumulative amount of morphine permeated in was measured. The results are shown in FIG.

Test Example 4:
In the same manner as in Test Example 1, a mixture composition of each example described in Table 4 below was applied to the stratum corneum side, and a phosphate buffer solution having a pH of 7.4 was applied to the dermis layer side. The experimental temperature was 32 ° C. 300 μL was sampled at 2, 4, 6 and 8 hours after the start of the experiment. Drug concentration was measured using HPLC. The result is shown in FIG.

  As can be seen from the results of each of the above Test Examples 1 to 4, the composition of the present invention has morphine permeated through the stratum corneum to the dermis side over time, and its effect is also sustained. It is understood that

  The effect is due to the fact that both the pyrrolidone derivative and the higher fatty acid having 10 to 18 carbon atoms are selected as essential components constituting the transdermal absorption composition as the composition of the present invention. That is, comparing the results of Examples 1 to 5 and Comparative Examples 1 and 2 of the present invention in Test Example 1, both the pyrrolidone derivative and the higher fatty acid having 10 to 18 carbon atoms are essential components in the present invention. The selected benefits are clearly understood.

  Furthermore, as can be seen from the results shown in Test Examples 2 to 4, by adding a transdermal absorption promoter such as an organic acid, a fatty acid ester, or an aromatic ester, it is more effective in the present invention. It is understood that a morphine-containing transdermal absorption composition is provided.

As described above, the composition for promoting percutaneous absorption provided by the present invention is a composition excellent in transdermal absorbability of morphine, and can maintain the effective blood concentration of morphine for a long time. It is. Therefore, it can be effectively applied to patients exhibiting pain symptoms, and an extremely high analgesic effect can be expected.
Furthermore, side effects such as digestive constipation, nausea, vomiting, dry mouth, loss of appetite, and other side effects such as central sleepiness and confusion, alleviated by the oral route, and reduced patient compliance. The medical value is great in that an excellent composition is provided.

It is a graph which shows the cumulative permeation | transmission amount-time behavior of morphine through the rat excision skin using the mixed composition based on the Example and comparative example which were shown in Table 1 of Test Example 1. It is a graph which shows the cumulative permeation | transmission amount-time behavior of morphine through the rat excised skin using the mixed composition based on the Example shown in Table 2 of Test Example 2. It is a graph which shows the cumulative permeation | transmission amount-time behavior of morphine through the rat extraction skin using the mixed composition based on the Example shown in Table 3 of Test Example 3. It is a graph which shows the cumulative permeation | transmission amount-time behavior of morphine through the rat extraction skin using the mixed composition based on the Example shown in Table 4 of Test Example 4.

Claims (3)

A transdermal absorption enhancing composition comprising N-methyl-2-pyrrolidone and oleic acid as essential components, and containing morphine as a drug. The composition for promoting percutaneous absorption according to claim 1, wherein the blending ratio of N-methyl-2-pyrrolidone and oleic acid is 1: 9 to 9: 1. The composition for promoting percutaneous absorption according to claim 1 or 2 , further comprising one kind selected from an organic acid, a fatty acid ester, and an aromatic ester.

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