TWI656883B - Pharmaceutical carrier for a photosensitizer or a prodrug thereof - Google Patents

Abstract

A pharmaceutical carrier comprising: an aqueous phase component, an oil phase component, an interfacial active agent, and an auxiliary surfactant; the aqueous phase component contains water, and the oil phase component comprises isopropyl myristate ( Isopropyl myristate, IPM) or propylene glycol monocaprylate (Caproyl 90), surfactant containing Brij 35, Brij 30, Tween 80, Span 20, TPGS, CEL, SLS, BC, CTMB, or In combination, the co-surfactant contains a C2 to C8 alcohol. Further, a pharmaceutical composition containing the above pharmaceutical carrier is also proposed.

Description

Pharmaceutical carrier for photosensitizer or its prodrug

The present invention relates to a pharmaceutical carrier, and in particular to a pharmaceutical carrier of a photosensitizer or a precursor thereof.

Photodynamic therapy (PDT) achieves therapeutic effects by illuminating photosensitizers with light of a specific wavelength to produce toxicity to specific tumor cells or pathogens. For example, protoporphyrin IX (PPIX) is a photosensitizer for the treatment of skin cancer or bladder cancer. In normal cells, protoplast IX will combine with ferrous ions to form heme. Conversely, protoplast IX is poorly metabolized in tumor cells, and tumor cells are abnormally transported or regulated by iron. Procyanidin IX accumulates in tumor cells. Thereby, the tumor cells can be selectively destroyed by light irradiation. In vivo, 5-aminolevulinic acid (ALA) can be converted into protoplast IX and converted to methyl aminolevulinate (MAL) to 5-aminoethyl propyl acrylate. Acid, so the clinical application of protopherin IX precursor drug methylaminoacetic acid directly in the affected area. Methylaminoethionine is not easily penetrated into individuals and must be mixed with a pharmaceutical carrier to form an emulsion, such as the commercially available emulsion Metvix® cream. However, such commercially available emulsions still contain a large amount of methylaminoacetic acid to increase individual penetration, which not only increases the cost of the treatment, but also shows other side effects such as burning sensation and tingling. , knotted hard skin, redness, peeling, skin ulceration, or skin discoloration.

For the sake of the job, the problem of improving the penetrability of the photosensitizer or its precursor drug individual is indeed one of the problems actively solved by those skilled in the art and/or the industry.

An object of the present invention is to provide a novel pharmaceutical carrier comprising: an aqueous phase component, an oil phase component, a surfactant, and an auxiliary surfactant; the aqueous phase component contains water, and the oil phase group The mixture contains isopropyl myristate (IPM) or propylene glycol monocaprylate (Caproyl 90), and the surfactant contains Brij 35, Brij 30, Tween 80, Span 20, TPGS, The CEL, SLS, BC, CTMB, or a combination thereof, the co-surfactant contains a C2 to C8 alcohol.

Another object of the present invention is to provide a novel pharmaceutical composition comprising: a pharmaceutical carrier as hereinbefore described, and a photosensitizer or a prodrug thereof.

In order to make the above and/or other objects, functions and features of the present invention more comprehensible, the following detailed description of the preferred embodiments,

The first embodiment of the present invention provides a pharmaceutical carrier capable of efficiently transporting a photosensitizer or a precursor drug thereof to the body, particularly transdermal or buccal membrane, thereby improving the problem of poor penetrability of the photosensitizer or its precursor drug. And reduce the amount of photosensitizer or its precursor drug used. The pharmaceutical carrier comprises at least one aqueous phase component, one oil phase component, one surfactant, and one auxiliary surfactant. The aqueous phase component contains water; the oil phase component contains isopropyl myristate or propylene glycol monocaprylate; the surfactant contains Brij 35, Brij 30, Tween 80, Span 20, TPGS, CEL, SLS, BC, CTMB, or a combination thereof, examples of which may be, but are not limited to, Tween 80, Brij 35, SLS, BC, CTMB, a mixture of Brij 35 and Brij 30, a mixture of Tween 80 and Span 20, a mixture of TPGS and Brij 30, Or a mixture of CEL and Brij 30; the auxiliary surfactant contains a C2 to C8 alcohol, examples of which may be, but not limited to, ethanol, propylene glycol, 1,5-pentanediol, or card Carbitol. It should be noted that the terms "Brij 35" and "poly(oxy)(23) lauryl ether" are synonymous with each other, the terms "Brij 30" and "polyoxyethylene (4). "Poly(oxy)(4) lauryl ether" is synonymous with each other. The term "Tween 80" and "polysorbate 80" are synonymous with each other. The terms "Span 20" and "Sorbus" Sorbitan monolaurate is synonymous with each other. The term "TPGS" is synonymous with "D-α-tocopherol polyethylene glycol succinate". The term "CEL" and "Cremophor EL" is synonymous with each other. The term "SLS" is synonymous with "sodium lauryl sulfate". The terms "BC" and "benzylammonium chloride" are synonymous. (benzalkonium chloride) is synonymous with each other. The term "CTMB" is synonymous with "cetrimonium bromide".

In this embodiment, the pharmaceutical carrier may be in the form of a water-in-oil (W/O) or an oil-in-water (O/W). The term "water-in-oil" means that the oil phase component coats the aqueous phase component with the surfactant and the auxiliary surfactant to form water droplets, preferably water droplets or nanometer water droplets; the term "oil-in-water" By means of the aqueous phase component, the oil phase component is coated with a surfactant and an auxiliary surfactant to form oil droplets, which are preferably micron oil droplets or nano oil droplets. The pharmaceutical carrier can be regarded as a one-micron carrier under conditions of formation of micron-sized water droplets or micron-sized oil droplets; the pharmaceutical carrier can be regarded as a nano-scale carrier under the conditions of formation of nano-sized water droplets or nano-sized oil droplets.

In the present embodiment, the surfactant may have a hydrophilic-lipophile babance (HLB) of from 10 to 13, preferably from 10.99 to 12.5.

In the present embodiment, if the surfactant is a mixture of Brij 35 and Brij 30, the weight ratio between Brij 35 and Brij 30 may be 1:1 to 1:4, preferably 1:1.47 to 1:3.7. If the surfactant is a mixture of Tween 80 and Span 20, the weight ratio between Tween 80 and Span 20 may be 1:1 to 1:2, preferably 1:1.5; if the surfactant is TPGS and Brij 30 For the mixture, the weight ratio between TPGS and Brij 30 may be from 1:1 to 1:2, preferably 1:1.35; if the surfactant is a mixture of CEL and Brij 30, the weight between CEL and Brij 30 The ratio may be from 1:1 to 1:2, preferably from 1:1.35.

In this embodiment, the weight percentage of the aqueous phase component, the oil phase component, the surfactant, and the auxiliary surfactant may be 35% to 65%, 2.5% to 7.5%, respectively, based on the total weight of the pharmaceutical carrier. 1% to 30%, and 25% to 40%, preferably 40% to 63.5%, 3% to 5%, 1.5% to 25%, and 30% to 36%, respectively.

A second embodiment of the present invention provides a novel pharmaceutical composition in the form of an emulsion and comprising: a pharmaceutical carrier as hereinbefore described, and a photosensitizer or a prodrug thereof. The photosensitizer or its precursor drug may be included in the oil phase component or the aqueous phase component in the pharmaceutical carrier according to its nature, and examples thereof may be, but not limited to, porfimer sodium, verteporfin, 5-Aminoacetylpropionic acid, propurin IX, methylaminoacetic acid, temoporfin, talaporfin, texaphyrin, sulfonic acid Sulfonated aluminium phthalocyanine or rospaporfin.

In the present embodiment, the photosensitizer or its precursor drug may comprise from 0.1 to 20 parts by weight, preferably from 0.5 to 16 parts by weight, based on 100 parts by weight of the pharmaceutical carrier.

In the present embodiment, the pharmaceutical composition may further contain a thickener to enhance the viscosity of the pharmaceutical composition to effectively adhere to the affected part, such as skin or oral buccal membrane; and examples thereof may be, but not limited to, chitosan (chitosan) ), hydroxypropyl methylcellulose (HPMC), carbomer 940 (Carbopol 940), or polyvinylpyrrolidone (PVP). Further, the thickening agent may comprise from 0.5 to 25 parts by weight, preferably from 1 to 20 parts by weight, based on 100 parts by weight of the pharmaceutical carrier.

The above embodiments of the present invention are described in detail by the following examples:

Preparation of emulsion

According to Tables 1 and 2, different types and different parts by weight (100 parts by weight of the pharmaceutical carrier) of the aqueous phase component, the oil phase component, the surfactant, and the auxiliary surfactant are vortexed to obtain Pharmaceutical carrier. Referring again to Tables 1 and 2, thickeners of different types and weights (100 parts by weight of the pharmaceutical carrier) are added to the resulting pharmaceutical carrier. Finally, as shown in Tables 1 and 2, a photosensitizer precursor drug of different weight ratios (100 parts by weight of the pharmaceutical carrier) was added to the resulting mixture to obtain an emulsion. Table 1. Compositions of the emulsions of Examples 1 to 16 and their parts by weight relative to the pharmaceutical carrier   Photosensitizer precursor drug thickener auxiliary surfactant surfactant phase component water phase component example methylamino acetyl propionate polyvinylpyrrolidone carbomer 940 hydroxypropyl methylcellulose chitin card Alcohol 1,5-pentanediol B35/B30=3/4.4 (HLB value=12.5) CEL/B30=2/2.7 (HLB value=10.99) TPGS/B30=2/2.7 (HLB value=10.99) T80/S20 = 2/3 (HLB value = 11) B35/B30 = 1/3.7 (HLB value = 11.01) Isopropyl myristate water 0.5 - - - - 10.0 20.0 - - - - 15.0 5.0 50.0 1 0.5 - - - - 10.0 20.0 - - - - 20.0 5.0 45.0 2 0.5 - - - - 15.0 15.0 - - - - 20.0 5.0 45.0 3 0.5 - - - - 30.0 - - - - - 20.0 5.0 45.0 4 0.5 - - - - 10.0 20.0 - - - - 18.0 5.0 47.0 5 0.5 - - - - 10.0 20.0 - - - - 25.0 5.0 40.0 6 0.5 - - - - 10.0 20.0 - - - - 20.0 5.0 45.0 7 0.5 - - - - 10.0 20.0 - - - 20.0 - 5.0 45.0 8 0.5 - - - - 10.0 20.0 - - 20.0 - - 5.0 45.0 9 0.5 - - - - 10.0 20.0 - 20.0 - - - 5.0 45.0 10 0.5 - - - - 10.0 20.0 20.0 - - - - 5.0 45.0 11 0.5 - - - 2.0 15.0 15.0 - - - - 20.0 5.0 45.0 12 0.5 - - - 2.0 10.0 20.0 - - - - 20.0 5.0 45.0 13 0.5 - - 10.0 - 10.0 20.0 - - - - 20.0 5.0 45.0 14 0.5 - 1.0 - - 10.0 20.0 - - - - 20.0 5.0 45.0 15 0.5 20.0 - - - 10.0 20.0 - - - - 20.0 5.0 45.0 16 Table 2. Compositions of the emulsions of Examples 17 to 32 and their parts by weight relative to the pharmaceutical carrier   Photosensitizer precursor drug thickener auxiliary surfactant surfactant phase component water phase component example methylamino acetaminophen hydroxypropyl methylcellulose carbitol 1,5-pentanediol propylene glycol Ethanol CTMB BC SLS B35 T80 propylene glycol monocaprylate water 0.5 - - - - 30.0 - - - - 20.0 5.0 45.0 17 0.5 - - - 30.0 - - - - - 20.0 5.0 45.0 18 0.5 - - - - 30.0 - - - 20.0 - 5.0 45.0 19 0.5 - - - 30.0 - - - - 20.0 - 5.0 45.0 20 0.5 - 10.0 20.0 - - - - 1.5 - - 5.0 63.5 21 0.5 - 10.0 20.0 - - - - 2.0 - - 5.0 63.0 22 0.5 - 10.0 20.0 - - - - 3.0 - - 5.0 62.0 23 0.5 - 10.0 20.0 - - - - 5.0 - - 5.0 60.0 24 0.5 - 10.0 20.0 - - - - 8.0 - - 5.0 57.0 25 0.5 - 10.0 20.0 - - - 2.0 - - - 5.0 63.0 26 0.5 - 1 0.0 20.0 - - 2.0 - - - - 5.0 63.0 27 0.5 1.0 10.0 20.0 - - - - 2.0 - - 5.0 63.0 28 0.5 2.0 10.0 20.0 - - - - 2.0 - - 5.0 63.0 29 0.5 3.0 10.0 20.0 - - - - 2.0 - - 5.0 63.0 30 16.0 2.0 10.0 20.0 - - - - 2.0 - - 5.0 63.0 31 16.0 2.0 10.0 20.0 - - - 2.0 - - - 5.0 63.0 32 Table 3. Compositions of the emulsions of Examples 33 to 43 and their relative to pharmaceutical carriers Parts by weight   Photosensitizer Precursor Drug-Assisted Surfactant Surfactant Oil Phase Component Water Phase Component Example 5 - Amino acetonitrile propionate carbitol ethanol CEL T80/S20 = 2/3 (HLB value = 11) B35/B30 =1/3.7 (HLB value = 11.01) Isopropyl myristate water 0.5 - 36.0 - - 12.0 3.0 49.0 33 0.5 36.0 - - - 12.0 3.0 49.0 34 0.5 - 36.0 - 12.0 - 3.0 49.0 35 0.5 - 36.0 12.0 - - 3.0 49.0 36 0.5 36.0 - 12.0 - - 3.0 49.0 37 0.5 - 30.0 - - 20.0 5.0 45.0 38 0.5 - 30.0 - 20.0 - 5.0 45.0 39 0.5 - 30.0 20.0 - - 5.0 45.0 40 0.5 32.0 - - - 15.0 5.0 48.0 41 0.5 30.0 - - - 20.0 5.0 45.0 42 0.5 - 30.0 - - 20.0 5.0 45.0 43 Table 4, the components of the emulsions of Examples 44 to 47 and their parts by weight relative to the pharmaceutical carrier   Photosensitizer precursor drug thickener auxiliary surfactant surfactant phase component water component component Example 5 - Aminopropyl propyl hydroxypropyl methylcellulose carbitol 1,5-pentanediol BC SLS propylene glycol monocaprylate water 0.5 - 10.0 20.0 - 1.5 5.0 63.5 44 0.5 - 10.0 20.0 - 2.0 5.0 63.0 45 0.5 - 10.0 20.0 2.0 - 5.0 63.0 46 20.0 2.0 10.0 20.0 - 2.0 5.0 63.0 47

Penetration analysis of drugs

The following test was carried out using a Franz diffuser cell, which was controlled with a circulating water tank to control the water temperature. First, the rat skin or its buccal membrane was taken out from the -20 ° C refrigerator and warmed to room temperature. After the mouse skin or its oral buccal membrane is cut to an appropriate size, it is placed on a plane between the donor chamber and the receptor chamber. Next, after tightly supplying the chamber to the receiving chamber, Na ₂ HPO ₃ . 2H ₂ O-citrate buffer (pH 5.5) was filled into the receiving chamber through a sampling port, and the receiving chamber was equipped with a stir bar. After 1 milliliter of emulsion was applied to the supply chamber, the upper opening of the supply chamber was sealed with a parafilm sealing film. Finally, at a specific time point after administration, 0.5 ml of buffer was taken from the receiving chamber for high performance liquid chromatography (HPLC) analysis for component analysis, and 0.5 ml of fresh buffer was added immediately after removal. Liquid into the receiving chamber.

As shown in Figs. 1 to 4, the methylaminoacetylpropionic acid penetration cumulative amount and the intradermal deposition amount of the emulsions of Examples 1 to 30 were respectively exhibited 6 hours after administration.

As shown in Figures 5 to 7, the emulsion of Example 31 and the commercial product Metvix® cream (containing 160 mg of methylaminoethionate per gram) were respectively given for 6 hours after administration of methylaminoacetate. The cumulative amount of acid penetration and the amount of intradermal deposition.

As shown in Figs. 8 and 9, the methylaminoethionate penetration cumulative amount and the intradermal deposition amount of the emulsion of Example 32 and the commercial product Metvix® cream were respectively exhibited for 6 hours.

As shown in Figs. 10 and 11, the 5-aminolevulinic acid penetration cumulative amount and the intradermal deposition amount of the emulsions of Examples 33 to 47 were respectively exhibited 6 hours after administration.

In summary, it was confirmed that the pharmaceutical carrier of the present invention can effectively deliver a photosensitizer or a prodrug thereof to the body percutaneously or orally. Thus, the problem of poor penetration of the photosensitizer or its precursor drug can be improved and the amount of the photosensitizer or its precursor drug used can be reduced.

Although the present invention has been disclosed in its preferred embodiments, it is not intended to limit the invention, and the invention may be modified by those skilled in the art without departing from the spirit and scope of the invention. The scope of the present invention is intended to be in accordance with the scope of the appended claims.

no

Figure 1 is a statistical bar graph illustrating the cumulative amount of drug penetration 6 hours after administration of the emulsions of Examples 1 to 16. Figure 2 is a statistical bar graph illustrating the amount of intradermal drug deposition 6 hours after administration of the emulsions of Examples 1 to 16. Figure 3 is a statistical bar graph showing the cumulative amount of drug penetration 6 hours after the administration of the emulsions of Examples 17 to 30. Figure 4 is a statistical bar graph showing the amount of intradermal drug deposition 6 hours after the administration of the emulsions of Examples 17 to 30. Figure 5 is a line graph showing the cumulative amount of drug penetration at different times after administration of the commercially available emulsion Metvix® cream. Figure 6 is a line graph showing the cumulative amount of drug penetration at different times after administration of the emulsion of Example 31. Figure 7 is a statistical bar graph showing the amount of intradermal drug deposition of the emulsion of Example 31 and the commercial emulsion Metvix® cream 6 hours after administration. Figure 8 is a statistical bar graph illustrating the cumulative drug penetration for the 6 hours after administration of the emulsion of Example 32 and the commercial emulsion Metvix® cream. Figure 9 is a statistical bar graph showing the amount of intradermal deposition of the drug of Example 32 and the commercial emulsion Metvix® cream 6 hours after administration. Figure 10 is a statistical bar graph showing the cumulative amount of drug penetration 6 hours after the administration of the emulsions of Examples 33 to 47. Figure 11 is a statistical bar graph showing the amount of intradermal drug deposition 6 hours after administration of the emulsions of Examples 33 to 47.

Claims (7)

A pharmaceutical composition comprising: a pharmaceutical carrier comprising: an aqueous phase component comprising water in an amount of 63% by weight; and an oil phase component comprising propylene glycol monocaprylate , Caproyl 90), which is 5% by weight; a surfactant, selected from the group consisting of sodium lauryl sulfate (SLS), benzalkonium chloride (BC), or a combination thereof The group, which is 2% by weight; and a co-surfactant, contains a C2 to C8 alcohol in a weight percentage of 30%; and a photosensitizer or a precursor thereof. The pharmaceutical composition according to claim 1, wherein the auxiliary surfactant is ethanol, propylene glycol, 1,5-pentanediol, or carbitol. . The pharmaceutical composition according to claim 1, wherein the photosensitizer or the prodrug thereof is porfimer sodium, verteporfin, 5-aminoacetic acid (5- Aminolevulinic acid (ALA), protoporphyrin IX (PPIX), methyl aminolevulinate (MAL), (temoporfin), talaporfin (talaporfin), dexoxalin ( Texaphyrin), sulfonated aluminium phthalocyanine, or rostaporfin. The pharmaceutical composition according to claim 1, wherein the photosensitizer or its prodrug is present in an amount of from 0.1 to 20 parts by weight based on 100 parts by weight of the pharmaceutical carrier. The pharmaceutical composition according to claim 1, further comprising: a thickener. The pharmaceutical composition according to claim 5, wherein the thickener is chitosan, hydroxypropyl methylcellulose (HPMC), carbomer 940 (Carbopol 940), or poly Polyvinylpyrrolidone (PVP). The pharmaceutical composition according to claim 5, wherein the thickener accounts for 0.5 to 25 parts by weight of the pharmaceutical carrier in an amount of 100 parts by weight.