TW200819147A - Photosensitizer formulations for topical applications - Google Patents

Abstract

Highly flexible penetrating liposomal carrier systems are formulated with enhanced skin penetration properties. These specialized formulations of highly flexible penetrating liposomal delivery systems comprise one or more phospholipids, lysophosphatides and hydrophobic photosensitizer. This new formulations can squeeze liposomal particles through intercellular regions of stratum corneum as intact structures, and, in this way, deliver encapsulated photosensitizer to the epidermis, dermis, hypodermis and surroundings. The penetrating liposomal formulation provides therapeutically effective amounts of the hydrophobic photosensitizer through topical application with better skin penetration thus improving drug targeting and the efficacy of photodynamic therapy (PDT).

Description

200819147 IX. OBJECTS OF THE INVENTION: BACKGROUND OF THE INVENTION [Technical Field] The invention is a music delivery system. The present invention generally relates to a highly elastic, penetrating liposome formulation for loading a photosensitizer which can transport a photosensitizer across the skin barrier to the deep layer, in the case of --^, Oral skin problems, as well as other cancer or pre-cancerous skin conditions.

Information disclosure instructions [Prior Art] Skin has been used for decades as a topical drug for the treatment of skin problems, application of cosmetics, and treatment of cancer and pre-cancerous skin conditions. The primary purpose of "topical drug delivery" is to maximize delivery of the therapeutic agent in the formulation through the stratum corneum into the deeper layers of the skin. The second objective is to promote uniform absorption, provide controlled delivery of the therapeutic agent, and reduce side effects. ;" The skin is a composite layer composed of different layers. The upper stratum corneum is the main physical barrier for percutaneous penetration of local administration of drugs. There are several different pharmaceutical products: they are targeted to enter the body through the skin, and these include Transdermal drug delivery system (patch), liposomes, creams, ointments, lotions, gels, and subcutaneous implants. In contrast to traditional oral drug administration, the use of transdermal drugs: , several & One is through the metabolism of the liver, the acidic environment of the gastrointestinal tract, and the problem of absorption in the stomach, etc. The molecular weight and drug carrier penetration rate are affected by many factors during local administration, such as the interaction between the drug carrier and the skin. Many other factors are related to their lipophilicity and are inversely proportional to the size of the molecule. It has been attempted to overcome this limitation. Different drug delivery systems for overcoming skin disorders have been described in the art. Many, have been used as liposomes for the skin application system. However, most studies have shown that these liposome vesicles are not extremely effective in penetrating physical skin disorders. Because these traditional liposome vesicles are very hard. Special liposomes that are elastically permeable to the skin are being explored. In US Patent No. 165,500 _, one such system of insulin systemic administration is described by Greg〇r Ceve. The transferor (Uansfers〇mes) in the embodiment of the mussels. The transferor is a plastid vesicle that breaks into a molecular edge activator that deforms and squeezes through the microspores in the stratum corneum. Similarly, liposomes (ni〇s〇mes) and ethosomes are another carrier for dermal administration of drugs. Alcohol-containing liposomes are high ethanol content liposomes that make alcohol Liposomes and the stratum corneum are fluidized in two layers, thus allowing for penetration; whereas liposomes use nonionic surfactants. _ Many of the above drug delivery systems are not effective enough to transport light. Agents span skin disorders, most of which face many problems with stability, such as liposome vesicles deforming through the pores of the skin, which may cause damage to the carrier system' resulting in leakage of active compounds loaded in the liposomes. Other problems are liposomes Vesicles may accumulate as they pass through skin disorders, reducing their effectiveness and the ability to bring light medications to the desired site of treatment. The success of this drug delivery system relies on the amount of drug sufficient to achieve its desired therapeutic effect, penetrating through The ability of the skin. It has been shown that the fluidization of the intercellular functional sites and thus the stratum corneum, in order to improve the possible mechanism of drug-encapsulated vesicles 7 200819147. Different methods used in the prior art to modify the 'break characteristics of the hornbone layer And to improve drug penetration through the skin, #include the use of chemical penetration enhancers; iontophoresis, which uses low-current currents to plaque the ionic therapeutic agent through the skin; and ultrasound transdermal method (ph. Qing hGresis), which uses ultrasound energy to increase penetration through the skin. Photodynamic Therapy (PDT) is one of the most promising new technologies and is being explored for its use in a variety of medical applications and is known as fully-recognized tumor destruction therapy. Because of the inherent properties of photosensitizers, it limits the use of pDT in the treatment of various types of diseases. These include their high cost, prolonged residues in the host organism, phototoxicity of the skin, low solubility in physiological solutions ("this reduces their use in intravascular administration, as it may cause thrombosis! Base accidents, as well as low standard dryness. These shortcomings often result in a very high dose of photosensitizer that suddenly increases the likelihood that the photosensitizer will accumulate in the un-damaged tissue with a risk of affecting the un-damaged site. Because the application of photodynamic therapy is used to treat many skin diseases, as well as cancer and pre-cancerous skin conditions, there is a need to develop a TK delivery system that can be administered topically. In order to optimize and standardize the abnormal cells in and under the skin by topical application, side effects such as skin photosensitivity in other normal skin cells are reduced. The drug delivery system designed in the present invention is better than the prior art system. These delivery systems effectively penetrate the skin barrier and optimize the concentration of the drug in the deep layers of the skin. 9 The present invention seeks to overcome the impermeability of intact human skin, penetrates in a reversible and non-invasive manner, and is designed to treat photodynamic therapy in the treatment of 200819147 to transport hydrophobic photosensitizers. Therapeutic effective skin (four) material delivery (four) system [Abstract] The purpose and summary of the invention The purpose of this month is to formulate a liposome carrier system for topical application. $Dosing Density Another object of the present invention is to use this delivery system to deliver a hydrophobic photosensitizer over the stratum corneum more quickly and efficiently. "

A further goal of Benming is to use the novel formulation to optimize the photosensitizer and target it to the deeper layers of the skin via local remedies. Another object of the present invention is to increase drug penetration through skin disorders and reduce side effects on the skin. Briefly, the present invention provides a highly elastic penetrating liposome carrier system formulated to have enhanced skin penetration characteristics. A proprietary formulation of this highly elastic penetrating liposome delivery system, comprising one or more phospholipids, lysophospholipids, and a hydrophobic photosensitizer. The novel formulation can compress the liposome particles, pass the intercellular region of the stratum corneum intact, and deliver the encapsulated photosensitizer to the epidermis, dermis, subcutaneous tissue, and surrounding. This penetrating liposome formulation provides a therapeutically effective S hydrophobic photosensitizer via topical application with better skin penetration, thus improving photodynamic therapy (PDT) drug pirin and efficacy. [Embodiment] DETAILED DESCRIPTION OF THE INVENTION Penetrating liposome formulations are specialized topical drug delivery systems that reach cells in the deep layers of the skin 'but avoid systemic absorption of the drug, 9 200819147 thus minimizing side effects. The highly specialized penetrating liposome of the present invention: a formulation comprising one or more phosphonium waxes, one or more lysosomal lipids, and a hydrophobic photosensitizer. These novel formulations are tailor-made elastomeric steroids that, even when applied topically, can easily penetrate cells that reach deeper layers of the skin through horny beaks. This allows the drug to be delivered to have no significant side effects often reported during systemic administration. Topical application of a dermatological drug can now be used, at the site of application or = to achieve a local therapeutic effect. The primary goal of topical drug delivery is to maximize delivery of the drug or active ingredient from the formulation through the stratum corneum, the upper epidermis, and into the subcutaneous tissue, further minimizing absorption through the skin into the systemic circulation, and further Promote a more uniform reduction in "frequency" and improved cosmetic or aesthetic appeal of the formulation. The main i θ like ', his & Le Lu # 'transport across the skin also has several disadvantages, > all the drugs are local Appropriate candidates for dosing. It has been confirmed that some parameters will affect the uptake of drugs by the skin, such as the size of the vesicles, the molecular enthalpy, which affects the diffusion process, and the changes in the penetrating type. Anti-cardiac, brother, the skin permeability of the knife is directly proportional to its lipophilicity, and the disciplinary + gentry /, large] is inversely proportional. Sometimes seeing the damaged stratum corneum is not better than the intact skin. The layer is more versatile. It has also been found that the stratum corneum has increased permeability by reducing the barrier properties. :: Ming's novel penetrating liposome formulation overcomes most of the = phase A number of disadvantages. These new formulations have been shown to improve the .7 P疋 not-collected and stable, and have a better loading capacity. The deployment of penetrating liposomal vesicles on a rice scale facilitates easier transport通10 200819147 Over skin disorders, because particle size is an important criterion for percutaneous penetration. These newly formulated penetrating lipid f-body particles can squeeze themselves through the intercellular region of the stratum corneum with intact structure, and in this way The encapsulated photosensitizer is delivered to the dermis. The invention is further illustrated by the following examples, without being limited thereto.

Highly elastic penetrating liposome vesicles containing mTHpc (meta_tetrahydroxyphenylchlorin) prepared according to the following general procedure, a special penetrating lipid of mTHpc, also known as temoprofen Body Formulation: In a sealed glass test tube, the lipid solution (3:1) was vigorously mixed using a vortex shaker for 5 minutes. Then m_THpc and penetration enhancer were added and the mixture was mixed again. Then oscillate with ultrasound for 5 minutes. An appropriate amount of phosphate buffered saline Η7·4 was added dropwise, the mixture was hydrated, and again mixed for 5 minutes with a thirst quenching, followed by ultrasonic shock. The resulting mixture was then extruded (filtered) through a different polycarbonate filter paper having a pore size ranging from 400 nm to as high as 5 Å. The entire process is carried out at room temperature. Using the procedure described above, a highly penetrating liposome formulation of m-THPC was prepared as follows: 'Usage weight/% by weight 0. 2 to 1.5 mg/ml 10 ingredients

mTHPC Soy fat filling (Phospholip〇n) (^8〇 200819147 ethanol

Na2HP04 kh2p〇4 Cineol Citral Limonene 3 2 mg/ml 0.2 mg/ml 0.9 0.9 0.2 Water As needed

Soybean phospholipid 80 is a commercially available lipid mixture comprising from about 73.0 to about 76.0% by weight of (3411-phospholipid) choline, up to 6 weight percent. (3-sn-hemolytic phospholipid) choline, up to 7% by weight of cephalin and up to 7% by weight of phosphatidic acid (the soy phospholipid 80 used in the present invention to prepare penetrating liposomes;

Supply by Phospholipid GmbH; Nattermannallee l; D-50829 Koln,

Germany) ° A lipid mixture other than soybean phospholipid 80 may be used, which includes commercially available large ugly phospholipids 50 (including about at least 5 〇% by weight of 3-Sn-phospholipid choline and up to 6% by weight of 3_Sn_lysophospholipid 醯Choline), soy phospholipid 9 〇 (including taking about 90 weight less / ◦ 3-Sn-phospholipid choline, up to 6 weight% / 〇 3-Sn-lysophosphatidylcholine choline and up to 3 weight. Tocopherol), as well as soy sauce 100' also have a mixture of other phospholipids. The use of penetration enhancers increases skin permeability by reversibly injuring the physicochemical properties of the stratum corneum, reducing its diffusion resistance. Good skin penetration enhancers should be non-irritating, pharmacologically inert, non-toxic and should be readily compatible with the other ingredients of the formulation. In the above formulations, the use of boxenes, such as eucalyptin (2,2,4-trimethyl_3_ hired bicyclo[2 2 2]octane), lemon 12 200819147 (3,7) - Dimercapto 2,6-octadiene brewing) and lemon strontium (1 - methyl propyl succinyl-2-yl-cyclohexene) as a penetration enhancer, so as to change | a The permeabilized liposome formulated mTHPC passed through the skin and stratum corneum barrier. The FDA has classified many terpenes as GRAS (safe). Wearing a provocative, * μ tooth-promoting agent can increase the fluidity of the stratum corneum, thereby reducing its resistance, while the temporary & t helps the novel penetrating liposome formulation to easily pass through major skin disorders. . The scale ' used in the novel liposome formulation of the present invention shows a better variableness to the vesicles, resulting in better skin penetration.

Stability data a. Excluding mTHPC (four) quasi-high elastic penetrating liposome (stored at 4 °C), day, 3, 6 and 12 months measurement time effective 0 (nano) 0 day 139 nm ~ 3 Monthly 172 nm ~ 6 months 187 nm ~ 12 months 170 nm b · Stability data of high elastic penetrating liposomes with different concentrations of mTHPC prepared by the ultra turrax method

13 200819147 C·Permeability of penetrating liposomes with 0·75 mg THPC/ml content Example 1 (stored at temperature 4 ° C) Measurement time effective 0 (nano) ~ 3 months 105 〜 6 months 117 ~ 12 months 115 Example 2 (stored at temperature 4. (: down) Measurement time effective 0 (nano) ~ 3 months 107 ~ 6 months 115 ~ 12 months 102 Above data shows wear Permeable liposome mTHpC formulation is stable

14 Stability of 200819147. Therefore, ph8〇 is a better specific fact than Ph50 in the preparation of liposomes suitable for most applications. Filtration behavior of highly elastic penetrating liposomes The dilute solution of the penetrating liposome with mTHpc was measured at two different wavelengths' evaluation during filtration through 〇·2 μm and 〇〇 2 μm crepe paper (mTHPC) percentage of loss. Penetrating liposomes are able to cross the 〇·〇2 micron membrane system without substantial loss of drug, whereas traditional lipid bodies are not. This shows the high elasticity of the liposomes because they are capable of passing over a membrane having a pore size less than 20% of its own diameter. The difference in mTHp (the difference in content between two different wavelengths (649 and 703 nm) was calculated, showing no net loss of mTHPC content between before and after filtration. This confirms the high potency of drug encapsulation. Limiting mTHPC Gel filtration of highly specialized liposome formulations on a parent-linked dextran G50 column in a proprietary penetrating liposome formulation. As shown in Figure 1, lipids and lipids were included in all filters. mTHPC showed the same distribution, indicating the physical interaction of the two components, ie mTHPC was integrated into the membrane bilayer, demonstrating high encapsulation efficacy and stability. Animal studies at 6 to 8 weeks of age, inoculation of HT29 human colorectal cancer In vivo studies of cells in female NMRI mice. There were three treatment groups, the first group served as the control group, while the second and third groups received novel penetrating liposomes in the left thigh and tumor, respectively, in mTHPC. In the treatment group, the mTHPC content was examined at different times in order to study the efficacy of the novel penetrating liposome formulation to transport the 15 200819147 music through the skin barrier to the target area of the deep layer of the skin. The mTHPC content in the blood, skin, treated skin, tumor, muscle, liver and spleen was recorded in the 0, 0.5, 3 and 寸 mother groups after penetrating liposomes formulated with mTHPC. mTHPC wet weight in blood, liver, muscle, skin, treated skin, spleen and tumor after topical application of penetrating liposomes to the left thigh of mice for 0, 5, 3 and 6 hours Concentration. At the 0.5 hour of local administration, the highest concentration of mTHPC was achieved in the tumor, thus reducing the drug light interval. Immediately clear the mTHPC concentration in other tissues. The second group was treated with a penetrating liposome formulation loaded with mTHPC. The mice were 'locally applied to the tumor and plotted against wet weight concentrations of mTHPC in blood, liver, muscle, skin, treated skin, spleen and tumor at different time intervals in _3. The maximum myocardial concentration was reached in the tumor 0.5 hours after administration of the novel liposome formulation. Figure 4: 〇, 〇·5, 3 and 6 for topical administration of novel liposome formulations on the left thigh of the mouse After the time, the injection in different tissues; the hundred-knife ratio in ^. Figure 5 illustrates the local application of penetrating liposomes to the mouse tumor on the sputum, 〇.5, 3 and 6 hours after the different tissues Percentage of injected dose of mTHPC. The highest tumor concentration was observed after 5 hours of topical administration on the tumor. In all of the above studies, it was greatly reduced in other tissues, especially the liver and spleen^ The concentration of mTHPC, thus reducing the toxicity to these important tissues in the body. 16 200819147 The accompanying drawings are intended to describe the preferred specific facts of the invention, and it should be understood that the invention is not limited Various changes and modifications are made without departing from the scope and spirit of the invention, as defined in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a gel filtration curve of temoporfin, a chemical name-tetrahydroxyphenyl chlorin (mTHpc) formulated with 鬲 elastic penetrating liposome. Both the lipid component and mTIiPC showed the same distribution in all of the collected filters. Figure 2 illustrates the topical application of high-elastic penetrating liposome formulations loaded with mTHpc on the left thigh of mice after 〇, 5, 3 and 6 hours in blood, liver, muscle, skin, treated skin, spleen and The wet weight concentration of mTHPC in the tumor. Figure 3 depicts the wet weight concentration of mTHPC in blood, liver, muscle, skin, treated skin, spleen and tumor at different time intervals for administration of loaded highly elastic penetrating liposome formulations on tumors in mice. Figure 4 is a graph showing the percentage of injected doses of mTHPC in different tissues at different time intervals for topical administration of a highly elastic penetrating liposome formulation of mTHpc on the left thigh of a mouse. Figure 5 shows the percentage of injected doses of mTHpc in different tissues at the same time as the permeabilized liposomes were applied directly to the tumor of the mouse. 17 200819147 [Explanation of main component symbols]

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Claims (1)

200819147 X. Patent Application Range: 1 · A pharmaceutical liposome formulation for topical application of photodynamic therapy to improve penetration stability and delivery, comprising: a highly elastic, penetrating liposome carrier system, wherein The carrier system is a liposome bilayer comprising a phospholipid; a therapeutically effective amount of a hydrophobic photosensitizer incorporated into the liposome bilayer; an additional skin penetration enhancer; Wherein the highly elastic penetrating liposome carrier system can penetrate the intact stratum corneum or wound surface without prematurely removing the hydrophobic photosensitizer from the bilayer and as they pass through the stratum corneum or The liposomal bilayer also does not agglomerate on the surface of the wound. 2. A pharmaceutical liposome formulation for topical application of photodynamic therapy according to claim 1 wherein the phospholipid is selected from the group consisting of 3-phospholipid choline, 3-phospholipid choline, a group of phosphatidic acid and cephalin.曰3. A Le Liposomal Formulation for Topical Administration of Photodynamic Therapy as in Item 2 of the patent application, wherein the relative percentage of the phospholipid is about 73-76% by weight of the 3 squamous sputum test, about 6 % by weight of 3 hemolytic lipid choline, approximately 7% phosphatidic acid and approximately 7% cephalin. - 4. For patent application |! ® 帛 2 可供 for topical application of photodynamic therapy: the liposome formulation, the relative percentage of the fat in the mash is about % by weight. /. 3-phosphocholine choline, about 6% by weight of 3 lysophosphatidylcholine, and about 3% by weight of tocopherol. 5. If you apply for a patent range! Item for photodynamic therapy for topical application 200819147 The pharmaceutically acceptable liposomes are formulated with a wide variety of terpenes selected from the group consisting of -monomethyl-2,6-octane dilute I. A topical application of photodynamic therapy. 6. A pharmaceutical liposome formulation according to claim 1, wherein the hydrophobic photosensitizer is selected from the group consisting of dihydro- and tetrahydro-porphyrins. 7. A pharmaceutical liposome formulation for topical application of photodynamic therapy as claimed in claim 6 wherein the hydrophobic photosensitizer is mTHpc (temopor < temporfln). 8. A Le Liposomal Formulation for Topical Administration of Photodynamic Therapy as claimed in claim 1, wherein the photosensitizer is therapeutically effective at a concentration of from 0.0001 to 0.4% by weight. XI. Schema: as the next page 20