KR100649860B1 - Transmucosal and transdermal delivery preparation of alprostadil - Google Patents

Abstract

An object of the present invention is to develop alprostatil as a transmucosal and transdermal absorbent which is excellent in the treatment of erectile dysfunction and impotence in men caused by mental and physical factors.

Transmucosal and transdermal absorption agents of the present invention are pharmacologically a) effective amounts of alprostadyl; b) a polyhydric alcohol fatty acid ester conjugate obtained by ester-bonding a fatty acid having 6 to 18 carbon atoms to a polyhydric alcohol selected from propylene glycol, glycerin and polyethylene glycol; And at least one skin permeation promoter selected from polyoxyethylene fatty alcohol ether binders in which polyoxyethylene ether-bonded fatty alcohols having 6 to 18 carbon atoms; c) a mixture of a nonvolatile solvent and a volatile solvent; d) A pharmaceutical composition containing a thickener or further containing an aqueous phase to form a supersaturated delivery system for the skin permeation promoter.

By selecting an optional skin permeation promoter and forming a supersaturated delivery system for the skin permeation promoter, the skin permeation rate of alprostadil can be greatly increased and the initial delay time for skin permeation can be significantly reduced.

Alprostadil

Description

Transprotocosal and transdermal delivery preparation of alprostadil

Figure 1 shows the skin permeation amount of the transmucosal membrane and transdermal absorbent of the present invention using a polyhydric alcohol fatty acid ester conjugate as a skin permeation accelerator.

Figure 2 shows the skin permeation amount of the transmucosal membrane and transdermal absorbent of the present invention using a polyethylene glycol fatty acid ester conjugate and a polyoxyethylene fatty alcohol ether conjugate as skin permeation accelerator.

Figure 3 compares the skin permeation amount of the transmucosal and transdermal absorbents of the present invention and the comparative formulation containing no skin permeation accelerator.

Figure 4 compares the skin permeation amount of the transmucosal transdermal absorption agent of the present invention to form a supersaturated delivery system with respect to the skin permeation accelerator and a comparative agent that does not form a supersaturated delivery system.

Figure 5 shows the stability results according to the storage conditions of the transmucosal and transdermal absorption preparation of the present invention.

The present invention relates to a pharmaceutical composition used for the treatment of erectile dysfunction by absorbing alprostadil with excellent vasodilation through the local mucosa or skin.

Many drugs have been applied for the treatment of erectile dysfunction in men caused by mental and physical factors. In 1980, drugs such as nitroglycerin using the role of nitric oxide in erectile dysfunction were attempted as injections and transdermal absorbents. Since 1990, alprostadil and sildenafil have been applied to the treatment of erectile dysfunction. have. However, nitroglycerin has excellent skin absorbency but low blood vessel selectivity, which does not induce sufficient erection. In addition, alprostadil is developed as an injection and urethral suppositories due to low skin absorption rate, and has the disadvantage of low adaptability to patients, and sildenafil is applied as an oral drug, resulting in excellent adaptability of patients but frequently causing side effects due to systemic absorption. . Therefore, in recent years, it is expected that the development of an agent that can increase the skin absorption rate of alprostadil will bring dramatic progress in the treatment of erectile dysfunction.

Alprostadil is a poorly soluble substance having a molecular weight of 354.49 and is known to induce penile cavernous erection by showing selective arterial vasodilation when applied to the penis as a prostaglandin E1 existing in a normal body. However, as mentioned above, alprostadil's low skin absorption and long delay in skin penetration have been a major problem in the development of mucosal and skin absorption preparations. In addition, alprostadil has a very short half-life from 30 seconds to 10 minutes in human plasma, depending on the in vivo condition. The unit dose is about 1000 μg, when the drug is administered by suppository, the amount of corpus cavernosum reaches less than 1%.

Therefore, the key to the development of alprostadil mucosa and skin absorbents is maximization of skin absorption rate and increase of in vivo stability.

In fact, research on the development of alprostadil mucosa and skin absorbents is divided into two categories. The first is to select an optimal skin permeation accelerator to maximize skin permeability and increase the amount of drug administered in the body. And more than 1% of the drug will reach the corpus cavernosum. The second is to form cyclodextrins and liposome inclusions even when the skin absorption is low, so that the drug is stabilized in plasma to reach the corpus cavernosum without being degraded. However, the second solution alone has been pointed out as a problem that clinical application is difficult due to the delayed time of expression. As a result, in the development of alprostatil mucosa and skin absorbents, increasing the skin permeation rate of the drug is a problem to be solved first.

To date, alprostadil has been developed for injection and urethral suppositories for this reason and they do not improve patient adaptability.

Prior arts of urethral suppositories include U.S. Pat.Nos. 5,242,391, 5,474,535, 5,718,917, 5,773,020, and 5,820,587, and Korean Patent Registration No. 207,224 and Korean Patent Publication Nos. 98-74807, 98-703052, 99-74975 and 00-22734. US Patent No. 5,820,587 and Korean Patent Publication No. 98-703052 describe periodic dosing and urethral injection tools, and US Patent Nos. 5,242,391 and 5,773,020 provide urethral suppository infusions for drug release from surface coatings. 5,474,535 describes an infusion method for administering a solid suppository to the urethra. In addition, US Patent No. 5,718,917, Korean Patent Registration No. 207,224, and Korean Patent Publication No. 98-74807 describe a drug delivery system of suppositories or external preparations in which a drug is encapsulated in lyophilized liposomes, and Korean Patent Publication No. 99-74975 is Pollock. Preparation of suppositories using a summer and microemulsion system, Korean Patent Laid-Open Publication No. 00-22734 describes a suppository in which viscosity increases upon injection using a self-emulsifying system. All of the patents except Korean Patent Publication No. 98-74807 in the above patents do not mention the technology for the mucosal and skin permeation mechanisms, and only mention No. 98-74807 that the liposome is formulated by mixing the skin penetration enhancer. However, in No. 98-74807, skin permeation experiments were not carried out by the skin penetration enhancer, and simply added Azone, dimethyl sulfoxide, decylmethyl sulfoxide, and lauryl alcohol.

Meanwhile, prior arts related to increasing skin penetration of alprostadil include US Pat. Nos. 5,942,545 and 6,046,244, Korean Patent Publication Nos. 99-87057, Japanese Patent No. 3,083,926, and European Patent No. 722,323. US Pat. Nos. 5,942,545 and 6,046,244 and Korean Patent Publication No. 99-87057 describe external preparations that increase the skin permeation rate of alprostadil by adding a skin permeation accelerator. Japanese Patent No. 3,083,926 describes cyclodextrins and skin. For external preparations using a permeation accelerator, European Patent No. 722,323 describes the preparation of external preparations using physicochemical complexes with lecithin. Among them, U.S. Patent Nos. 5,942,545, 6,046,244 and Japanese Patent No. 3,083,926 proved that the skin permeation of alprostadil was increased by using a skin permeation accelerator, and Alp has excellent efficacy as a transmucosal and transdermal absorbent. Lostadil ointment, creams and gels were prepared. U. S. Patent No. 5,942, 545 uses a combination of 1,3-dioxane, 1,3-dioxolane and acetal group as a fatty alcohol group having 6 to 20 carbon atoms as a skin permeation accelerator, and U. S. Patent No. 6,046,244 to a fatty alcohol. Japanese-American Patent No. 3,083,926 used 1- [2- (decylthio) ethyl] azabicyclopent-2-one as a skin permeation accelerator for a conjugate in which amino acids or amino acids and amino alcohols were combined. However, the skin permeation promoter mentioned in these patents is not only a substance that is completely different from the skin permeation promoter used in the present invention, but the concept of a supersaturation delivery system for the skin permeation promoter described in the present invention has not been proved. The result of U.S. Patent No. 6,046,244, in which the skin dosage of the drug is further improved by the use of, does not fall short of the alprostadyl skin dosage according to the present invention. In the case of Korean Patent Publication No. 99-87057, the skin permeation accelerator is different from the ester sunscreen having a benzene ring as the skin permeation accelerator, and no specific experimental example for increasing the skin permeation of alprostadil is described. .

Further, prior arts for matrix structures or devices for skin penetration include US Pat. Nos. 4,594,240, 5,380,760, 5,741,511, 5,889,875, and 6,036,977. Among them, U.S. Patent Nos. 4,594,240, 5,380,760 and 6,036,977 describe formulations in which the drug is released from a solid matrix made of a polymer, but there is no experimental example of skin permeation by a skin permeation accelerator, and only the polymer composition of the matrix is disclosed. U.S. Patent Nos. 5,741,511 and 5,899,875 describe a cylindrical skin penetrating device into which a penis is inserted.

The prior art using the chemical combination of esters and ethers used as skin permeation promoters as simple excipients, not as skin permeation promoters, is described in US Pat. Nos. 4,151,274, 4,409,239, 4,794,106, 5,569,461, 5,580,572. And 5,593,682 and Japanese Patent 7,330,609. US Pat. No. 4,151,274 is used as a suppository base, US Pat. No. 4,409,239 is used as a stabilizer for the solution phase of prostaglandin, US Pat. No. 4,794,106 is used as a surfactant of HLB 9-12, US Pat. No. 5,569,461 and No. 5,593,682 was used for the purpose of antiseptic, antimicrobial and skin compatibility of propylene glycol esters and in US Pat. Nos. 5,580,572 and 7,330,609 as plasticizers of the matrix. These patents have not been applied to prostaglandins except US Pat. No. 4,409,239 and there are no experimental examples of skin permeation. In the case of U.S. Patent No. 4,409,239, a propylene glycol lower fatty acid diester including propylene glycol dicapric acid ester was added for the purpose of stabilizing prostaglandins, but the formulation is an external preparation including ointments, gels and creams for transmucosal or transdermal absorption. It was prepared only in the form of a prostaglandin solution for the purpose of injection, and no experimental example was found to reveal skin permeability improvement.

Prior arts using chemical combinations of such esters and ethers for the purpose of promoting skin permeation include US Pat. Nos. 4,602,040, 4,788,062, 6,019,988 and 6,205,839. U.S. Patent No. 4,602,040 used the above chemical combination of polyhydric alcohol and fatty acid to promote skin penetration of meclofenamic acid, and U.S. Patent No. 4,788,062 was used to promote skin penetration of sex hormone matrix formulation. No. 6,019,988 designed a dual mixed formulation and designed a formulation in which the drug and the skin permeation promoter were mixed separately when used. US Pat. No. 6,205,839 was used for the purpose of promoting skin permeation in the film formulation. However, the role of skin permeation promoters for drugs is specific, so even if they promote excellent skin permeation for one substance, the role of skin permeation promoter for other substances is unknown. Therefore, the above patents suggest skin permeation promoting ability for substances that are completely different from the chemical structure of prostaglandins including alprostadil, and apply alprostadil to penis skin, glans and urethral mucosa as in the present invention. No introduction into the formulation. In the case of US Pat. No. 6,019,988, a skin permeation accelerator is used in a dual-mix formulation, which has a similar aspect to the present invention, but separates and uses the drug and the skin permeation accelerator to solve the problem of reducing the mutual stability of the drug and the skin permeation promoter. It differs from the present invention in that it is a formulation mixed with.

The present inventors have solved the following two technical problems through many efforts to maximize the skin absorption rate of alprostadil and increase the stability in vivo, through which the alprostadyl transmucosal and transdermal absorption preparations can be developed.

The first is to select a skin permeation accelerator that can be used pharmaceutically and significantly improve skin permeability in order to improve the low skin permeability of alprostadil. To this end, the present inventors evaluated skin permeability by structure for skin permeation accelerators of various structures, and found that surprisingly, skin permeability improvement was observed among excipients that have been used and proven to be safe.

The second is to provide an erectile dysfunction treatment drug that can suppress the initial absorption delay of alprostadyl and can be expressed in a short time. To this end, in the present invention, the initial absorption delay time can be minimized by causing the thermodynamic potential of the skin permeation accelerator rather than the drug (pharmacologically active substance). In other words, the supersaturation of the skin permeation accelerator belonging to the lipophilic induction to accelerate the skin migration of the skin permeation accelerator, and as a result it was confirmed that the initial delay for promoting the skin permeation is generally minimized.

The present invention is applied to the penis, glans, urethra, scrotum and perineal region of the male genitalia, as a transmucosal and transdermal absorbent which induces normal erection in patients with erectile dysfunction and impotence, a lipophilic part (A) and a hydrophilic part (B). Or it consists of a lipophilic part (A) only and relates to a pharmaceutical composition that forms a supersaturated delivery system for the mucosa and the skin permeation accelerator below when applied. In other words,

(A): As a lipophilic part, with respect to the total formulation weight

a) pharmacologically effective amount of alprostadyl;

b) a polyhydric alcohol fatty acid ester conjugate obtained by ester-bonding a fatty acid having 6 to 18 carbon atoms to a polyhydric alcohol selected from propylene glycol, glycerin and polyethylene glycol; And 0.5 to 20% by weight of one or more skin permeation promoters selected from polyoxyethylene fatty alcohol ether conjugates ether-bonded fatty alcohols having 6 to 18 carbon atoms to polyoxyethylene.

c) 10 to 95 wt% of a mixed solution of a nonvolatile solvent and a volatile solvent; And

d) 0.1 to 5% by weight of a soluble thickener soluble in c) as a solvent

It is a pharmaceutical composition for forming a supersaturated delivery system for the skin permeation accelerator.

(B): As the hydrophilic part, the total weight of the formulation

a) 0.1 to 5% by weight of a water soluble thickener; And

b) a pharmaceutical composition which forms a supersaturated delivery system for the skin permeation accelerator further comprising a suitable amount of water or an acidic buffer at a pH of 3.0 to 7.4, or

(B): a hydrophilic portion, further comprising a suitable amount of water or an acidic buffer of pH 3.0 to 7.4 to form a supersaturated delivery system for the skin permeation accelerator or

(B): As a hydrophilic part, it is a pharmaceutical composition which mixes physiological urine and forms a supersaturated delivery system with respect to a skin permeation promoter.

In addition, the hydrophilic portion (B) can be stored in a separate container and mixed upon application to mucosa and skin to form a supersaturated delivery system for the skin permeation promoter.

Hereinafter, the components contained in the composition of the present invention will be described in detail.

The lipophilic portion and the hydrophilic portion of the present invention are meant to be relative concepts of lipophilicity and hydrophilicity, not concepts separated with absolute criteria. This does not mean that all of the compositions belonging to the lipophilic part are incompatible with water, but rather hydrophobic (lipophilic) in comparison with the hydrophilic part and do not contain water or contain less than 1% by weight of the total formulation weight. By hydrophilic part is meant a part which directly contains water. The lipophilic moiety of the present invention may achieve the object of the present invention alone without a hydrophilic moiety, which has an HLB value of 4 or less, so that the skin permeation accelerator may be achieved by volatilization of a volatile solvent without addition of a hydrophilic moiety. This is because supersaturation of can be induced. If the HLB value is 4 or more, a supersaturated delivery system is formed for the skin permeation accelerator through mixing of the hydrophilic portion with the volatilization of the volatile solvent.

Alprostadil as a pharmacologically active substance in the composition of the lipophilic portion of the present invention is prostaglandin E1 (PGE1) having vasodilatation action, [11,15-dihydroxy-9-oxoprost-13-ene- Lonic acid; And 3-hydroxy-2- (3-hydroxy-1-actenyl) -5-oxo-cyclopentaneheptanoic acid] or chemical and physical derivatives thereof without departing from the scope of the present invention.

In addition, pharmacologically active substances include prostaglandins including prostaglandin E2 and papaverine, pentoramine, prazosin, minoxidil, nitroglycerin, alpha blockers, NO donors and VIPs that have vasodilatation and are available for erectile dysfunction. A protein drug may also be used, and may be used in combination or in combination with alprostadyl and the above pharmacologically active substance.

The preparation of the present invention can adjust the amount of alprostatil per unit according to the degree of symptoms of erectile dysfunction, generally it is preferred to use 50 μg ~ 4 mg per unit, more preferably 100 μg ~ 2 mg. In addition, the alprostadyl content in the formulation is preferably used in an amount of 0.01 to 5% by weight based on the total weight of the formulation, more preferably 0.1 to 2% by weight.

Skin permeation promoter for promoting the mucous membrane and skin absorption of the active material in the composition of the polyhydric alcohol fatty acid ester conjugates ester-bonded fatty acid having 6 to 18 carbon atoms to polyhydric alcohol selected from propylene glycol, glycerin and polyethylene glycol; And polyoxyethylene fatty alcohol ether conjugates obtained by ether-bonding fatty alcohols having 6 to 18 carbon atoms to polyoxyethylene may be used.

As skin permeation accelerators, propylene glycol fatty acid ester conjugates of propylene glycol and glycerin and fatty acids and glycerin fatty acid ester conjugates have the structures of formulas (1) and (2), respectively.                     

Polyethylene glycol fatty acid ester conjugate of polyethylene glycol and fatty acid has the structure of formula (3)

The polyoxyethylene fatty alcohol ether conjugate of polyoxyethylene and fatty alcohol has the structure of formula (4).

In the formulas (1) to (4), X represents hydrogen or a hydroxyl group, n ₁ represents an integer of 4 to 16, and n ₂ represents an integer of 1 to 6, respectively.

The propylene glycol fatty acid ester conjugate and the glycerin fatty acid ester conjugate of the present invention include hydroxyl groups of propylene glycol and glycerin and fatty acids having 6 to 18 carbon atoms (capric acid, lauric acid, palmitic acid, myristic acid, stearic acid, oleic acid, linoleic acid, etc.). ) Is a material ester-bonded 1: 1 to 1: 2. The polyethyleneglycol fatty acid ester conjugate refers to a substance in which a fatty acid having 6 to 18 carbon atoms is ester-bonded 1: 1 in the terminal hydroxyl group of polyethyleneglycol polymerized with 1 to 6 monomers. The polyoxyethylene fatty alcohol ether conjugate is a fatty alcohol having 6 to 18 carbon atoms (capryl alcohol, lauryl alcohol, palmityl alcohol, myristyl alcohol, stearyl alcohol, oleyl) in polyoxyethylene in which monomers are polymerized to 1 to 6 Monoalcohol and linoleyl alcohol, etc.) refers to a substance in which the ether is 1: 1.

The skin permeation accelerators of the present invention are hydrophobic fatty acids and fatty alcohols in which hydrophilic substances (polyhydric alcohols, polyethylene glycol and polyoxyethylene) are combined, and have a relatively high HLB (oil distribution coefficient) value as compared to fatty acids and fatty alcohols. It is preferable to have a value of 10, more preferably 2 to 8, insoluble in water, but soluble in lower alcohols having 4 or less carbon atoms, and dissolving in a mixed liquid of water and lower alcohols depending on the mixing ratio.

When using general fatty acids and fatty alcohols as skin permeation accelerators, the initial delay time required for skin permeation does not show rapid drug expression in the treatment of erectile dysfunction, but the skin permeation accelerators of the present invention are based on the combination of appropriate hydrophobic fat chains and hydrophilic groups. It maintains emulsions for a certain period of time even in thermodynamically unstable supersaturation, resulting in rapid and sustained skin penetration promoting effect. Therefore, the mixing ratio (100: 0 to 5:95) of the lipophilic portion and the hydrophilic portion of the present invention is not intended for simple mixing but is determined by the solubility of the skin permeation accelerator. For example, the propylene glycol lauric acid ester of the skin permeation promoter is completely dissolved in the ratio of lipophilic portion and hydrophilic portion of 55:45 or more and less than emulsion, suspension and precipitation in the formulation, The composition showing the short initial delay time and the highest skin penetration rate is the mixing ratio of the lipophilic portion and the hydrophilic portion at which the emulsion of the skin permeation accelerator begins to form. In addition, in the above example, when the ratio of the lipophilic portion to the hydrophilic portion is 80:20, the saturation of the skin permeation accelerator is reduced, so that the initial delay time is very long, and thus the object of the present invention, which requires rapid drug efficacy, cannot be achieved. Conversely, when the ratio is 20:80, the saturation increases, but the total amount of skin permeation accelerator that can act due to precipitation decreases, resulting in a significant decrease in the overall skin permeability of the drug (including the initial delay time and skin penetration rate). Was observed. However, in the case of the propylene glycol stearic acid ester conjugate having an HLB value of 4 or less, supersaturation occurs even at a ratio of 100: 0 of the lipophilic portion and the hydrophilic portion, and in this case, the volatilization of the volatile solvent in the lipophilic portion is not added. It was confirmed that the supersaturation according to the present invention can sufficiently achieve the object of the present invention. Therefore, it is the core of the present invention to induce supersaturation of the skin permeation accelerator by controlling the use of a selective skin permeation accelerator and the ratio of the lipophilic portion and hydrophilic portion according to the active material.

Skin permeation accelerators include fatty acid ester conjugates of propylene glycol, glycerin and polyethylene glycol; And it is preferable to use at least 0.5 to 20% by weight, more preferably 1 to 10% by weight based on the total weight of the formulation of at least one selected from the polyoxyethylene fatty alcohol ether binder.

Non-volatile solvents and volatile solvents in the composition of the lipophilic portion of the present invention include, but are not limited to the following.

As the non-volatile solvent, at least one selected from ethylene glycol, propylene glycol, propylene carbonate, propylene glycol acetate, glycerin, polyethylene glycol, and polypropylene glycol has a high boiling point and can be mixed with water to buffer the volatile solvent. It is a liquid substance.

And as a volatile solvent, C4 or less lower alcohols, such as methanol, ethanol, and isopropanol; And at least one selected from acetone and the like, and a liquid substance capable of volatilization at room temperature. These volatile solvents, together with the non-volatile solvents, form the solvent of the lipophilic portion of the present invention, thereby functioning to induce and maintain supersaturation of the skin permeation promoter. That is, the volatile solvent is volatilized to induce supersaturation of the skin permeation accelerator and to maintain the supersaturated state by the buffering action of the nonvolatile solvent. This results in the formation of a supersaturated delivery system that induces a thermodynamic potential, thereby increasing the skin migration of the skin permeation accelerator, reducing the initial delay time of the drug's mucosa and skin permeation, and significantly improving skin permeability.

The nonvolatile solvent and the volatile solvent are 10 to 95% by weight based on the total weight of the formulation as a mixed solution. The mixing ratio of the volatile solvent and the nonvolatile solvent is preferably 10:90 to 90:10, more preferably 30:70 to 70:30.

Thickeners used in the lipophilic portion of the present invention include, but are not limited to the following. Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyethylene oxide, chitosan, alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, poly (methylvinylether / maleic anhydride) polymer, poly (vinylpyrrolidone) Polymers such as polyvinylacetate), carbopol and polycarbophil; and one or more selected from sugars such as lactose, chitooligosaccharide, fructose and dextrose. However, derivatives of these polymers prepared by combining functional groups such as salts, hydroxyl groups, amine groups and alkyl groups or complex groups thereof with the above polymers are also included in the scope of the thickener of the present invention.

The thickener is preferably used in an amount of 0.1 to 5% by weight, more preferably 0.2 to 2.5% by weight based on the total weight of the formulation.

Water-soluble thickeners in the composition of the hydrophilic portion of the present invention are as follows, but is not limited thereto. Hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyethylene oxide, acacia gum, xanthan gum, chitosan, alginic acid, polyvinylpyrrolidone, polyvinyl alcohol, poly (methyl vinyl ether / Polymers such as maleic anhydride) polymer, poly (vinylpyrrolidone / polyvinylacetate), carbopol and polycarbophil; and one or more selected from sugars such as white sugar, chitooligosaccharide, lactose, fructose and dextrose; can do. However, derivatives of these polymers prepared by combining functional groups such as salts, hydroxyl groups, amine groups and alkyl groups or complex groups thereof with the above polymers are also included in the scope of the thickener of the present invention.

The thickener is used in 0.1 to 5% by weight based on the total weight of the formulation, preferably 0.2 to 2.5% by weight.

And the composition of the hydrophilic portion of the present invention is preferably used to have water or acid buffer of pH 3.0 ~ 7.4 as the remainder and the total amount is 100%. Since alprostadil is most stable at pH 3.0 in aqueous solution and most stable at pH 5.0 in emulsion, acid buffer is preferred for drug stability. However, when using a skin permeation accelerator of HLB 4 or less, the hydrophilic portion can be omitted in the composition of the present invention.

In addition, the hydrophilic portion may be replaced with a physiological solution containing human urine, and the total amount may be 100%. Human urine is known to be within pH 4.0-7.0 which is weakly acidic under normal conditions, and when applied in the urethra, it acts as a good acid buffer without producing a separate hydrophilic part.                     

The composition of the present invention may additionally be added to the preservatives, stabilizers and pain inhibitors and the like as a pharmaceutically acceptable additive. At least one preservative selected from methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and benzoic acid; and at least one stabilizer selected from tocopherol, butylhydroxyanisole (BHA) and butylhydroxytoluene (BHT). issue; And one or more pain inhibitors selected from menthol, thymol, cineol and lidocaine and the like can be added in a pharmaceutically acceptable range.

The alprostadyl transmucosal and transdermal absorption composition of the present invention can be applied to male periods with erectile dysfunction or impotence due to vascular abnormalities, nervous system abnormalities, trauma, mental stress, pelvic surgery and other drug side effects.

The composition can be applied on the penis skin and glans mucosa of the male genital organs or applied only to the glans mucosa and can also be applied to the urethral mucosa, scrotum and perineal skin. When the composition is composed of a lipophilic portion and a hydrophilic portion, it can be applied by mixing or pre-mixing while applying by massage at the application site, and also applying any one part first and reapplying the remaining part to the same site. can do. On the other hand, when the composition is composed of only the lipophilic portion can be applied by massage to the application site. In addition, when applied to the urethra (urinary tract), the hydrophilic part is not added separately and only the lipophilic part is injected and then mixed with urine through a massage. The composition of the present invention applied to the mucous membrane and skin through this induces and maintains the supersaturation of the skin permeation accelerator, and the conventional research (US Patent No. 5,380,760; US Patent No. 6,046,244; Int. ), 229; J. Pharm. Sci. Vol. 87 (1998), 721) showed superior alprostadil skin penetration rates.

Referring to the manufacturing method of the alprostadil transmucosal and transdermal absorption preparations according to the present invention as a whole, but is not limited thereto.

First, a non-volatile solvent and a volatile solvent were added to the thickener of the lipophilic portion to prepare a transparent gel or a viscous liquid. A certain amount of the drug and the skin absorption accelerator were added to the mixture so as to completely dissolve the mixture, thereby preparing a composition of the lipophilic portion of the present invention. The hydrophilic portion was added water or acid buffer to the thickener and stirred to produce a transparent gel or viscous liquid, which was used as the composition of the hydrophilic portion. However, a hydrophilic part can be prepared separately or the physiological fluid can be replaced as a hydrophilic part. And other pharmaceutically acceptable additives can be added to the lipophilic or hydrophilic part depending on the physical properties and uses.

The final formulation of the present invention is prepared by storing the lipophilic portion and the hydrophilic portion separately in two storage containers, or by separating the lipophilic portion and the hydrophilic portion by placing a separator which does not pass moisture in the same container. Stability was secured during the storage of the deal. In use, the two containers are applied to the same area of the mucous membrane and skin by squeezing and mixing, or in the case of the same container, the separator is destroyed or removed to be mixed and applied, but not limited thereto.

Hereinafter, the present invention will be described with reference to specific examples. However, the present invention is not limited to these examples. However, unless otherwise indicated, the quantity described in this specification and an Example means weight%.

Examples 1-5

Alprostadyl was used as a pharmacologically active ingredient, and propylene glycol fatty acid ester and glycerin fatty acid ester were added as skin permeation accelerators to prepare as shown in Table 1 below.

Composition of Examples 1-5 Furtherance Example 1 Example 2 Example 3 Example 4 Example 5 Lipophilic part Alprostadil One One 0.5 One One Propylene Glycol Capric Acid Ester 5 - - - - Propylene Glycol Lauric Acid Ester - 5 5 - - Propylene Glycol Stearic Acid Ester - - - 5 - Glycerin Oleic Acid Ester - - - - 5 Propylene glycol 24.25 26.73 26.73 46.53 28 ethanol 24.25 26.73 26.73 Isopropyl Alcohol 46.53 28 Hydroxypropyl cellulose 0.5 0.54 0.54 0.94 0.56 Hydrophilic part Hydroxyethyl cellulose 0.45 0.4 0.4 - 0.38 pH 5.0 buffer q.s q.s q.s - q.s Sum 100 100 100 100 100

Examples 1, 2, 4 and 5 were prepared to contain all 1% of alprostadyl as a pharmacologically active substance and Example 3 to contain 0.5%. In the lipophilic portion, propylene glycol capric acid ester, propylene glycol lauric acid ester, propylene glycol stearic acid ester, and glycerin oleic acid ester were contained 5% as skin permeation accelerators of Examples 1 to 5, and Ethanol (Examples 1, 2, 3) and isopropyl alcohol (Examples 4, 5) were used as the volatile solvent, and hydroxypropyl cellulose was added and mixed as a thickener of the lipophilic portion. In addition, hydroxyethyl cellulose and an acidic buffer solution were added to the hydrophilic portion to mix and dissolve. However, in Example 4, a hydrophilic part is not manufactured separately. The compositions of Examples 1 to 5 prepared through this were separately stored and stored in the lipophilic portion and the hydrophilic portion, and were used by mixing. All skin permeation accelerators of Examples 1 to 5 exhibited a supersaturation state by mixing two portions and evaporating a volatile solvent during use.

Examples 6-8

Alprostadyl was used as a pharmacologically active ingredient, and polyethylene glycol fatty acid ester conjugate and polyoxyethylene fatty alcohol ether conjugate were added as skin permeation accelerators to prepare as shown in Table 2 below.

Compositions of Examples 6-8 Furtherance Example 6 Example 7 Example 8 Lipophilic part Alprostadil One One One Polyethylene glycol (2) ^a oleic acid ester 5 - - Polyoxyethylene (2) ^a lauryl alcohol ether - 5 - Polyoxyethylene (2) ^a oleyl alcohol ether - - 5 Propylene glycol 46.53 20.79 28.22 ethanol - 20.79 - Isopropyl Alcohol 46.53 - 28.22 Hydroxypropyl cellulose 0.94 0.42 0.57 Hydrophilic part Hydroxyethyl cellulose - 0.52 0.38 pH 5.0 buffer - q.s q.s Sum 100 100 100

a: number of monomers in the polymer

Examples 6 to 8 were prepared to contain all 1% of alprostadil as a pharmacologically active substance. And in the lipophilic portion, 5% of polyethylene glycol (2) oleic acid ester, polyoxyethylene (2) lauryl alcohol ether, and polyoxyethylene (2) oleyl alcohol ether were included as skin permeation accelerators of Examples 6 to 8. Propylene glycol was used as a nonvolatile solvent and isopropyl alcohol (Examples 6 and 8) and ethanol (Example 7) as volatile solvents, and hydroxypropyl cellulose was added and mixed as a lipophilic thickener. . In addition, hydroxyethyl cellulose and an acid buffer solution were added to the hydrophilic portion to dissolve and mix. However, in Example 6, a hydrophilic part is not manufactured separately. The composition of Examples 6 to 8 prepared through this is to separate and store the lipophilic portion and the hydrophilic portion, and to use the mixture when used. All skin permeation accelerators of Examples 6 to 8 exhibited a supersaturated state by mixing two portions and evaporating volatile solvents in use.

Examples 9-11

Examples 9 to 11 were prepared by using alprostadil as a pharmacologically active ingredient, propylene glycol lauric acid ester as a skin permeation accelerator, and varying the ratio of the lipophilic portion to the hydrophilic portion.

Composition of Examples 9-11 Furtherance Example 9 Example 10 Example 11 Lipophilic part Alprostadil One One One Propylene Glycol Lauric Acid Ester 5 5 5 Propylene glycol 31.43 24.13 17.94 ethanol 31.43 24.13 17.94 Hydroxypropyl cellulose 0.64 0.49 0.36 Hydrophilic part pH 5.0 buffer q.s q.s q.s Sum 100 100 100 Mixing of lipophilic and hydrophilic parts Transparency Transparency emulsion Applying Plate After Mixing emulsion emulsion emulsion

Examples 9 to 11 are prepared by varying the ratio of lipophilic moiety to hydrophilic moiety based on Example 2 to contain both 1% alprostadyl and 5% propylene glycol lauric acid ester as a pharmacologically active substance. It was. Considering that the ratio of the lipophilic moiety to the hydrophilic moiety where the propylene glycol lauric acid ester starts to be supersaturated is about 55:45, Example 9 is about 68:32, and Example 10 is about 52:48. Example 11 was prepared by varying the ratio to about 39:61. When the hydrophilic portion and the lipophilic portion were mixed, Examples 9 and 10 formed a transparent viscous liquid or gel, and Example 11 formed an emulsion. And when Examples 9 to 11 were applied to the plate and observed, after about 10 minutes all showed the properties of the emulsion.

The lipophilic moieties of Examples 9 to 11 can be applied to the urethral mucosa separately without mixing the hydrophilic moiety, in which case the role of the hydrophilic moiety is replaced by a small amount of urine remaining in the urethra of a normal person to form the same supersaturated delivery system in the urethra. To be done.

Examples 12-13

Alprostadyl was used as a pharmacologically active ingredient and polyoxyethylene fatty alcohol ether was added as a skin permeation accelerator to prepare as shown in Table 4 below.

Compositions of Examples 12-13 Furtherance Example 12 Example 13 Lipophilic part Alprostadil One One Polyoxyethylene (2) ^a lauryl alcohol ether 5 - Polyoxyethylene (2) ^a oleyl alcohol ether - 5 Propylene glycol 20.79 28.22 ethanol 20.79 - Isopropyl Alcohol - 28.22 Hydroxypropyl cellulose 0.42 0.57 Lidocaine HC1 0.4 - L-menthol - 0.5 Hydrophilic part Hydroxyethyl cellulose 0.52 0.38 Methyl paraoxybenzoate 0.05 0.05 pH 5.0 buffer q.s q.s Sum 100 100

a: number of monomers in the polymer                     

Examples 12 and 13 were prepared to contain all 1% of alprostadyl as a pharmacologically active substance. In the lipophilic portion, polyoxyethylene (2) lauryl alcohol ether and polyoxyethylene (2) oleyl alcohol ether were each contained 5% as a skin permeation accelerator, propylene glycol as a nonvolatile solvent and ethanol (as a volatile solvent). Example 12) and isopropyl alcohol (Example 13) were used and hydroxypropylcellulose was added as a lipophilic portion thickener and lidocaine HCl (Example 12) and L-menthol (Example 13) were added as additives. Mixed and dissolved. In addition, hydroxyethyl cellulose and an acidic buffer solution were added to the hydrophilic part, and methyl paraoxybenzoate was added as an additive, mixed, and dissolved. The compositions of Examples 12 and 13 thus prepared are separately stored and stored in the lipophilic portion and the hydrophilic portion, and the skin permeation accelerators of Examples 12 and 13 exhibit a supersaturated state by mixing two portions and evaporating a volatile solvent when used.

Comparative Examples 1 to 3

Comparative Examples 1 to 3 were prepared as shown in Table 5 below. Comparative Examples 1 and 2 are cases in which the skin permeation promoter was not added, and Comparative Example 3 was prepared by introducing a microemulsion system.

Composition of Comparative Examples 1 to 3 Furtherance Comparative Example 1 Comparative Example 2 Comparative Example 3 Lipophilic part Alprostadil One One One MCT Oil - - 20 Polyethylene glycol (8) ^a glycerin linoleic acid ester - - 26.7 Polyoxyethylene Hydrogenated Castor Oil - - 52.3 Sodium cholate - - - Propylene glycol 24.25 49 - ethanol 24.25 49 - Isopropyl Alcohol - - Hydroxypropyl cellulose 0.5 One - Hydrophilic part Hydroxyethyl cellulose 0.45 - - pH 5.0 buffer q.s - - Sum 100 100 100

a: number of monomers in the polymer

Comparative Example 1 was prepared by mixing the lipophilic portion and the hydrophilic portion of about 1: 1 except for the skin permeation accelerator in Example 1, Comparative Example 2 was prepared by using only the lipophilic portion, except for the skin permeation accelerator in Example 4 It was. Comparative Example 3 introduced and prepared a self-microemulsifying drug delivery system (SMEDDS) in which a transparent microemulsion was formed when an aqueous phase was added, so that the aqueous phase formed a microemulsion over the entire phase (0 to 99%).

Comparative Example 4

Comparative Example 4 was prepared by using alprostadil as a pharmacologically active ingredient and propylene glycol lauric acid ester as a skin permeation accelerator.

Composition of Comparative Example 4 Furtherance Comparative Example 4 Lipophilic part Alprostadil One Propylene Glycol Lauric Acid Ester - Propylene glycol 17.94 ethanol 17.94 Hydroxypropyl cellulose 0.36 Hydrophilic part pH 5.0 buffer q.s Sum 100 Mixing of lipophilic and hydrophilic parts Transparency Applying Plate After Mixing Transparency

Comparative Example 4 exhibited transparent properties when both the lipophilic portion and the hydrophilic portion were mixed and applied to the plate after mixing. Comparing the results of Comparative Example 4 with the results of Examples 9 to 11, the occurrence of the emulsion properties in Examples 9 to 11 was caused by the propylene glycol lauric acid ester (skin permeation accelerator) due to the mixing of the hydrophilic part and the evaporation of the volatile solvent. ) Was observed to be supersaturated.

Comparative Examples 5-6

Alprostadil was used as a pharmacologically active ingredient, and propylene glycol lauric acid ester was added as a skin permeation accelerator, and the ratio of the lipophilic portion and the hydrophilic portion was prepared as shown in Table 7 below.

Composition of Comparative Examples 5-6 Furtherance Comparative Example 5 Comparative Example 6 Lipophilic part Alprostadil One One Propylene Glycol Lauric Acid Ester 5 5 Propylene glycol 46.29 11.75 ethanol 46.29 11.75 Hydroxypropyl cellulose 0.94 0.24 Hydrophilic part pH 5.0 buffer - q.s Sum 100 100 Mixing of lipophilic and hydrophilic parts Transparency Emulsion or precipitation Flat coating after mixing Transparency Precipitation

Comparative Examples 5 and 6 were prepared by varying the ratio of lipophilic moiety to hydrophilic moiety to contain both 1% alprostadyl and 5% propylene glycol lauric acid ester as pharmacologically active substances. Comparative Example 5 was prepared by varying the ratio of the lipophilic portion and the hydrophilic portion to 100: 0 and Comparative Example 6 to about 25:75.

In Comparative Example 5, since the supersaturation of the propylene glycol lauric acid ester was not induced, the transparent phase was maintained even when left for 10 minutes after mixing the lipophilic portion and the hydrophilic portion and applying the plate. In Comparative Example 6, since the hydrophilic portion was relatively excessive, supersaturation occurred, but precipitation occurred upon plate coating. That is, Comparative Example 5 is a case where the saturation of the skin permeation promoter in the composition of the present invention is too low, and Comparative Example 6 is a case where precipitation occurs due to excessive saturation.

Experimental Example 1

Skin permeation test was performed using Examples 1 to 5 as samples. The skin was used to cut the skin of a hairless mouse. As a diffusion cell device, Franz-type Cell (effective diameter 0.9 cm, effective volume 4.5 ml) was used, and as a medium, a pH 7.4 buffer solution was used at 37 ° C. Maintained and used. The skin was placed on the cell device with the stratum corneum up, and at the start of the test, about 100 mg (1 unit) of each sample was finally applied onto the stratum corneum. Then, the medium was taken at 1, 2, 3, 4 hours from the start of the test, and the skin permeation amount of alprostadyl was analyzed by HPLC and expressed as the skin permeation amount (μg / cm ² ) per unit area. The result is shown in FIG.

As a result of the experiment, the addition of only 5% of the skin permeation promoter of the present invention showed an excellent increase in skin permeation rate. In general, the initial delay time of 4 hours to 24 hours was significantly reduced when the skin was permeated with alprostadil. Could be observed.

Experimental Example 2

Skin permeation test was performed in the same manner as in Experiment 1 using Examples 6 to 8 as the samples. The result is shown in FIG.

As a result of the experiment, a very good increase in skin permeation was observed with a similar tendency to Experimental Example 1, and the initial delay time was significantly decreased.

Experimental Example 3

The skin permeation test was carried out in the same manner as in Experiment 1 using Comparative Examples 1 to 3 as samples, and the skin permeation was compared with the results of Examples 2 and 8. The result is shown in FIG. 3.                     

Experimental results showed that the skin penetration rates (Flux) of Examples 2 and 8 were about 185 and 119 (µg / cm ² / hr), respectively. Little permeation was seen. From the results of Comparative Examples 1 and 2, it was confirmed that the skin permeation promoter of the present invention is an essential element for skin permeation of alprostadil. And in the case of Comparative Example 3, a mixture of aqueous phase in a ratio of 100: 0, 50:50 and 20:80 pH 5.0 buffer to the composition of Comparative Example 3 to prepare a variety of microemulsion and carried out a skin permeation test, but all tests In 4 cases, no skin penetration of alprostadil was observed.

Experimental Example 4

Skin permeation test was carried out in the same manner as in Experiment 1 using Examples 9 to 11 and Comparative Examples 5 and 6 as samples. The result is shown in FIG. 4.

As a result, in Examples 9 to 11, an excellent increase in skin penetration was observed, but in Comparative Examples 5 and 6, an increase in skin penetration was relatively low. This means that even if the same skin permeation accelerator is used, there is a great difference in the skin permeation promoting effect depending on the external delivery system. Comparative Example 5, Examples 9, 10, 11 and Comparative Example 6 were prepared by sequentially increasing the saturation of the skin permeation accelerator, Comparative Example 5 when the flat coating is low saturation does not form an emulsion and Examples 9 to 11 are suitable An emulsion is formed by showing saturation, and Comparative Example 6 is an example in which precipitation occurs due to excessive saturation. Compared with the results of Figure 4, Examples 9 to 11 formed a suitable supersaturation delivery system is a rapid skin migration of the skin permeation promoter is excellent skin penetration promoting effect and the saturation is too low or excessive saturation to maintain the supersaturation delivery system Comparative Examples 5 and 6 that have not been demonstrated to exhibit very low skin permeation effect. Therefore, it was found that the object of the present invention can be achieved only by selecting a selective skin permeation promoter and a composition capable of forming an appropriate supersaturation delivery system.

Experimental Example 5

The stability test was done using said Example 2, 12, and 13 as a sample. Each sample was stored for 60 days in a light-tight airtight container under refrigeration and storage at 30 ° C., and the content thereof was analyzed by HPLC. The result is shown in FIG.

As a result, no change of content was observed in the cold storage of all samples, and some decrease was observed in storage at 30 ℃. However, when the storage conditions of the preparation of the present invention compared to the refrigerated storage, considering that the storage at 30 ℃ is a very very harsh condition, all the samples showed a good stability.

The composition of the present invention has the same pharmacologically active substance and skin permeation accelerator in the same phase, and adds a nonvolatile solvent and a volatile solvent which are inert to the active substance to stabilize the water-stable alprostadil formulation during the storage period. By forming a supersaturated delivery system that induces a thermodynamic potential upon application of mucous membranes and skin, it is possible to further increase the skin permeability of the skin penetration promoter. That is, the transmucosal and transdermal absorption preparations according to the present invention significantly improve the skin permeability of alprostadil with very low skin permeability by selecting a selective skin permeation accelerator for alprostadyl and form a supersaturated delivery system. The initial delay of the accelerator can be minimized. In addition, the present invention has been developed alprostadyl transmucosal and transdermal absorption preparations with significantly improved skin permeability using the components of excellent safety and stability, the application areas that have been limited to penis skin, glans mucosa, urethral mucosa and scrotum By making it applicable to perineal skin etc., the adaptability of a patient can be improved further.

Claims (10)

Transmucosal and transdermal absorbents, based on the total weight of the formulation a) pharmacologically effective amount of alprostadyl; b) a polyhydric alcohol fatty acid ester conjugate obtained by ester-bonding a fatty acid having 6 to 18 carbon atoms to a polyhydric alcohol selected from propylene glycol, glycerin and polyethylene glycol; 0.5 to 20% by weight of one or more skin permeation promoters selected from polyoxyethylene fatty alcohol ether conjugates in which ether-bonded fatty alcohols having 6 to 18 carbon atoms to polyoxyethylene; c) 10 to 95 wt% of a mixed solution of a nonvolatile solvent and a volatile solvent; And d) 0.1 to 5% by weight of a thickener that can be dissolved using c) as a solvent A pharmaceutical composition for treating erectile dysfunction, comprising: forming a supersaturated delivery system for a skin permeation accelerator. The method of claim 1, wherein the total formulation weight a) 0.1 to 5% by weight of a water soluble thickener; And b) A pharmaceutical composition, further comprising an appropriate amount of water or an acidic buffer of pH 3.0-7.4. The pharmaceutical composition of claim 1, further comprising an appropriate amount of water or an acidic buffer of pH 3.0-7.4. The pharmaceutical composition of claim 1 comprising physiological urine. The pharmaceutical composition according to claim 1, wherein the composition of claim 2 or 3 is stored separately and mixed and used when applying mucosa and skin. The pharmaceutical composition according to claim 1, wherein alprostadil is used in an amount of 0.01 to 5% by weight based on the total weight of the formulation. The pharmaceutical composition according to claim 1, wherein the nonvolatile solvent comprises at least one selected from ethylene glycol, propylene glycol, propylene carbonate, propylene glycol acetate, glycerin, polyethylene glycol, and polypropylene glycol. . The method of claim 1, wherein the volatile solvent is a lower alcohol having 4 or less carbon atoms including methanol, ethanol and isopropane; And at least one selected from acetone. The pharmaceutical composition of claim 1, further comprising at least one selected from preservatives, stabilizers and pain inhibitors as an additive. The pharmaceutical composition of claim 1, wherein the composition is applied to at least one mucosa and skin selected from the penis, glans, urethra, scrotum and perineum of the male genitals.

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