TWI422399B - Improved pharmaceutical composition for enhancing transdermal delivery of pde-5 inhibitor - Google Patents

Description

Pharmaceutical composition for promoting transdermal absorption of a fifth type phosphodiesterase inhibitor

The invention discloses the use of an absorption enhancer for drug delivery, and the disclosed absorption enhancer can increase the efficiency of the active pharmaceutical ingredient to penetrate the animal or human skin.

Phosphodiesterase exists in various tissues. As more and more specific phosphodiesterase (PDE) inhibitors are invented, the medical application of inhibiting PDE activity is gradually gaining importance. Inhibitors can reduce the occurrence of side effects. Sildenafil, vardenafil and tadalafil, which are sexual dysfunction, are type 5 phosphodiesterase (type 5 phosphodiesterase, PDE-5) inhibitor.

PDE-5 inhibitors have been used to treat sexual dysfunction or primary pulmonary hypertension. Pulmonary hypertension is a vascular disease caused by the narrowing of the arteries of the lungs, which in turn blocks blood flow and produces high blood pressure. As for sexual dysfunction, there are currently three oral PDE-5 inhibitor formulations available, including sildena (Viagra; Pfizer), which contains vardenafil. (Levitra; Bayer and GlaxoSmithKline) or Cialis (Lilly), which contains 20 mg of sildenafil (Revatio; Pfizer) Approved for treatment of primary pulmonary hypertension by the US Food and Drug Administration.

Oral administration is a convenient and non-invasive method of administration, but it still has some disadvantages, such as the liver's first-pass metabolism affects the speed and efficacy of the drug.

On the other hand, drugs do not only act on the target tissues, but often also have systemic or systemic side effects. For example, oral aphrodisiac drugs often cause headaches, palpitations, flushing and color blindness.

Aphrodisiac drugs directly act on the genitals through skin absorption, and should avoid the systemic side effects caused by oral aphrodisiac drugs. Many substances can help or promote the penetration of drugs into the skin. These substances may be surface active agents that change or destroy the structure of the skin and increase permeability. Because of this, only mild and not harmful to the skin. Surface agents can be applied to transdermal absorption formulations. Specific organic solvents have also been found to promote transdermal absorption of drugs such as dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) or N,N-dimethyl B. N, N-dimethyl acetamide can promote the penetration of drugs into the stratum corneum of the skin. However, these organic solvents have high affinity for body tissues, sometimes exposed to excessive exposure to such organic solvents. Down, it causes unexpected side effects.

The invention provides a progressive percutaneous absorption formula composition and a preparation method thereof, which can overcome the defects mentioned above and utilize the selected several absorption enhancers to help the transdermal absorption of the fifth type phosphodiesterase inhibitor. The effect that these absorption enhancers do not damage the skin structure or the systemic exposure of the system, and therefore the formulation of the present invention and the preparation method thereof have great medical value and can be applied to diseases in which the fifth type phosphodiesterase activity is disordered or Is the symptom above.

The specific chemical substances disclosed in the present invention have the effects of promoting percutaneous absorption of PDE-5 inhibitors. Therefore, these chemicals can be used as components or adjuvants for external use agents to develop disorders due to PDE-5 activity. A therapeutic drug for a related disease or symptom, such as a drug for developing sexual dysfunction or pulmonary hypertension.

It is a primary object of the present invention to provide an improved pharmaceutical composition which increases the transdermal absorption of a PDE-5 inhibitor. According to an embodiment of the present invention, the improved transdermal absorption pharmaceutical composition comprises a PDE-5 inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein The skin absorption pharmaceutical composition is improved in that it contains an absorption enhancer, and both the PDE-5 inhibitor and the absorption enhancer are used in the modified transdermal absorption pharmaceutical composition of the present invention in a ratio of 17:1 to 3: Between 1, in the preferred embodiment, the ratio is approximately 4:1.

The absorption enhancer for promoting the percutaneous absorption of the PDE-5 inhibitor disclosed in the examples of the present invention is selected from the group consisting of a cocamidopropyl betaine, a sodium lauroamphoacetate, and a season. A group consisting of ammonium salt-60 (quaternium-60), isostelaramidopropyl morpholine lactate, dipropylene glycol, and combinations thereof. In one embodiment, the absorption enhancer is an alkylguanamine betain. In another embodiment, the absorption enhancer is a mixture of alkylguanamine betaine and sodium lauroamphoacetate. In still further embodiments, the absorption enhancer is a mixture of alkylguanamine betaine, sodium lauryl ammonium acetate, and quaternary ammonium salt-60. In a preferred embodiment, the absorption enhancer used is an alkyl decylamine betaine, sodium lauroamphoacetate, quaternary ammonium salt-60, isostearium propyl morpholine lactate and double propylene. a mixture of glycols. The PDE-5 inhibitor used may be sildenafil, vardenafil or tadrinafil, and in the preferred embodiment is the amorphous form of vardenafil.

The improved pharmaceutical composition of the present invention may be formulated into a liquid, ointment, lotion, gel or patch. In one embodiment, the improved pharmaceutical composition is formulated into a gel, and In one embodiment, the improved pharmaceutical composition is formulated into a dermal patch. In another aspect, the invention provides a method of enhancing transdermal absorption of a PDE-5 inhibitor in an animal, according to the disclosed embodiment, the method comprising the step of applying the modified composition to an animal, the improved combination Containing a PDE-5 inhibitor, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients; and an improvement in the improved composition comprising the inclusion of an absorption enhancer, wherein the PDE The ratio of the -5 inhibitor to the absorption enhancer in the modified composition is between 17:1 and 3:1. In the preferred embodiment, the ratio of the two is approximately 4:1.

An absorption enhancer which can promote the percutaneous absorption efficiency of a PDE-5 inhibitor according to an embodiment of the present invention is selected from the group consisting of alkylguanamine betaine, sodium lauroamphoacetate, Quaternary ammonium salt-60, isostearyl propylamine morpholine lactate, dipropylene glycol, and combinations thereof. In one embodiment, the absorption enhancer is an alkylguanamine betain. In another embodiment, the absorption enhancer used is a mixture of alkylguanamine betaine and sodium lauryl acetate. . In still further embodiments, the absorption enhancer is a mixture of alkylguanamine betaine, sodium lauroamphoacetate and quaternary ammonium salt-60. In a preferred embodiment, the absorption enhancer used is an alkyl decylamine betaine, sodium lauroamphoacetate, quaternary ammonium salt-60, isostearium propyl morpholine lactate and double propylene. a mixture of glycols. As for the PDE-5 inhibitor suitable for use in the present invention, it may be sildenafil, vardenafil or tadrinafil. In a preferred embodiment, the PDE-5 inhibitor used is vardenafil in an amorphous state.

The method and pharmaceutical composition formulation disclosed in the present invention have medical utility even in the case of a low PDE-5 inhibitor content.

Noun definition

In order to make the content of the specification clearer, the nouns and terms used herein are defined as follows.

Absorption enhancer: refers to a specific chemical substance, when it is added to a drug composition, it can increase the absorption kinetic energy and bioavailability of a drug active molecule such as a PDE-5 inhibitor on the skin, but the specific chemical substance It does not have medical effects by itself.

Percutaneous absorption: refers herein to the process by which a drug-active molecule penetrates the skin.

Excipient: as used herein, means any substance other than a pharmaceutically active molecule (such as a PDE-5 inhibitor) and an absorption enhancer in the percutaneous absorption composition, which may be a liquid or a powder.

The improved transdermal absorption pharmaceutical composition and method of use thereof disclosed in the present invention will actually exhibit the effect of the absorption enhancer of the present invention on enhancing transdermal absorption of a PDE-5 inhibitor by animal testing. According to an embodiment of the present invention, the improved transdermal absorption pharmaceutical composition comprises a PDE-5 inhibitor, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, And the improvement thereof comprises additionally comprising an absorption enhancer selected from the group consisting of alkylguanamine betaine, sodium laurate amidoacetate, quaternary ammonium salt-60, and iso-hard Lipidamine propyl morpholine lactate, dipropylene glycol, and mixtures thereof. In the present invention, the ratio of the PDE-5 inhibitor to the absorption enhancer in the improved transdermal absorption pharmaceutical composition is between 17:1 and 3:1. PDE-5 inhibitors suitable for use in the present invention are not limited only to sildenafil, vardenafil and tadrinafil. In a preferred embodiment, the PDE-5 inhibitor used is vardenafil.

The absorption enhancer suitable for use in the present invention is not limited to alkylguanamine betaine, sodium lauroamphoacetate, quaternary ammonium salt-60, isostearyl propylamine morpholine lactate, dipropylene glycol or a combination of them. Alkylamine amine betaine is a chemically synthesized surface agent formed by the reaction of coconut oil with N,N-dimethyl-1,3-diaminopropane. Sodium laurate amidoacetate is an amphoteric acetate that is often used as a humectant. Quaternary ammonium salt-60 is a quaternary ammonium salt which is soluble in propylene glycol. In the presence of these absorption enhancers, the solubility and stability of the PDE-5 inhibitor in the improved pharmaceutical composition is improved, not only does it not cause crystallization, but also increases the penetration of the PDE-5 inhibitor into the skin. The ability of the epidermis.

According to the information disclosed in the embodiments of the present invention, the relative ratio of the PDE-5 inhibitor to the absorption enhancer in the improved pharmaceutical composition is between 17:1 and 3:1, and the preferred relative ratio is 4. :1. In one embodiment, the modified composition comprises a PDE-5 inhibitor and an absorption enhancer which is vardenafil and alkylguanamine betaine in a relative ratio of 17:1. In another embodiment, the PDE-5 inhibitor contained in the composition is vardenafil and the absorption enhancer is a mixture of alkylguanamine betaine and sodium laurate amidoacetate, PDE- The relative ratio of the 5 inhibitor to the absorption enhancer was 6:1. In a further example, the PDE-5 inhibitor contained in the composition is vardenafil, and the absorption enhancer is composed of alkylguanamine betaine, sodium lauroamphoacetate and quaternary ammonium salt-60. The relative ratio of PDE-5 inhibitor to absorption enhancer was 4:1. In the final embodiment, the PDE-5 inhibitor used in the composition is vardenafil, and the absorption enhancer is an alkylguanamine betaine, sodium lauroamphoacetate, quaternary ammonium salt-60, and different A mixture of stearyl propyl morpholine lactate and dipropylene glycol, the relative ratio of PDE-5 inhibitor to absorption enhancer is 3:1.

The improved pharmaceutical compositions disclosed in the present invention may be formulated into skin preparations, and excipients commonly used in skin preparations are also used in the present invention, and these dosage forms may be liquid preparations, ointments, creams, lotions, ointments. , gel, spray, aerosol or skin patch. Typical excipients are water, ethanol, polyvinylpyrrolidone, propylene glycol, mineral oil, stearyl alcohol or a thickener and the like. These dosage forms or excipients are processes and ingredients that are frequently used in the pharmaceutical industry, and the compositions of the present invention do not affect their pharmaceutical utility by modulating into different dosage forms.

When the improved pharmaceutical composition disclosed by the present invention is formulated into a liquid preparation, it will contain volatile ethanol and water as well as non-volatile medium carbon chain triglycerides and straight carbon chain fatty alcohols, so a typical liquid The PDE-5 inhibitor contained in the composition has a weight percentage of 1 ^to 20%, an absorption enhancer containing 0.2 ^to 5% by weight, and a volatile and nonvolatile substance of 0.5. ^~ 98%.

When the improved pharmaceutical composition disclosed in the present invention is formulated into an emulsion, it contains extremely fine insoluble particles and a thickener, and thus the weight percentage of the PDE-5 inhibitor contained in a typical emulsion composition is Between 1 ^and 20%, the weight percentage of the absorption enhancer is 0.2 ^to 5%, the insoluble matter is 0.5 ^to 5%, and the thickener is 2 ^to 5%.

When the improved pharmaceutical composition disclosed in the present invention is formulated into a cream, it contains a wetting agent, an emulsifier, an antioxidant, and a preservative, so that the weight of the PDE-5 inhibitor contained in a typical cream composition is The percentage is between 1 ^and 20%, the weight percentage of the absorption enhancer is 0.2 ^to 5%, the humectant is 0 ^to 50%, and the emulsifier is between 0 ^and 20%.

When the improved pharmaceutical composition disclosed in the present invention is prepared into a gelling agent, the thickening agent and the gelling agent are contained therein, and the gelling agent may be a very fine insoluble substance, which absorbs moisture and entangles to form a network structure. , in turn, restricts the free diffusion movement of other substances, so the typical gel composition contains PDE-5 inhibitor in the weight percentage of 1 ^~ 20%, and the absorption enhancer contained in the weight percentage of 0.2 ^~ 5%, the weight percentage of the thickener is 2 ^~ 5%, and the gelling agent contained is 0 ^~ 20%.

When the improved pharmaceutical composition disclosed in the present invention is formulated into a spray, the weight percentage of the PDE-5 inhibitor contained is between 1 ^and 20%, and the weight percentage of the absorption enhancer is 0.2 ^to 5 %, the co-solvent or propellant contained in the weight percentage of 10 ^~ 90%, the excipient used in the present invention also has a co-solvent function, can stably maintain the PDE-5 inhibitor in a dissolved state, typically Propellants are generally hydrofluorocarbons such as 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, pentafluoropropane, 1,1-difluoroethane. Alkane and difluoromethane, etc., typical cosolvents include alcohols, polyols, alkoxy derivatives, fatty acid alkyl esters, polyalkylene glycols, dimethyl alum, and the like.

The improved pharmaceutical compositions disclosed herein are formulated into dermal patches with some excipients. In the gel dosage form 2-4 of Example 2, it can be adhered to a gauze or a non-woven material to form a patch type, and after the patch is attached to the skin of the animal for a while, the PDE-5 inhibitor will be in the dosage form. Released and passed through the skin of the animal, the patch type can be multi-layered and contain an adhesive layer that increases adhesion. The transdermal patch may also contain other substances that promote transdermal absorption of PDE-5 inhibitors, many of which are known for absorption. Promoters can also be used in the present invention to aid in the transdermal absorption of PDE-5 inhibitors.

In accordance with the above, the present invention provides a method of treating a disease or condition associated with a PDE-5 inhibitor, such as an erectile dysfunction or primary pulmonary hypertension, in an animal, particularly a human, the method disclosed The improved pharmaceutical compositions of the present invention are applied to animals, especially humans, for therapeutic purposes by enhancing the transdermal absorption of PDE-5 inhibitors.

To fully understand the objects and features of the present invention, the progress of the compositions and dosage forms of the present invention is illustrated by the following non-limiting examples, in conjunction with the accompanying drawings.

Example 1 Analysis of transdermal permeation effect in vitro

The degree of percutaneous penetration of the PDE-5 inhibitor was analyzed by a Franz cell percutaneous absorption apparatus having a diffusion zone of about 0.785 square centimeters and a Sprague-Dawley rat. The mouse cortex is sandwiched between the upper and lower cups of the vertical Franz cell. After clamping with the clamp, a solution of 1% vardenafil containing different absorption enhancers is added to the upper cup and the buffer is added to the lower cup. (PBS), after 6 hours, the lower cup trough solution was taken, and the content of vardenafil was analyzed by high performance liquid chromatography (HPLC). The experimental group contents are as follows: Group 1: 1% vardenafil; Group 2: 1% vardenafil + 0.3% alkyl guanamine betaine; Group 3: 1% vardenafil +1% sodium laurate amidoacetate; Group 4: 1% vardenafil + 1% quaternary ammonium salt-60; Group 5: 1% vardenafil + isostearyl propylamine morpholine lactate; Group 6: 1% vardenafil +1% dipropylene glycol

The results, as shown in Figure 1, in the presence of an absorption enhancer, promoted the cortex of more vardenafil-penetrating mice and entered the lower cup of the Franz cell, showing approximately 50 ^to 200% from the data. Improvement effect.

Example 2 Analysis of percutaneous absorption in vivo Preparation of vardenafil gel

The formulas of dosage forms 1 ^to 4 in the following list can be divided into water-soluble and water-insoluble. The water-soluble and water-insoluble components are pre-mixed and stirred uniformly, and then the two are mixed and continuously stirred until the gel Formation, the colloidal pH value is controlled between 2.5 ^~ 3.5, the value of each component in the list represents the weight percentage concentration.

Preparation of vardenafil skin patch

In the following list, the dosage form 5 was prepared in the same manner as the gel dosage form, and the formed colloid was applied to the surface of the non-woven fabric and allowed to stand for seven days to cause the colloid to be crosslinked to form a patch structure having no fluidity.

The rabbits were treated with vardenafil gel (formulations 1 ^to 4) and patch (formulation 5), and the percutaneous absorption of vardenafil in vivo was observed, about 0.5 ml of gel or 3 cm × 5 cm × A 0.15 cm skin patch was applied to the left ear of the white rabbit. After one hour (gel treatment) or six hours (patch treatment), 1 ml of rabbit blood was taken from the right ear artery and serially connected by liquid chromatography. Mass spectrometry (LC-MASS) was performed for analysis. The results shown in Figure 2, the absorption enhancer alone or in combination under, vardenafil can be increased in vivo rabbit skin penetrating into the blood circulation which, with the control group (dosage form) may improve the comparison of about 400 ^to 500 %.

The above description is only for the preferred embodiment of the present invention, and those skilled in the art can make various improvements according to the present invention. However, the specifications, components, examples and data described in the present invention have fully explained the present invention. The embodiments, structures, and spirits of the present invention, even if the embodiments of the present invention have certain particularities, are modified by the skilled artisan as reference information, but these changes still belong to the spirit of the present invention. Among the defined patents.

The first figure shows that in vitro experiments, different absorption enhancers can enhance the effect of vardenafil penetrating mouse cortex into the cup solution below the Franz cell.

The second embodiment is an explanation Formulation 2 in Example 1 ^to 5 vardenafil promoting effect for percutaneous absorption in vivo.

Claims (3)

An improved percutaneous absorption pharmaceutical composition comprising vardenafil or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the characteristics of the transdermally absorbable pharmaceutical composition Including comprising an absorption enhancer selected from the group consisting of alkylguanamine betaine, sodium lauroamphoacetate, quaternary ammonium salt-60, isostearyl propyl morpholine lactate, dipropylene glycol In the group formed by the alcohol and the combination described above, both vardenafil and the absorption enhancer are present in the modified transdermal absorption pharmaceutical composition in a ratio of between 17:1 and 3:1. The improved percutaneous absorption pharmaceutical composition according to claim 1, wherein the ratio of vardenafil to the absorption enhancer is 4:1. The improved percutaneous absorption pharmaceutical composition of claim 1, wherein the vardenafil is in an amorphous state.