Fluorouracil-containing preparations

Abstract

To provide a topical formulation containing fluorouracil and not exhibiting contact sensitization.SOLUTION: A pharmaceutical composition for use in treatment of superficial basal cell carcinoma, actinic keratosis, solar keratosis, acne or scars comprises pharmaceutically compatible nanoparticles and at least 0.5 wt.% of fluorouracil, where the nanoparticles comprise at least 50 wt.% of hydrolyzable silicon and are surface-coated with phospholipid, the coated nanoparticles are associated with fluorouracil, the fluorouracil is electrostatically associated with the surface of the nanoparticles and / or the phospholipid bilayer, and the nanoparticles are associated with a willow bark extract.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to an improved topical formulation containing fluorouracil and to the use thereof. That is the case. [Background technology]

[0002] Fluorouracil (international common name) is a chemical substance 5-fluoro-2,4(1H,3H)- It is pyrimidinedione. Fluorouracil is useful as an anticancer agent for the breast, bladder and Fluorouracil has been used in the systemic treatment of various cancers, including pancreatic cancer. To treat basal cell carcinoma, actinic keratosis, solar keratosis, and various forms of scarring and severe acne. It is used topically. Topical formulations containing fluorouracil are currently available. However, although effective, it can cause side effects, the main side effects being skin irritation and Related side effects include pain, ulcers, and erythema. Fluorouracil has minimal side effects. There is a need for improved formulations that deliver effective transdermal doses.

[0003] U.S. Patent No. 6,670,335 states that fluorouracil is a "microsponge." In porous microparticles called "and in emulsions," their hydrophilicity likely contributes to the The use of a formulation consisting of an oil-in-water emulsion, which is also present in the aqueous phase of the emulsion, is disclosed. It is.

[0004] There is a demand for an improved delivery system to enable topical administration of fluorouracil. It still exists.

[0005] This invention provides silicon with improved properties compared to the fine particles of U.S. Patent No. 6,670,335. Using silicon nanoparticles, the substantial properties of silicon nanoparticles and fluorouracil are achieved. This relates to an improved formulation in which the whole is associated. Those nanoparticles then one The above waxy fatty acid esters are encapsulated within a lipid matrix containing the lipid matrix X is virtually fluorouracil-free and exhibits excellent bioavailability when administered. It can be processed into a powder suitable for various topical formulations that reduce side effects.

[0006] silicon nanoparticles Several methods have been developed to deliver active pharmaceutical ingredients in a controlled or sustained-release manner. However, However, once the function of delivering and releasing the active ingredient is performed, the end of the carrier material is Until now, little attention has been paid to this. This invention provides a silicon-based carrier material that is beneficial after administration. A delivery system that converts to quality is used.

[0007] Extensive research has been conducted to enable local delivery of active ingredients to the stratum corneum in a controllable manner. As a result of focusing on developing methods to temporarily disrupt the layer barrier, drugs have become sufficiently predictable. It can penetrate in sufficient quantities and has reached a therapeutic level. Iontophoresis therapy and ultra Some technologies, such as sound waves, have been explored as means of enhancing skin absorption. However, most attempts involve reversibly removing the stratum corneum to allow large amounts of the drug to penetrate the skin. We have focused on identifying non-toxic chemical penetration enhancers that can interact with the barrier. Early attempts to destroy it used a single solvent or a mixture of solvents, surfactants, and fatty acids. These substances can increase the penetration of many chemicals into the skin, but undesirable It is often associated with undesirable side effects, and these side effects are caused by the extraction or processing of components of the skin. By associating with the ability to interact, it elicited a stimulus response.

[0008] Silicon is an essential trace element for plants and animals. Silicon is found in the composition of complexes of proteins and glycosaminoglycans found in the matrix of mammalian connective tissue, with a structural role as a constituent and a metabolic role in growth and bone formation (the presence of silicon promotes the process of bone mineralization). Thus, silicon is essential for the normal development of bone and connective tissue. Silicon is also known to play an important role in skin health, acting as a collagen and elastin promoter and participating in the antioxidant process in the body. Silicon is involved in the production of glycosaminoglycans, and the advantages of the natural tissue construction process are increased by silicon-dependent enzymes.

[0009] For medical applications, silicon can be produced as microparticles or nanoparticles, and these [[ID=Q3]] microparticles or nanoparticles facilitate administration via a number of routes such as topical uptake, oral uptake, injection or implantation. Biodegradable silicon-based particles are further used for drug targeting. However, the bioavailability of silicon is often limited by its poor solubility, and many organic silicon-containing substances tend to exhibit unacceptably high toxicity, and their use is limited to cosmetic, skin care and pharmaceutical applications. [[ID=q3]]

[0010] Porous silicon was first accidentally discovered in 1956 by Arthur Ullrich Jr. and Ingeborg at Bell Laboratories in the United States. The production of porous silicon, from its initial formation, involves immersing single crystals in hydrofluoric acid (HF) solution or the use of a dye etching or an anodic oxidation cell using polycrystalline silicon, and it can be. By forming pores in silicon, both the decomposition of substances and the activation of silicon pores enable both the filling of the compound. The use of porous silicon as a carrier for other active compounds has been described (Saffie-Siebert R et al., Drug Disco very World 2005; 6: 71-6; Saffie-Siebert , R et al., Pharmaceutical Technology Europe, 17(4), 21-28 (2005); Luo, D., Saltzman, W.M., Gene Therapy (2006) 13, 585-586; Ahola, M., Kortesuo, P., Kangasniemi, I. , Kiesvaara, J., Yli-Urpo, A., Int. J. P harm. 195 (2000) 219 227. Ahola. M., Sai[[ID=​​​​​​​​​​​​​​​​​ The dissolution product of silicon in an aqueous environment is silicic acid. Silicic acid has the general formula [SiO₂]. x ( OH) 4-2x ] n The general group of chemical compounds of elements such as silicon, hydrogen, and oxygen. These are typical names. Metasilicic acid (H2SiO3), orthosilicic acid (H4SiO4, at 25°C) pK a1 =9.84, pK a2 =13.2), metanicilicate (H2Si2O5) and pyro Some single silicic acids, such as silicic acid (H6Si2O7), can be identified in a sufficiently diluted aqueous solution. Furthermore, silica (SiO2) silicic acid polymers (PolySA) are the endpoint of complete polymerization. This represents silicic acid in monomeric form; alternatively, monosilicic acid. d) Orthosilicic acid (OSA), also known as silica, is energetically favored by silica. The opposite side of the silicon-based reaction, representing the appropriate form, is shown. The concentration and pH are related to the direction of the reaction and the monomer. The equilibrium state between the polymer and silica is determined.

[0012] [ka]

[0013] Silicic acid can be considered a buffer molecule. Orthosilicic acid (OSA) is a very weak acid. For example, it is weaker than carboxylic acids. Orthosilicic acid (OSA) has the following pK at 25°C: 1 dissociates at 9.84.

[0014] [ka]

[0015] Since silicic acid has a pKa of approximately 9.8, it is a mixture of acids that ionize in solution and do not dissociate. This shows the ionized species (H3SiO4). - ) acts as a proton scavenger, and from solution It removes protons, thus raising the pH of the solution. On the other hand, non-dissociated species are hydroxide This can raise the pH of the solution by donating protons to neutralize the on. In this way, silicic acid buffers the solution. This buffering capacity develops rapidly at low Si concentrations. It is worth noting that when the Si concentration is high, the pH decreases, and dimer Silicic acid undergoes a condensation reaction to produce a (H6Si2O7) body, or a higher-order structure and water. Promote these dimers and higher-order structures (SiO x OH y ) are hydroxide ions in solution By reacting with it, the pH decreases, allowing it to revert to monomers or lower-order structures. Similarly, these polymerized acids can neutralize hydroxides at high pH, ​​further... It dissociates into [a certain form]. Therefore, polysilicic acid can also act as a buffer, but the reaction is relatively [a certain type of] It is slow.

[0016] Silica [SiO2] shows the endpoint of complete polymerization of OSA, reducing its solubility, Therefore, it reduces bioavailability, biodegradability, and safety.

[0017] Enthalpy of dimerization and further polymerization reactions at ambient temperature under biological pH conditions. Therefore, polymerization generally proceeds via the following route.

[0018] [ka]

[0019] Since this is a reversible process, the reverse reaction from silica to OSA is theoretically possible. , also, since it requires a pH value exceeding 13 and high temperature, it is not thermodynamically suitable under physiological conditions. It is not suitable.

[0020] The reaction of OSA with itself to form silica can be limited by reducing its concentration until the association of two OSA molecules in solution becomes similar to the dimer of silicic acid that associates and dissociates with OH ions in solution. The limiting concentration of a pure solution containing only silicic acid is about 10 - Mol.L (Studies of the kinetics of the precipitation of uniform silica particles through the hydrolysis and condensation of silicon alkoxides, Journal of Colloid and Interface Science, Volume 142, Issue 1, March 1, 1991, pages 1 - 18, G.H Bogush and C.F Zukoski IV). When this concentration is exceeded, other PolySA species are formed, making it impossible to identify pure OSA. However, at high concentrations, orthosilicic acid can prevent polymerization through the addition of other chemical species. 10 -4 Mol.L -1 and C.F Zukoski IV), and when this concentration is exceeded, other PolySA species are formed, making it impossible to identify pure OSA. However, at high concentrations, orthosilicic acid can prevent polymerization through the addition of other chemical species. f the precipitation of uniform silica pa rticles through the hydrolysis and conde nsation of silicon alkoxides, Journal of Colloid and Interface Science, Volume 1 42, Issue 1, March 1, 1991, pages 1 - 18, G.H Bogush and C.F Zukoski IV), and when this concentration is exceeded, other PolySA species are formed, making it impossible to identify pure OSA. However, at high concentrations, orthosilicic acid can prevent polymerization through the addition of other chemical species. However, at high concentrations, orthosilicic acid can prevent polymerization through the addition of other chemical species. However, at high concentrations, orthosilicic acid can prevent polymerization through the addition of other chemical species.

[0021] [Chemical formula]

[0022] The kinetics of dissolution depends on the pH and availability of the reactive species, ignoring the surface area. The main reactive species in the dissolution process is water in its protonated and deprotonated forms (dual form). Dynamic data regarding reaction rates in one direction are available from Brinker "sol-gel sc See "science and technology"). However, other molecules The addition of this substance causes the equilibrium state to be shifted to silica or silicon oxide (glass) depending on the pKa values ​​of the other molecules. It is possible to create a significant shift and generate side reactions.

[0023] While pH adjustment allows for control of dissolution during storage, the pH within the body varies depending on the individual. It is strictly controlled. Therefore, the dissolution rate is adjusted based on particle size and surface chemical properties. This must be done before use in the body. Protonation is used only to increase the dissolution rate. Hydroxylated silicon is preferred. It is desirable to slow down the dissolution rate of the silicon particles. In this case, an oxide layer of appropriate thickness will have a lag in dissolution characteristics as the oxide layer dissolves slowly. This generates the oxide layer. The thickness of this oxide layer determines the length of the delay period before water can access the silicon core. To decide.

[0024] Since the binding of drug molecules is highly dependent on surface energy, care must be taken when treating silicon surfaces. This may be necessary.

[0025] The proliferation of oxides on the surface increases the contact angle, which is favorable for the bonding of hydrophobic molecules, and polarity Molecular bonding is reduced. On the other hand, surface hydroxylation reduces the bond between the silicon surface and the drug. The reduced contact angle between the molecule and the substrate is advantageous for the bonding of hydrophilic molecules such as fluorouracil.

[0026] OSA is a very weak acid that is unstable at pH levels below 9.5 and is harmful to the human body. It rapidly precipitates or forms sols or gels with almost no bioavailability. Therefore, ortho Preparing high-concentration solutions of silicic acid and low polymers (silicon exceeding 0.5%) is extremely difficult. This is difficult. Furthermore, the types of silicic acid produced by the formulation include silicic acid and silicon compounds. The concentration of OSA and the pH of the medium in which this dissolution occurs are largely determined. To obtain it, the silicate concentration must be strictly controlled.

[0027] International Publication No. 2011 / 012867 describes how stabilized silicon-based materials can be advantageous compounds. It is proposed to use it as a delivery agent for [purpose]. Stabilization is achieved by polysilicic acid (poly By reducing the production level of SA, the element silicon is converted into biologically active orthosilicic acid. Product safety is enhanced by implementing measures to control the disassembly process.

[0028] This invention relates to a method described in International Publication No. 2011 / 012867, which stabilizes with a stabilizer. The advantages of ricon nanoparticles that contribute to the invention of International Publication No. 2011 / 012867, that is, In addition to providing improved degradation of biologically usable OSA, it also stabilizes them. The modified silicon nanoparticles are filled with sufficient fluorouracil into the stabilized silicon nanoparticles. Fluorouracil can be bound and delivered so that it can be released as needed, and it can also be stabilized. These silicon nanoparticles can be encapsulated in a waxy lipid to produce a powder containing solid particles. A process including the decomposition of eel silicon, and a waxy lipid compounded for topical administration This is particularly possible through a process in which any surrounding medium is substantially free of fluorouracil. This is based on the fact that the amount of fluorouracil that does not associate with particles This is in stark contrast to the remarkably large number of formulations described in U.S. Patent No. 6,670,335. According to the present invention... Therefore, after the first dose, fluorouracil is excessively released into the skin (dose dumping). This alleviates side effects such as burning and irritation on the skin surface while maintaining therapeutic effects. This allows for the administration of a certain dose.

[0029] The advantage of using silicon nanoparticles smaller than the fine particles of the prior art is that the silicon material itself The body is biocompatible, biodegradable, and can be arbitrarily made into highly porous nanoparticles, with the particle size being small. Excessive use can block the pilosebaceous ostratum or sweat gland ducts (pores). Because it cannot be done otherwise, it can be fabricated in the 20-400nm range, which is ideal for skin delivery, and the size is small. As a result, the particles actively penetrate the bottom of the hair follicle rather than simply acting as a surface reservoir for the drug. This means it is a formulation that can penetrate the body and allows for a high level of adjustment.

[0030] The use of silicon nanoparticles is necessary because, otherwise, waxy compounds would only be suitable for hydrophobic compounds. Hydrophilic fluorouracil is applied to hydrophobic, waxy powder particles, also known as microspheres. Because it is compoundable, it is particularly suitable for use in compositions containing fluorouracil. ru. [Prior art documents] [Patent Documents]

[0031] [Patent Document 1] U.S. Patent No. 6,670,335 [Patent Document 2] International Publication No. 2011 / 012867 [Non-patent literature]

[0032] [Non-Patent Document 1] Saffie-Siebert R et al., Drug Discovery World 2005; 6: 71-6 [Non-Patent Document 2] Saffie-Siebert, R et al., Pharmaceutical Technology Europe, 17(4), 21-28 (2005) [Non-Patent Document 3] Luo, D., Saltzman, W.M., Gene Therapy (2006) 13, 585-586 [Non-Patent Document 4] Ahola, M., Kortesuo, P., Kangasniemi, I., Kiesvaara, J., Yli-Urpo, A., Int. J. Pharm. 195 (2000) 219 227 [Non-Patent Document 5] Ahola. M., Sailynoja, ES, Raitavuo, MH, Vaahtio, MH, Salonen, JI, Yli-Urpo, AUO, Biomat. (2001), 15, 2163-2170 [Non-Patent Document 6] Lu, J., Liong, M., Zink, J., Tamanoi, F, Small. 2007, 3: 1341-1346 [Overview of the Initiative] [Means for solving the problem]

[0033] According to the first aspect, the present invention relates to at least 50% by weight coated with phospholipid pharmaceutically suitable nanoparticles comprising a hydrolyzable silicon surface, which are coated The nanoparticles provided are nanoparticles that associate with fluorouracil.

[0034] According to a second aspect, the present invention relates to pharmaceutically suitable nanoparticles according to the first aspect of the present invention. A pharmaceutically acceptable powder containing one or more solid particles of waxy fatty acid esters encapsulated within. The composition contains 90% by weight or more of fluorouracil, which is optionally coated with The present invention provides a powder that associates with particles. Preferably, the powder contains salicylic acid, for example, powder It may contain willow bark extract.

[0035] According to a third aspect, the present invention relates to a pharmaceutical suitable for topical administration to the skin or other body surface. A suitable cream or gel formulation, which is pharmaceutically suitable according to the second aspect of the present invention. The present invention provides a cream or gel formulation comprising a cream or gel base in which a powder is suspended.

[0036] According to a fourth aspect, the present invention relates to an adhesive patch comprising a backing layer and an adhesive film. The adhesive film is a pharmaceutically suitable powder according to a second aspect of the present invention or the present invention. The present invention provides an adhesive patch comprising a cream or gel according to a third embodiment.

[0037] According to a fifth aspect, the present invention relates to a first aspect of the present invention for use as a pharmaceutical agent. pharmaceutically suitable nanoparticles, a pharmaceutically suitable powder according to a second aspect of the present invention, and A pharmaceutically suitable cream or gel according to a third aspect of the invention, and a fourth aspect of the invention Provides an adhesive patch.

[0038] According to the sixth aspect, the present invention relates to superficial basal cell carcinoma or actinic keratosis, solar keratosis, and scarring. Alternatively, a pharmaceutically appropriate drug for use as a treatment for acne, according to the first aspect of the present invention Compatible nanoparticles, a pharmaceutically compatible powder according to a second aspect of the present invention, and a third aspect of the present invention A pharmaceutically suitable cream or gel according to the embodiment of the present invention, and an adhesive according to the fourth embodiment of the present invention. We will provide the patch.

[0039] According to the seventh aspect, the present invention relates to superficial basal cell carcinoma or actinic keratosis, solar keratosis, and scarring. Alternatively, a pharmaceutically acceptable method according to the first aspect of the present invention for manufacturing a drug for treating acne. Nanoparticles, a pharmaceutically suitable powder according to a second aspect of the present invention, and a third aspect of the present invention A pharmaceutically suitable cream or gel formulation according to the specifications, and an adhesive pad according to the fourth aspect of the present invention. To provide.

[0040] According to the eighth aspect, the present invention relates to superficial basal cell carcinoma or actinic keratosis, solar keratosis, and scarring. Alternatively, a method for treating acne, wherein the third aspect of the present invention is pharmaceutically suitable. Applying a therapeutically effective amount of a cream or gel according to the fourth aspect of the present invention, or The present invention provides a treatment method that includes administering a patch. [Modes for carrying out the invention]

[0041] definition According to this disclosure, derivatives of the compound have substantially the same structure but with one or more substitutions. It may be a compound having one or more chemical groups, by adding, deleting, or adding another group. It may be substituted with. In certain preferred embodiments, the derivative has the drug activity of the original compound or This represents at least a portion of the cosmetic activity, for example, at least 90% of the activity of the derived compound. They hold 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiments, the derivative exhibits increased pharmaceutical or cosmetic activity compared to the original compound. This can indicate that an addition was made.

[0042] For example, in relation to peptides, peptide derivatives have one or more amino acid residues added, The peptide may contain deletions or substitutions with other amino acid residues. In the case of substitution, the substitution is retained. It may be a conservative or non-conservative substitution, but a conservative substitution is preferred.

[0043] According to the first aspect, the present invention comprises at least 50% by weight of hydrolyzable silicon Lipids (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidyl) Ethanolamine, one or more components of lecithin and their derivatives, especially phosphatidyl The surface is coated with one or more of the following: choline, hydrogenated phosphatidylcholine, and its derivatives. The pharmaceutically acceptable nanoparticles are coated nanoparticles, and the coated nanoparticles are fluoro Provides nanoparticles that associate with racil.

[0044] The phospholipid coating preferably alters the hydrolysis rate of silicon and / or The polymerization rate of thutosilicic acid is suppressed. The phospholipid coating involves the hydrolysis of the silicon-containing material. It is preferable to suppress the rate of decomposition.

[0045] In one embodiment, the hydrolysis rate of a silicon-containing substance is determined by the hydrolysis rate of phospholipids (e.g., phospholipids). Phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylethanolamine, reci One or more components of tin and their derivatives, in particular phosphatidylcholine, hydrogenated phosphatidylcholine The presence of tidylcholine and one or more of its derivatives slows down the rate of phospholipids. The hydrolysis rate of the same composition is less than 50%, preferably less than 30%, and especially less than 10%. It will be changed to do so.

[0046] The hydrolysis rate is determined by whether OSA is assimilated in the body or removed from the delivery site, for example, by diffusion. By slowing the process down to a level lower than that required, the polymerization of OSA can be avoided or at least It was found that this could be reduced, enabling the effective delivery of OSA to the body.

[0047] Since the decomposition products of monomeric silicic acid are naturally available to the human body, the present invention The use of the product significantly reduces the risk of toxins, which is a significant advantage over many other delivery systems. This offers advantages that far exceed the present invention. The delivery system according to the present invention provides advantages to known live Another advantage is that the carrier is broken down to provide a composition that can be used in the body. OSA is finely divided into specific cell types, including fibroblasts, endothelial cells, and keratinocytes. It is known to stimulate cell proliferation and cell migration.

[0048] Advantageously, the nanoparticles according to the present invention (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine) One of the components of zilcholine, phosphatidylethanolamine, lecithin, and their derivatives One or more, in particular, phosphatidylcholine, hydrogenated phosphatidylcholine and its derivatives Biocompatible orthosilicic acid obtained by the decomposition of nanoparticles coated with one or more layers. However, it itself serves as a nutrient for the skin, bones, hair, nails, and connective tissue, and is beneficial for arthritis or bone. It is effective in treating or preventing bone or joint diseases such as osteoporosis.

[0049] Silicon nanoparticles coated with phospholipids, especially the phospholipid coating When in the form of a bilayer of one or more phospholipids, it is particularly suitable for association with fluorouracil. It was found that this association is preferably caused by the attractive force between opposite charges. For example, the charge of the phospholipid bilayer and / or the charge on the surface of silicon nanoparticles, and fluor electrostatic association between the charge of Lauracil The bond may be on or ionic. In all aspects of the present invention, preferred embodiments are as follows: According to this, association is facilitated by the presence of amino acids, and therefore all products of the present invention (For example, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidyl ethanol One or more of the components of lecithin and its derivatives, in particular phosphatidylcholine A surface coated with one or more of the following: The particles are preferably amino acids, particularly arginine or a mixture of arginine and glycine. Includes objects.

[0050] The presence of amino acids (e.g., one or more of arginine and glycine) also contributes to silicon nano It stabilizes the charge on the surface of the particles, and phospholipids (e.g., phosphatidylcholine, hydrogenated phospholipids) Phosphatidylcholine, phosphatidylethanolamine, lecithin components and their derivatives One or more of the following, particularly phosphatidylcholine, hydrogenated phosphatidylcholine and its derivatives It helps to improve association with one or more (and fluorouracil). The presence of amino acids contributes to the sustained release of fluorouracil and the stability of silicon over time. It helps to control both the solution rate and the solution rate. In its broadest sense, the term "amino acid" is Any artificial or naturally occurring amine (-NH2) functional group and carboxyl (-COOH) ) Includes organic compounds containing functional groups. The term "amino acid" includes α, β, γ and δ It contains amino acids. The term "amino acid" includes amino acids in any chiral stereochemistry. It is included. According to some embodiments, it is preferable that it be a naturally occurring α-amino acid. Proteinogenic amino acids or non-proteinogenic amino acids (carnitine, levothyroxine) It may be hydroxyproline, ornithine, or citrulline, etc. Arginine may also be It is particularly preferable to include glycine, or a mixture of arginine and glycine. It is preferable that 30% of the amino acids consist of arginine.

[0051] Therefore, the present invention is suitable for pharmaceutically compatible nanoparticles (e.g., phosphatidylcholine). The components include hydrogenated phosphatidylcholine, phosphatidylethanolamine, and lecithin. and one or more of their derivatives, particularly phosphatidylcholine and hydrogenated phosphatidylcholine. Silicon nanoparticles coated with one or more of its derivatives are coated The nanoparticles contain fluorouracil and (preferably arginine, glycine, and mixtures thereof). It associates with an amino acid (most preferably selected from both arginine and glycine). It's eel.

[0052] The present invention includes nanoparticles (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine and Nanoparticles coated with one or more of those derivatives, wherein the nanoparticles are full Nanoparticles that associate with olouracil and optionally with one or more arginine and glycine. The presence of willow bark extract associated with it also improves the association between nanoparticles and fluorouracil. It helps to do so. (American willow and / or European white willow, preferably) Willow bark extract (extracted from American willow) contains fluorouracil. This leads to a matrix that increases the association between fluorouracil and nanoparticles. This provides that when nanoparticles are delivered to the treatment site, for example, the nanoparticles of the present invention When the substance is delivered locally to the skin surface in the form of a cream or gel, fluorouracil It should help ensure that the release is controlled. Furthermore, willow Bark extracts typically contain salicin, which is metabolized to form salicylic acid, an anti- It is known to exhibit inflammatory and antioxidant activity.

[0053] According to preferred embodiments, fluorouracil is present in the products of all embodiments of the present invention. At least 80% by weight, for example, at least 90% by weight, of the coated nanoparticles ( For example, phosphatidylcholine, hydrogenated phosphatidylcholine, and one of their derivatives. The nanoparticles coated as described above, wherein the nanoparticles associate with fluorouracil. , willow bark extract, and / or one or more of the following: It associates with nanoparticles (which can also associate with amino acids).

[0054] Molecular interaction between fluorouracil and phospholipid-coated silicon nanoparticles Advantageously, when silicon nanoparticles or their coatings are decomposed, fluorescein It is guaranteed that lorasil will be bioavailable. The rate of degradation by hydrolysis is mainly The resolution rate can be controlled, so the speed at which fluorouracil becomes bioavailable can be controlled. Furthermore, dose-dumping is avoided and / or nanoparticles do not reach the skin surface. The aim is to guarantee release only when it moves to a distant location (for example, the basal site). It can be controlled in this way.

[0055] Nanoparticles according to all aspects of the present invention (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine) Nanoparticles coated with one or more tidylcholine derivatives thereof, The nanoparticles associate with fluorouracil, willow bark extract, and / or arginine and Nanoparticles (which can associate with one or more amino acids, such as glycine) are porous. It is preferable to do so. For example, the porosity is such that the surface area of ​​a non-porous material of equivalent size is equal to the surface area of ​​a non-porous material of equivalent size. The surface area can be increased by at least 1.5, 2, 2.5, 3, 3.5, or 4 times.

[0056] Phospholipids Phospholipids for use in all aspects of the present invention (e.g., phosphatidylcholine) Hydrogenated phosphatidylcholine, phosphatidylethanolamine, lecithin components and One or more derivatives of, particularly phosphatidylcholine, hydrogenated phosphatidylcholine and its One or more of the derivatives are silicon-containing in aqueous solutions, such as phosphate-buffered saline (PBS). To arbitrarily change the hydrolysis rate of a substance, for example, to decrease it or set it to zero, and / or Once formed by suppressing the polymerization rate of OSA and generating an inert support, it looks like this. It is a compound that stabilizes OSA in solution. Therefore, phospholipids are, for example, aqueous solutions. In particular, silicon in commonly used buffer solutions such as Tris or phosphate-buffered saline. Hydrolysis of the contained substances promotes the formation of OSA, and / or the silicon-containing substance lasts for 24 hours After hydrolysis, it can act as an agent to suppress the polymerization rate of OSA in aqueous solution.

[0057] Generally, PBS consists of the following components: NaCl 137mM, KCl 2.7mM, and Contains 10 mM basic sodium phosphate, 2 mM potassium dihydrogen phosphate, and pH 7.4. PBS is used as a model of physiological conditions at a temperature of 37°C.

[0058] As described above, silicon is hydrolyzed to OSA in an aqueous medium, and then various chain lengths The molecular entities of the structure polymerize, ultimately forming a water-insoluble silicate. The product is optimized for the biodegradation process so that the polymerization of the formed OSA is substantially suppressed. The decomposition product is transformed. In this way, the decomposition product is stable and its properties, especially solubility and viscosity, It is controlled to maximize bioavailability. This is achieved by chemically modifying the surface of the nanoparticles. In other words, the surface is stabilized with a phospholipid stabilizer (for example, phosphatidylcholine, hydrogenated phosphatidylcholine). Coated with one or more tidylcholine and / or derivatives thereof, and optionally one or more A Coating by surface association with amino acids (e.g., one or more of arginine and glycine). This is achieved by doing so. Optionally, the nanoparticles are also associated with willow bark extract.

[0059] Without phospholipid coating, polymerization occurs at 9.6 mg / L or 0.48 mg / 50m 10, which corresponds to L -4 OSA at concentrations exceeding M progresses rapidly. In one embodiment, , phospholipid coating, 10 -4 Concentrations exceeding Mmg / L, for example, 0.5mg / L The OSA solution is stabilized at concentrations of 0 mL or higher, especially at concentrations of 0.80 mg / 50 mL or higher. It is possible. Advantageously, phospholipid coating is 0.90 mg / 50 mL or more, for example. For example, an OSA solution of 0.95 mg / 50 mL or higher, especially 1.0 mg / 50 mL or higher, is stable. It can be made to happen.

[0060] In one embodiment, the product of the first aspect of the present invention (optionally, willow bark extract, and / or containing one or more amino acids such as arginine and glycine) Also 5% by weight of phospholipids (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine, One or more of the components of phosphatidylethanolamine, lecithin, and their derivatives, in particular (containing one or more phosphatidylcholine, hydrogenated phosphatidylcholine, and its derivatives) For example, at least 20% by weight based on the total weight of the coated nanoparticles, typically It contains at least 30% by weight, and especially at least 50% by weight, of phospholipids. In one embodiment, Therefore, the molar ratio of phospholipids to silicon is at least 0.8:1, for example, at The molar ratio of phospholipids to silicon is 1:1, usually at least 1.5:1. It was found that having a 2:1 ratio was particularly advantageous.

[0061] In one embodiment, phospholipids (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine) Lecorine, phosphatidylethanolamine, lecithin components, and one of their derivatives. The above, in particular, concerns phosphatidylcholine, hydrogenated phosphatidylcholine and their derivatives. (One or more) have a number-average molecular weight in the range of 500 to 1000. Particularly suitable phospholipids are These are glycerophospholipids. Particularly suitable phospholipids have a phosphine-like functional group at the polar head. It binds to the quaternary ammonium portion of tidylcholine (PC) or hydrogenated phosphatidylcholine. It is a combination of these. The type of lipid can be selected depending on the properties of the preparation, and can be neutral lipids or negatively charged lipids. Lipids are suitable for aprotic formulations, while positively charged lipids with small CH3 chains are suitable for protic formulations. It is suitable for rotonating formulations. Preferably, the side chain is polyethylene glycol or polypropylene A pyrene glycol chain, or other aliphatic side chains with 15 or more carbon atoms, or ether units with 6 or fewer carbon atoms. This is the repeating etheric side chain.

[0062] In one embodiment, a phospholipid stabilizer (for example, phosphatidylcholine, hydrogenated phosphatidylcholine) is used. Phatidylcholine, phosphatidylethanolamine, lecithin components and their derivatives One or more of the body, especially phosphatidylcholine, hydrogenated phosphatidylcholine and their inducements One or more conductors are electrostatically bonded to the silicon surface by van der Waals forces. It is an adsorbed species. Preferably, the contact angle of the stabilizer is such that the stabilizer is on the surface of the silicon wafer. The contact angle of the droplet is observed and measured by optical tension measurement, and a value of less than 45° is preferable. The contact angle should be less than 20°, ideally less than 10°. As the contact angle decreases, the surface stabilizes. Interaction with the agent increases. Chemical characteristics obtained with good van der Waals attraction include It contains hydrogen-saturated molecules such as saturated lipids.

[0063] Phospholipids are amphiphilic, meaning their "head" is hydrophilic and their "tail" is lipophilic.

[0064] Phospholipids form a phospholipid bilayer with the modified head facing outward and the lipid tail facing inward. It can be formed naturally. Preferred embodiment (for example, nanoparticles of phosphatidylco When coated with phosphorus, hydrogenated phosphatidylcholine, and one or more derivatives thereof Such nanoparticles may optionally contain willow bark extract, and / or arginine and glycy According to the present invention, the nanoparticles (which can associate with one or more amino acids, such as one or more of the 'n') The phospholipid coating the surface is a phospholipid bilayer, for example, phosphatidyl It exists as a phospholipid bilayer containing choline or hydrogenated phosphatidylcholine.

[0065] Uses relating to all aspects of the present invention, in addition to or as a substitute for phosphatidylcholine. Other suitable phospholipids for this purpose include phosphatidylethanolamine and lecithin components. , phosphoinositides (e.g., phosphatidylinositol, phosphatidylinositol) Phosphatidylinositol triphosphate, phosphatidylinositol biphosphate, and phosphatidylinositol triphosphate (Ceramide phosphorylcholine), ceramide phosphorylethanolamine, and ceramide phosphorylethanolamine. This includes sphingophospholipids such as midphospholipids. For example, one of these phospholipids The above describes nanoparticles containing willow bark extract and / or one or more of arginine and glycine, etc. It can be used when associating with one or more amino acids. Phosphate lipids used in accordance with the present invention Naturally, the quality can be used as a mixture of phospholipids. For example, a mixture of phospholipids The compound contains nanoparticles of willow bark extract and / or one or more of arginine and glycine, etc. It can be used when associating with one or more amino acids. Phospholipids can also be used with phospholipids, relatively A mixture of small amounts of nonphospholipid components, such as cholesterol or other lipids or sterols. It can be used in the following applications, and the non-phospholipid component fine-tunes the properties of the phospholipid bilayer. It can be useful for this purpose and can be included in the coating. For example, phospholipids and relatively The mixture with a small amount of nonphospholipid components contains nanoparticles of willow bark extract and / or arginine It can be used when it associates with one or more amino acids, such as phospholipid and glycine. The quality coating contains at least 60% phospholipids, for example, at least 70% or 80% It is preferable to include phospholipids. In certain embodiments, the phospholipid coating is ( For example, the nanoparticles may contain willow bark extract and / or one or more of arginine and glycine. (When associated with one or more amino acids) at least 60%, 70%, or 80% phosphatidyl Contains zircholine or hydrogenated phosphatidylcholine. The coating is at least 80% It is preferable to include a bilayer composed of hydrogenated phosphatidylcholine.

[0066] The nanoparticles of the present invention are produced in a process that includes the use of a molten, waxy fatty acid ester. Since it can be used to produce particles according to the second aspect of the present invention, phospholipid coating (For example, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidyl ethanol One or more of the components of lecithin, amines, and their derivatives, especially phosphatidylcholine. , a phospholipid coating containing one or more hydrogenated phosphatidylcholine and its derivatives The product can withstand heating, for example, to temperatures of 30°C, 35°C, 40°C, 45°C, 50°C, or 55°C. It is preferable to be able to do so.

[0067] Phospholipid coating is a phospholipid bilayer (e.g., phosphatidylcholine, hydrogenated The components of phosphatidylcholine, phosphatidylethanolamine, lecithin and their One or more derivatives, particularly phosphatidylcholine, hydrogenated phosphatidylcholine, and the It is preferable that the phospholipid bilayer contains one or more derivatives of these. For example, phosphor The lipid coating is applied at 30°C, 35°C, 40°C, 45°C, 50°C, or 55°C for 20 minutes. At least 80% hydrogenated phosphatidylcholine remains virtually unchanged even when heated. It may be a phospholipid bilayer containing .

[0068] Nanoparticles containing hydrolyzable silicon The product of the present invention contains silicon nanoparticles. The silicon nanoparticles have a phospholipid surface. Coated and associated with fluorouracil. Optionally, silicon nanoparticles are used in willow Bark extract, and / or one or more amino acids, such as arginine and glycine. They meet. The nominal diameter of silicon nanoparticles is 10-400 nm, for example, 50-350 nm. For example, 80-310nm, for example, 100-250nm, for example, 120-240nm, example For example, 150-220 nm, or about 200 nm. Silicon nanoparticles are made from pure silicon. It consists of either or a hydrolyzable silicon-containing substance. Silicon nanoparticles are porous. It is preferable to do the following. The silicon nanoparticles are subjected to hydrofluoric acid (HF) / ethanol Porous materials can be created using standard techniques, such as contacting them with a mixture and passing an electric current through them. HF concentration By changing the temperature, current density, and exposure time, the density and size of the pores can be controlled. It can be controlled and monitored by scanning electron microscopy and / or nitrogen adsorption / desorption volume isotherm measurement. .

[0069] Fluorouracil Fluorouracil is a bilayer of silicon nanoparticles and / or phospholipids (e.g., phospho Phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylethanolamine, reci One or more components of tin and their derivatives, in particular phosphatidylcholine, hydrogenated phosphatidylcholine The surface of a phospholipid bilayer containing one or more tidylcholine and its derivatives is electrostatically It associates with the products of the present invention (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine). Coated with phosphorus and one or more of its derivatives, optionally with willow bark extract, and / or silicon associated with one or more amino acids, such as arginine and glycine. At least 90% of the fluorouracil in the particles is silicon nanoparticles and / or fluorouracil. It is preferable that it physically associates with or adsorbs to the surface of the lipid bilayer. That is, fluorine Less than 10% of the total lorasil is free.

[0070] Willow bark extract Products of the present invention (for example, phosphatidylcholine, hydrogenated phosphatidylcholine and so Coated with one or more of these derivatives, associated with fluorouracil, and optionally, argy Silicon nanoparticles associated with one or more amino acids, such as one or more of nin and glycine, It may contain willow bark extract. Willow bark extract is commercially available from several sources. It is possible. For example, willow bark extract is found in 9 Via Petrolo Litta, 20010 Active Co in Bareggio (Milano) Italy Available from ncepts, Srl. Willow bark extract typically contains salicin. The structure is shown below.

[0071] [ka]

[0072] Salicin is a β-glucoside and a derivative of salicylic acid. Salicin is usually, It is metabolized into salicylic acid in the human body. When salicin is metabolized, its acetal ether The cross-linking breaks down, producing glucose and salicylic acid. Next, it is produced by the oxidation of the alcohol group of salicylic alcohol.

[0073] Willow bark extract is preferably derived from the bark of American willow or European white willow. It can be extracted from the bark of the American willow. Willow bark extract is obtained from crushed willow The product of the present invention may be supplied as a powder, such as powder derived from the bark of the willow tree. Alternatively, The bark extract may be supplied to the product of the present invention in the form of an aqueous solution or an ethanol solution. The liquid willow bark extract is typically colorless to light yellowish-brown in color.

[0074] Willow bark extract is known to exhibit antioxidant and anti-inflammatory activity. Bark extracts are therefore suitable for use as active ingredients in anti-aging preparations. (Willow bark extract) The excrete is usually 8-12% by weight of salicin (or more preferably 8-12% by weight of salicin) It is often sold for its analgesic properties because it contains cylates. Commercially available willow bark extracts contain salicin, salicylate, or salicylic acid. Often, it is characterized by containing a certain percentage of the substance.

[0075] powder According to a second aspect, the present invention relates to solid particles of one or more waxy fatty acid esters. Then, the solid particles are subjected to pharmaceutically suitable nanoparticles according to the first aspect of the present invention (for example, HO Sphatidylcholine, hydrogenated phosphatidylcholine, and one or more derivatives thereof It contains willow bark extract and / or one or more of the following: A pharmaceutically acceptable powder containing solid particles encapsulated with nanoparticles capable of associating with amino acids. Then, fluorouracil, which makes up more than 65% by weight of the composition, interacts with the coated nanoparticles. The powder is provided. Less than 10% by weight of fluorouracil in the composition is waxy in the composition. It is preferable that it be present in the fatty acid ester portion.

[0076] Powder (for example, a powder containing solid particles of one or more waxy fatty acid esters, The solid particles contain phosphatidylcholine, hydrogenated phosphatidylcholine, and their derivatives. Silicon nanoparticles coated with one or more of the above are encapsulated, and the coated silicon The nanoparticles contain fluorouracil, optionally willow bark extract, and / or arginine. The powder (which associates with one or more amino acids such as glycine) has a maximum diameter of 30-550 microns. It is preferable that the material contains approximately spherical particles. For example, at least 90% of the particles are Large diameters are 50-500 microns (or 100-500 microns, or 150-400 microns) It can be made into a chloron. The solid particles of the powder of the present invention are significantly more than the nanoparticles of the present invention. Because they are large, each particle typically contains a large number of the nanoparticles of the present invention.

[0077] Waxy fatty acid esters (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine) A waxy substance containing silicon nanoparticles coated with one or more of the silicon and its derivatives. The fatty acid ester of the said coated nanoparticles is fluorouracil and In addition to willow bark extract, and / or one or more amino acids such as arginine and glycine. The melting point of the associated waxy fatty acid esters is 25°C to 45°C, for example, 28°C to 42°C. For example, a melting point of 30°C to 40°C is preferable. The melting point is such that it melts upon skin contact. It is preferable that it be such. In a specific embodiment (for example, a waxy fatty acid ester, One or more of phosphatidylcholine, hydrogenated phosphatidylcholine, and their derivatives When coated silicon nanoparticles are encapsulated, the coated silicon nanoparticles It contains fluorouracil, optionally willow bark extract, and / or arginine and glycine. According to the study (which associates with one or more amino acids, etc.), waxy fatty acid esters are stearyl Although it is an ester of fatty alcohol, it is also an ester of other fatty alcohols, especially saturated fatty acid alcohols. For example, caprylic acid, decanoic acid, lauric acid, myristic acid, palmitic acid and oleic acid. An ester of an acidic alcohol may be used. The fatty component of the ester is heptanoic acid or capsulphate. It is preferable that it be a lylic acid. Preferred embodiment (for example, a waxy fatty acid ester) , one or more of phosphatidylcholine, hydrogenated phosphatidylcholine and their derivatives When coated silicon nanoparticles are encapsulated, the coated silicon nanoparticles The ingredients include fluorouracil, optionally willow bark extract, and / or arginine and glycyrrhetinol. According to the study (which associates with one or more amino acids such as decane), waxy fatty acid esters are decane. Acid esters (i.e., cetyl decanoate) and / Alternatively, it is a mixture of stearylheptanoic acid and stearylcaprylate. The composition is further The composition may further contain 1-hexadecanol. In certain preferred embodiments, the composition is Contains a mixture of stearylheptanoic acid, stearylcaprylate, and 1-hexadecanol. The waxy fatty acid ester is preferably one that has skin-softening properties.

[0078] Phase transition control agent Examples: Limonene and Pluronic® Powder (for example, a powder containing solid particles of one or more waxy fatty acid esters, The solid particles contain phosphatidylcholine, hydrogenated phosphatidylcholine, and their derivatives. Silicon nanoparticles coated with one or more of the above are encapsulated, and the coated silicon The nanoparticles contain fluorouracil, and optionally willow bark extract, and / or arginine Powders that associate with one or more amino acids such as glycine may optionally contain limonene, etc. Terpenes and / or Pluronic® (Poly(ethylene glycol)-block) Alternatives such as poly(propylene glycol)-block-poly(ethylene glycol) It may contain surfactants.

[0079] Limonene plays at least two roles. Firstly, limonene is a waxy fatty acid. By adjusting the phase transition temperature of Tel, this invention is effective in controlling the final melting point of the solid particles of the powder. It helps to exert its effects. Limonene acts as a skin penetration enhancer and fluorouracil It can also accelerate the absorption rate. Examples include Pluronic (especially Pluronic L-61). The other surfactant is preferably added to limonene rather than being a complete substitute. It can also be used. Limonene, due to its emulsifying properties, is also effective in the product of the present invention. Duration and stability can also be improved. Using (R)-(+)-limonene (~90%) It is preferable to use other forms of limonene with low purity, such as essential citrus oil. It can also be used, but a higher concentration is needed to achieve the same effect.

[0080] Topical creams and gels According to a third aspect, the present invention relates to a pharmaceutical suitable for topical administration to the skin or other body surface. The present invention provides a cream or gel that is suitable for the present invention, and the cream or gel This refers to a pharmaceutically suitable powder (for example, one or more waxy fats) according to a second aspect of the present invention. The solid particles contain acid ester solid particles, and the solid particles contain phosphatidylcholine and hydrogenated phosphatidylcholine. Silicon nanoparticles coated with one or more tidylcholine derivatives are encapsulated. The coated silicon nanoparticles contain fluorouracil and, optionally, willow bark (Extracts, and / or powders that associate with one or more amino acids such as arginine and glycine) It contains a cream base in which the substance is suspended.

[0081] FDA and EMA guidelines on the maximum level of fluorouracil in topical formulations The standard specifies a maximum recommended level of 5% by weight. Therefore, according to a preferred embodiment... For topical creams or gels, the maximum amount is 5% by weight, 6% by weight, 4% by weight, and 3% by weight. Contains fluorouracil in weight percent, up to 2% by weight, up to 1% by weight, or up to 0.5% by weight.

[0082] Common doses for the treatment of basal cell carcinoma are 1%, 2%, and 5%. For the treatment of keratosis. The usual dose is 0.5%. The recommended treatment duration for doses of 5% or less is 3-6 Although it takes a week, treatment will take approximately 10 to 12 weeks for the lesions to disappear.

[0083] A pharmaceutically acceptable cream contains a cream base. The cream base is usually oil-in-water. It is a drop-type or water-in-oil emulsion. The cream base consists of an oil phase containing lipids and sterols. and a mixture of skin softeners and a large portion of the powder of the second embodiment of the present invention (for example, at least 5 It is preferable that the emulsion is a water-in-oil type emulsion containing 0%, 70%, or 80% of the water-in-oil mixture. The terpenes mentioned above can be found in virtually the aqueous phase. Fluorouracil is present in very small amounts. The amount (for example, less than 5% by weight or less than 2% by weight of the total fluorouracil) in a cream or It is present in the aqueous phase of the gel and is present in very small amounts (e.g., less than 5% by weight of the total fluorouracil or 2%). It is preferable that a concentration (less than 1% by weight) is present in the oil phase of the cream.

[0084] A pharmaceutically acceptable gel formulation comprises a powder according to a second embodiment of the present invention diffused into the liquid phase of an oil droplet. The gelling agent is preferably a crosslinked polymer such as polyethylene oxide or polyacrylamide. Alternatively, agarose, methylcellulose, hyaluronic acid, elastin-like polypeptide, carb Hydrogels (colloidal gels) containing polyacrylic acid, gelatin, or collagen. It is (ru).

[0085] A hydrophilic matrix (for example, a carbomer gel containing triethanolamine) It may be preferable to use a gel agent that has the following properties, for the reason being that such a gel agent, once, The waxy fatty acid ester encapsulation ruptures, and fluorouracil comes into contact with the gel matrix. This is because it allows for the rapid absorption of fluorouracil to be advantageous.

[0086] A pharmaceutically suitable cream or gel according to the third aspect of the present invention is 0.05 to 4% by weight 0.05-3% by weight, 0.05-2% by weight, or 0.05-1% by weight of fluorouracil. For example, it may contain 0.05 to 5% by weight of fluorouracil. A pharmaceutically acceptable cream. Alternatively, the gelling agent may contain 1-5% by weight, 2-5% by weight, 3-5% by weight, or 4-5% by weight of fluorocarbons. May contain uracil. Optionally, 5 to 15 grams of pharmaceutically suitable cream or gel. %, 6-14% by weight, 7-13% by weight, or 8-12% by weight of salicylates, etc., 0.5- It further contains 20% by weight of salicylate.

[0087] Adhesive patch According to a fourth aspect, the present invention relates to an adhesive patch comprising a backing layer and an adhesive film. The adhesive film is a pharmaceutically suitable powder according to the second aspect of the present invention (for example, It comprises solid particles of one or more waxy fatty acid esters, and the solid particles contain phosphatidyl Coated with one or more of the following: choline, hydrogenated phosphatidylcholine, and their derivatives Silicon nanoparticles are encapsulated, and the coated silicon nanoparticles are fluorouracil The ingredients include, optionally, willow bark extract, and / or one or more of the following: arginine and glycine. Powder that associates with amino acids) or cream or gel according to a third aspect of the present invention (the present invention) A cream containing a cream base for suspending a pharmaceutically suitable powder according to the second embodiment or The present invention provides an adhesive patch containing a gel.

[0088] The patch according to the present invention is typically a transdermal patch and may be made of textiles, polymers, or paper. A backing layer that protects the patch from the external environment, and optionally a film, for example, fluorocarbon It consists of a polymer film that prevents uracil from passing through the backing layer and an adhesive. Lacil is a powder according to the second aspect of the present invention or a cream according to the third aspect of the present invention. It is preferable that it exists as a gel agent. The fluorouracil-containing product is used in the adhesive layer or patch It can be supplied to the reservoir of the ch, or if fluorouracil is included in the gel agent, the gel agent It can act as a reservoir in patch products (so-called "monolithic" devices). The ruorouracil-containing product is preferably present in the adhesive layer.

[0089] The patch reduces the likelihood of end users using it carelessly or improperly. It may be useful in ensuring the correct dosage for the target area. Furthermore, the patch can be used to treat the area. This limits its scope, preventing unintended spread to other areas.

[0090] treatment Products of the present invention (for example, phosphatidylcholine, hydrogenated phosphatidylcholine and so Nanoparticles coated with one or more of these derivatives, wherein the nanoparticles are fluorine It associates with lauracil, and further with willow bark extract, and / or arginine and glycine. Nanoparticles capable of associating with one or more amino acids are used in superficial basal cell carcinoma, actinic keratosis, and sun exposure. Suitable for use in the treatment of diseases including keratosis and scarring. Suitable scars for treatment include: This includes Lloyd's scars, hypertrophic scars, and post-surgical scars. The products of the present invention also include acne. It can also be used to treat severe acne, in particular.

[0091] The appropriate dosages for basal cell carcinoma (in terms of the weight of the product) are 1%, 2%, and 5%. Even lower doses, for example, 0.25% to 1% or 0.1% to 0.5%, are used under other conditions. For example, it may be suitable for treating scars.

[0092] Combination therapy In addition to fluorouracil products, the present invention includes one or more other active ingredients. Furthermore, the method of the present invention may include the use of another active ingredient (API). Another API can conveniently be prescribed simultaneously with fluorouracil (for example, another API). I is one of phosphatidylcholine, hydrogenated phosphatidylcholine, and their derivatives. The nanoparticles coated above, in such embodiments, the nanoparticles are also y Nagi bark extract, and / or association with one or more amino acids such as arginine and glycine. (Can be formulated simultaneously with fluorouracil due to delivery via nanoparticles.) In particular, basal nanoparticles Other APIs suitable for treating styloid carcinoma include imiquimod, bismodegib, and curcumin. In particular, other APIs suitable for treating keratosis include imiquimod and ingenol mebutate. , diclofenac, retinoids (e.g., adapalene, tazarotene, retinol, isopropyl alcohol) It contains retinoin, acitretin, and tretinoin. In particular, it is used for the treatment of keloid scars. Other suitable APIs include salicylic acid, corticosteroids, and interferon. In particular, other APIs suitable for treating acne include azelaic acid, benzoyl peroxide, and saline. Chilic acid, antibiotics, retinoids, nicotinamide and antihistamines or alternatives It contains various natural extracts from its source, namely willow bark extract.

[0093] Treatment plan Products of the present invention (for example, phosphatidylcholine, hydrogenated phosphatidylcholine and so The nanoparticles are coated with one or more of these derivatives, and the nanoparticles are fluoro It associates with uracil, and further with willow bark extract, and / or one of arginine and glycine. Products (which can also associate with amino acids such as those mentioned above) and methods may be administered as appropriate by any administration method deemed suitable. It can be used according to the plan. For example, treatment may continue until the disease is cured or until thereafter. Treatment can be continued until further improvement is achieved. Standard administration process for keratosis treatment. This lasts for 3 to 20 weeks, for example, 3 to 12, 5 to 15, or 5 to 12 weeks. Similar plans are available for other programs. This can be used as a condition.

[0094] Silicon-containing substance As used herein, the term "hydrolyzable silicon-containing substance" refers to any silicon-containing substance that can be hydrolyzed to OSA in a timely manner upon administration to a human or animal subject substance. Usually, 1 mg of nanoparticles of the hydrolyzable silicon-containing substance hydrolyzes in 1 hour at 37 °C in 100 mL of a physiological buffer, such as for example, PBS. The silicon-containing substance of the present invention contains at least 50% by weight of silicon. For example, the silicon-containing substance of the present invention contains at least 70% by weight of silicon. The silicon-containing substance can be a substantially pure silicon substance, for example, containing at least 90% by weight of silicon, preferably at least 95% by weight of silicon substance, particularly a substance containing at least 99% by weight of silicon. The hydrolyzable silicon containing substance is usually a semiconductor material such as amorphous silicon. The silicon of semiconductor grade usually contains high purity, for example, at least 99.99% by weight of silicon . The substantially pure silicon substance can contain trace amounts of other elements, optionally[[ID=2l]] , such as boron, arsenic, phosphorus and / or gallium, etc., as a semiconductor dopant. The substantially pure silicon substance can be, for example, a P-type doped silicon wafer containing trace amounts of boron or another Group III element, or an N-type silicon wafer containing trace amounts of, for example, phosphorus or another Group V element . The surface of the silicon substance usually contains silanol (Si-OH) groups. Suitable hydrolyzable silicon-containing substances for use in the present invention include, but are not limited to, semiconductor grade nanosilicon (single crystal or polycrystal) and nanosilicon . Suitably, the products of the present invention (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine

[0095] ​​​​​Comprising nanoparticles coated with one or more of phosphorus and their derivatives, said nanoparticles , associate with fluorouracil, and further associate with the bark extract of willow, and / or one or more amino acids such as arginine and glycine), the silicon content of the product) is in the range of 0.01 to 5 0 wt%, preferably in the range of 0.01 to 10 wt%, more preferably in the range of 0.1 to 1 0 wt%, most preferably in the range of 0.1 to 5 wt%. In one embodiment , the silicon content of the composition is 1 to 30 wt%, for example 2 to 20 wt%, preferably in the range of 3 to 15 wt% based on the total weight of the composition.

[0096] Nanoparticles For the purposes of the present invention, the term "nanoparticle" usually means that the particle has at least one size in the nanometer range, i.e., 300 nm or less, and is used to describe having the same behavior and properties as nanoparticles. For use in accordance with the present invention nanoparticles (e.g., nanoparticles coated with one or more of phosphatidylcholine, hydrogenated phosphatidylcholine and their derivatives, said nanoparticles associate with fluorouracil, and associate with one or more of the bark extract of willow, and / or arginine and glycine such as one or more amino acids) usually have an average particle size of less than 300 nm, preferably less than 200 nm, especially less than 100 nm. In one embodiment, the average particle size of the nanoparticles is 10 to 100 nm, preferably 20 to 80 nm, especially 10 to 50 nm. Other embodiments, the average particle size of the nanoparticles is 50 to 200 nm, 60 to 250 nm or 80 to 240 nm. Preferred embodiments (e.g., silicon nanoparticles, phosphatidyl choline Coated with one or more of the following: glycine, hydrogenated phosphatidylcholine, and their derivatives. These nanoparticles then associate with fluorouracil, and optionally with willow bark extract, and (and / or associate with one or more amino acids, such as arginine and glycine) The average particle size of nanoparticles is 30-100 nm. The average particle size is the average of the largest particles. It is understood that particles are not necessarily spherical, and particle diameter is, conveniently, Measurements can be taken using conventional techniques, such as microscopy, including scanning electron microscopy.

[0097] In some embodiments, silicon particles for use in accordance with the present invention (for example, One or more of phosphatidylcholine, hydrogenated phosphatidylcholine, and their derivatives Coated silicon particles, wherein the silicon particles associate with fluorouracil , willow bark extract, and / or one or more amino acids such as arginine and glycine. The average particle size of silicon particles (which can also associate with ions) is less than 1000 μm, for example, 1 to 10 It can be 00 μm, 100-1000 μm, or 500-1000 μm. The average particle size is less than 500 μm, for example, 1-500 μm or 100-500 μm. This can be done. The average particle size of the silicon particles is less than 50 μm, for example, 1 to 50 μm. Alternatively, it can be 25-50 μm. The average particle size of silicon particles is less than 10 μm, for example. For example, the particle size can be 1-10 μm or 5-10 μm.

[0098] In some embodiments (for example, silicon nanoparticles, phosphatidylcholine, hydrogen When coated with one or more of the phosphatidylcholine derivatives, these The nanoparticles associate with fluorouracil and optionally also with one or more amino acids such as one or more of bark extract, and / or arginine and glycine), related to the present invention The nanoparticles are spherical or substantially spherical. It is convenient that the shape can be evaluated by conventional optical microscopy or electron microscopy techniques [[ID=……]] Preparation of silicon-containing nanoparticles The silicon-containing nanoparticles related to the present invention can preferably be prepared by techniques conventional in the art, for example, by grinding or other known techniques for reducing particle size. The silicon-containing nanoparticles consist of sodium silicate particles, colloidal silica or silicon wafer materials. Macro or microscale particles are milled by ball mills, planetary ball mills, plasma or laser ablation methods or other crushing mechanisms. The resulting particles are air classified to recover the nanoparticles. Plasma methods and laser ablation can also be used for nanoparticle generation.

[0100] Porous nanoparticles can be prepared by techniques conventional in the art, including the methods described herein.

[0101] Addition of phospholipids Prior to the addition of stabilizing phospholipids (e.g., phosphatidylcholine, hydrogenated phosphatidylcholine, [[ID=3……]] phosphatidylethanolamine, components of lecithin and one or more of their derivatives, especially phosphatidylcholine, hydrogenated phosphatidylcholine and one or more of their derivatives), it is preferred that the porous nanoparticles are "activated" to improve the adhesion of the phospholipids. Activation can be carried out by any suitable means. For example, porous na ​​​​​The particles are in a volatile solvent that allows evaporation (for example, ethanol, methanol, acetone or It can be washed with xylene. Instead, porous nanoparticles are miscible with water and are volatile. Wash with a solvent (e.g., alcohol such as ethanol), then wash with water, and freeze-dry. The drying step is performed to dry the area.

[0102] Next, phospholipids can be added to the activated nanoparticles. This allows the phospholipids to... Dissolve in a volatile solvent such as methanol and alcohol, and nanoparticles After mixing, the solvent is evaporated while stirring the particles (for example, using a rotary evaporation system). It is preferable that this be done by having someone perform the action.

[0103] Preparation of powder The powder consists of nanoparticles coated with phospholipids (e.g., phosphatidylcholine, hydrogen Phosphatidylcholine, phosphatidylethanolamine, lecithin components and their Nanoparticles coated with one or more derivatives of fatty acids are melted and turned into a waxy fatty acid mixture. Sterling or a mixture thereof (preferably at 30°C, 35°C, 37°C, 40°C, 45°C, 50°C) Alternatively, it is prepared by adding and mixing (at a temperature of 55°C or below). The waxy fatty acid ester is Next, any appropriate means, for example, coagulation and pulverization or emulsification and coagulation This process transforms the material into a powder. The addition of terpenes such as limonene can promote emulsification.

[0104] Terpenes can also accelerate the phase transition state of the entire formulation. Some lipids that can constitute fatty acid esters or mixtures thereof can be administered to the skin. It does not melt (i.e., 1-hexadecanol). Using terpenes is not recommended when applied to the skin. When applied, these particles melt due to body temperature or friction caused by rubbing the powder on the skin. It works to one's advantage.

[0105] Preparation of creams and gels Creams and gels are simply made by dispersing powder in a cream or gel base (i.e., mixing...) It can be compounded by combining the ingredients. For example, the powder can be added to the medicinal cream base. It can be stirred. Regarding the gel agent, the powder is added to the gel agent matrix in powder form and stirred. The mixture can then be mixed and the gel can be hydrated, or it can be added to a pre-hydrated gel and stirred.

[0106] Patch preparation The patch can be prepared by any suitable method, for example, by a mucosal adhesive aqueous gel. A patch containing the present invention can be produced by dispersing the powder therein. The gel is then slowly steamed with water to form a film with the desired adhesive properties. It can be dried by generating a vapor. [Examples]

[0107] The present invention can be further explained by the following non-limiting embodiments.

[0108] material Distilled water, cetyl decanoate, limonene, sodium bicarbonate Lilium, 5-fluorouracil (5FU), 1-hexadecanol, activated silico Nanoparticles (SiNP, 100nm), hydrogenated phosphatidylcholine (PHOSPHOL IPON (registered trademark) 90 G, a yellowish waxy substance - hydrogen sufficiently soluble only in EtOH. Phosphatidylcholine, distilled water, ethanol.

[0109] Silicon preparation P-type or N-type silicon wafers polished on one side are supplied by Si-Mat GmbH in the Federal Republic of Germany. Purchased. All washing and etching reagents are sterile-grade. Resistivity is 0.005 Vcm -1 A P++ type Si(100) wafer was used as the substrate. 200nm nitride crystalline film A layer of ion was deposited using a low-pressure chemical vapor deposition apparatus. Standard photolithography was used. Using this, a pattern was formed using the EVG620 contact aligner. The particles were found in a mixture of hydrofluoric acid (HF) and ethanol (3:7 v / v), and 8 0mA cm -2 The high porosity layer was formed by applying the current density for 25 seconds. In a mixture of 49% HF:ethanol in a ratio of 2:5 (v / v), 320mA cm -2 This was formed by applying the current density for 6 seconds. Even smaller holes were formed by HF( In a mixture of 49% ethanol (3:7 v / v), at 80 mA cm -2 Current density It can be formed by applying the solution for 25 seconds. In certain cases, the pores are HF (49%) and E In a mixture with tanol (1:1 v / v), 6 mA cm -2 The current density is 1.7 Formed by application for 5 minutes. The nitride layer was removed with HF, and then isopropyl alcohol was applied. Particles were released by applying ultrasound to a pyro-alcohol solution for one minute. The shape was roughly semi-semi They are spherical and measured by scanning electron microscope (SEM). The size of the pores is determined by the absorption and removal of nitrogen. The deposition volume can be measured by determining it using an isotherm. After etching, the sample is treated with pure ethanol. It was cleaned and dried under a stream of high-purity, dry nitrogen before use.

[0110] Etched silicon wafers, P+ or N- are processed using a ball mill and / or crusher and powder The material was crushed using a crusher. The fine powder was weighed using a Retsch brand 38 μm sieve. The samples were then sieved using a shaker AS200. Selected size (20-100μ) Uniformity in m) is achieved by the size of the sieve opening. The particle size is Quanta Measurements were taken using Chrome's equipment and Malvern Instruments' PCS. The results were determined. The sample was stored in a sealed container until its next use.

[0111] Nanosilicon powder was also obtained from Sigma and HefeI Kaier, a Chinese company. Particle size was measured using PCS and recorded before packing and etching (sizes ranged from 20 to 1). (It was in the range of 00nm). The silicon wafer was processed using a ball mill or a grinder and It was crushed using a crusher. The fine powder was weighed using a Retsch brand 38um sieve. Using a container and a shaker AS200, the material is sieved to obtain uniform nanoparticles of the desired size. I collected it.

[0112] Activation of silicon nanoparticles 250 mL of ethanol and 500 mg of porous silicon nanoparticles with a particle size of 30-100 nm. The two were mixed and stirred for 30 minutes. Next, the solution was placed in a centrifuge at 3000 rpm for 30 minutes. The supernatant was discarded, the nanoparticles were washed with 5 mL of distilled water, and transferred to a round-bottom flask. The contents of the Rasco were frozen (-25°C for 2 hours). The frozen nanoparticles were freeze-dried overnight. The material was freeze-dried using a dryer. The resulting dried powder was activated silicon nanoparticles. He is a child.

[0113] Instead, use 250 mL of methanol and 50 porous silicon nanoparticles with a particle size of 30 nm. Mix 0g with the other ingredients and stir for 120 minutes. Place the resulting paste in a special tray for dehydration. Transferred and allowed the organic solvent residue to completely evaporate (at room temperature for 24 hours). Once a thin layer of solid was formed... Once obtained, this layer was crushed and pulverized to obtain a powder. The resulting dried powder was then used These are oxidized silicon nanoparticles.

[0114] Stabilization of hydrogenated phosphatidylcholine by a bilayer membrane 150 mg of hydrogenated phosphatidylcholine was prepared in 30 ml of ethanol. The sample was dried (for at least 5 minutes) by connecting it to a rotary evaporator at 45°C.

[0115] Rehydration of liposomes and filling with fluorouracil Transfer 15 mg of stabilized nanoparticles to a beaker, and add 300 ml of fluorouracil to it. g was also added. 20 mL of distilled water was added to the mixture, and the contents of the beaker were subjected to ultrasonic treatment. It was homogenized at 30°C for 1 minute, and then subjected to vortexing.

[0116] Drying of particles stabilized by filling with fluorouracil. The solution obtained using the previously described method was cooled in a refrigerator (at 4°C for at least 2 hours) and then frozen. (-20°C for at least 4 hours). Freeze-dry the frozen solution overnight to obtain a powder, then proceed to the next step. Store in the refrigerator until use. Disperse these stabilized particles directly into the appropriate gel. Alternatively, the API can be further coated to optionally alter its release dynamics. The particles may optionally be further associated with willow bark extract (according to the present invention). (See below for a protocol in which the particles further associate with willow bark extract.)

[0117] Production of powder containing fluorouracil nanoparticles 1.00 g of 1-hexadecanol and 0.7 g of cetyl decanoate are mixed in a tall 250 mL container. Transferred to a beaker. Fluorouracil-filled particles (i.e., prepared as described above). The powder was added to the beaker. In a separate beaker, 120 mL of distilled water was boiled. Then, 1.0 g of sodium bicarbonate was added together with 2 mL of a phase transition control agent. 1-F A beaker containing cetyl decanoate and 5FU in xadecanol, whose contents are an oily liquid. It was heated until it melted into the body. The Polymix rotary mixer was used to cool the surrounding coating inside the body. The mixture was prepared with ice cubes and acetone. The oily liquid mixture was transferred to a beaker. It was placed in a 930rpm polymix mixer. Boiling sodium bicarbonate / phase transition The solution of the agent was added to the oily liquid. After 30 seconds, the mixer speed was set to 830 rpm and 1 It was cooled from the outside for 5 minutes. The resulting powder was extracted from the solution using a filter. It took 5-6 days to dry.

[0118] Patch manufacturing - Disperse 1.0g of hypromellose powder in 40mL of warmed distilled water, and place in a beaker. The mixture was placed in a warming chamber (T=40℃, magnetic stirring rpm=7) for 3 hours. -When the resulting suspension turns opal-colored, stop the magnetic stirring and remove it from the incubator. Remove the sample, let it cool to room temperature, then move it to the refrigerator and leave it overnight. - When the temperature reaches 4°C, add 0.25g of Pluronic acid. - Gently mix the resulting mixture and add purified water until it reaches 50 mL. -Store the sample in the refrigerator until use. This gel is a compound containing an appropriate amount of 5FU. Please note that it is necessary to dilute it with 50 ml of the powder set aside separately. Measure the required amount and gently disperse it in 15 mL of gel. Disperse the resulting mixture into a microsphere. Homogenize the mixture to ensure that A is evenly dispersed in the gel. -The final concentration of the gel is [Hypromellose 1.0% and Pluronic L-61 0.25%] ]

[0119] method - Weigh out 0.05g of EDTA and place it in a suitable beaker with 20ml of water (warmed to 60°C). Disperse in L. Stir until completely solubilized. - Weigh out 0.05g of PVP (polyvinylpyrrolidone) K90 and disperse it in the above solution. Stir until completely dissolved. - Weigh out 0.80g of Natrosol(registered trademark) (hydroxyethylcellulose), Disperse the mixture in the above solution and stir gently. - Weigh out 0.15g of trehalose and disperse it in the above solution. Mix gently until homogeneous. Stir. -When the product reaches room temperature, add 15 mL of distilled water and 0.5 mL of limonene, and stir slowly. Stir. - Treat the above solution with ultrasound for 2 hours. - Measure 5.0 g of the above viscous solution and put it into a beaker. - 0.4 g of the powder according to the present invention, prepared as described above by filling with fluorouracil, was obtained. Add to the viscous gel and stir gently. - Mix the powder with the resulting viscous solution and place it in a silicone slotted mold (4.5cm x 4.5cm) Transfer to cm) and then to a constant temperature bath (30°C, 15-35% RE) and leave for 20 hours. The resulting membrane is filled with the powder of the present invention and is ready for administration to the skin, with appropriate backing. It is a mucosal adhesive membrane that can be further layered.

[0120] Preparation of silicon nanoparticles that associate with willow bark extract 0.5% by weight of fluorouracil and 10% by weight of willow bark extract filled with nanoparticles An exemplary protocol for preparing nanoparticles containing the following is as follows:

[0121] [Table 1]

[0122] Preparation of hydrogenated phosphatidylcholine (PC) stock solution (Solution A) - Dissolve 624 mg of PC in 250 mL of ethanol and sonicate. The final concentration is 2.5 The concentration is mg / mL.

[0123] Preparation of a rehydration solution (Solution B) for PC-willow bark dry foam. - Add 16 mg of activated silicon nanoparticles (SiNP) (30 nm) to the beaker. - Add 4 mg of arginine to the beaker. Next, add 2 mg of glycine to the beaker. . - Fluorouracil 1500 mg, containing the same as SiNP, arginine and glycine. Add to the beaker. - Disperse this mixture in 200 mL of distilled water by stirring for 15 minutes.

[0124] Lipid-based thin film PC-willow bark extract using phosphatidylcholine and willow bark extract Formation of dry skin foam - Dissolve 624 mg of hydrogenated phosphatidylcholine in 250 mL of ethanol, then bathe in water. Next, sonicate the mixture inside at 45°C for at least 10 minutes. Then, pour the mixture into a round-bottomed flask. Move it to the co. - Add 30 mL of willow bark extract to a round-bottom flask. - Connect the round-bottom flask to the rotary evaporation system. - Maintain rotational evaporation at maximum speed for 45 minutes (at room temperature). - Reduce the temperature to -45°C. Dry the sample for at least 15 minutes. - The product appears as a thick, white foam.

[0125] PC - Rehydration of lipid-based dry foam of willow bark - Add 16 mg of activated silicon nanoparticles (SiNP, 30 nm in size) to the beaker. . - Add 4 mg of arginine to the beaker. Next, add 2 mg of glycine to the same beaker. Add. - Fluorouracil 1500 mg, containing the same as SiNP, arginine and glycine. Add to the beaker. - Disperse this mixture by sonication in 120 mL of distilled water at 30°C for 5 minutes. To make someone do it. - Vortex the solution to homogenize the ingredients. -A round-bottom flask containing a formulation of dry foam (PC and willow bark extract) contains a solution Add the mixture. Vortex until the foam is completely dissolved. - Wash the round-bottom flask with 10 ml of distilled water. - The resulting dissolved foam (total volume 130 ml) is sonicated at 30°C for 30 minutes. - Leave it in the refrigerator for 1 hour, then transfer it to the freezer (-25°C) and leave it for about 3 hours. - Connect the tube to the freeze-drying apparatus for at least 3 days to evaporate the solvent and dry the powder To obtain. The resulting powder can be stored for reconstitution with purified water and for mixing with a suitable solvent. The freeze-drying step can be optionally omitted, and the ultrasonically treated and dissolved foam can be directly It can be mixed with the desired solvent.

[0126] Preparation of a gel for dispersing the final product [Table 2] - Disperse 1.0g of hypromellose powder in a beaker containing 40mL of distilled water. Place the car in a warming chamber (40°C, magnetic stirring at 7 rpm) for 3 hours. -When the resulting suspension turns opal-colored, remove the gel from the incubator and stir. Stop the process and allow the sample to cool to room temperature. Transfer to a refrigerator (4°C) and leave overnight. -Once the gel has cooled to 4°C, add 0.25g of Pluronic L-61. L-61 is a masking agent that utilizes the cloud point within the temperature range of 20-24°C. - Gently mix the resulting mixture and add up to 50 mL of distilled water. -Store the sample in the refrigerator until use. This gel is a pure solution of silicon nanoparticle suspension. 50 ml of the solution is equivalent to 1.0% hypromellose and 0.25% Pluronic L-61. It needs to be diluted until it reaches the correct concentration.

[0127] Preparation of the final product - Disperse the powder in 150 mL of distilled water. The powder consists of 3 g of salicylic acid per 150 mL of distilled water. And, 16 mg of silicon nanoparticles, 24 mg of PC6, and 1500 mg of 5-fluorouracil. It contains willow bark extract with equivalent amounts of g, 4 mg of arginine, and 2 mg of glycine. . - Add 150g of gel to this dispersion system. - Vortex the mixture for 20 minutes to homogenize it. -Store the final product at 4°C.

[0128] Examples In the following examples, silicon nanoparticles are used as shown in the protocol above, and lipids are used. (PC), willow bark extract, arginine, glycine, fluorouracil, and It was prepared by associating it with a gel containing promellose and Pluronic L-61. This formulation was then prepared. It was dispersed in distilled water along with EDTA.

[0129] Cytotoxicity assay of silicon nanoparticles associated with fluorouracil and willow bark extract The assay was prepared to test the cytotoxicity of the formulation. The results are shown below, and further details are provided. This indicates that the cells are 100% dissolved. From this, it can be seen that the normal organisms of fluorouracil... It was confirmed that the scientific activity is retained when associated with the nanoparticles of the present invention.

[0130] [Table 3]

[0131] Preservative efficacy test (PET) The formulation is based on the current United States Pharmacopeia (USP). <51> Category II preservative efficacy test (ant imicrobial preservatives effectiveness est) and USP <61> The product was tested using a preservative efficacy test that conforms to the conformity test. The test included: The following pathogen growth tests are included for bacteria, yeasts, and fungi: Group 1 S. au reus ATCC 6583, Group II P. aeruginosa ATCC 9027, Group III A. brasiliensis ATCC 16404 Group IV C. albicans ATCC 10231, Group V E. coli ATCC 8739. The result was a pass of PET for the number of bacteria and yeast / mold. The results are shown.

[0132] [Table 4]

[0133] Skin sensitization test (GLP test) in guinea pigs A Magnusson-Kligman sensitization test was performed on guinea pigs, and the present invention The study determined whether nanoparticles associated with fluorouracil induce skin sensitization reactions. This included intradermal and local induction and induction phases. The study met the following criteria: American National Standards Institute / Medical Devices Development Association / International Organization for Standardization (ANSI / AAMI / ISO) 10 993-1 - Biological evaluation of medical devices - Part 2: Animal welfare conditions, and ANSI / AAMI / ISO 10993-10 - Biological evaluation of medical devices - Part 10: Irritation and sensitization Sex test.

[0134] The results will be obtained at any test site 24 or 48 hours after removal of the induction patch. It was demonstrated that there was no stimulation. Based on these results and evaluation system, The nanoparticles of the present invention, formulated with fluorouracil, are not considered contact sensitizing substances. do not have.

[0135] [Table 5]

[0136] [Table 6]

[0137] Clinical safety studies evaluating skin irritation / sensitization in humans (cumulative irritation and sensitization studies - RIPT) ) All human skin clinical trials are double-blind studies conducted on human patients (n=52). . Test safety regarding skin irritation / sensitization (Cumulative Irritation and Sensitization Test - RIPT) In human subjects, 0.2 ml of the test substance is directly dispersed over a designated area of ​​the subject's skin, and air is blown over it. It was designed to dry. This was applied to a series of nine consecutive patch areas, three days a week. This was repeated for three weeks. Next, when there were 10 to 14 days remaining, the substance was applied to the subject. Further administration was performed, and evaluations were conducted at 24 and 48 hours later.

[0138] The evaluation system is as follows: 0 - No effectiveness recognized 0.5 - (Barely perceptible) Tiny, uniform or patchy erythema (pale pink). 1 - (Mild) A uniform, pinkish erythema covering most of the contact area. 2 - (Moderate) Pink / red erythema uniformly present across the entire contact area. 3 - Bright red erythema with (noticeable) edematous petechiae or papules. 4 - (Severe) Dark red erythema with vesicular formation or vesicles, or without eczema.

[0139] In the skin irritation evaluation of the 24-hour patch test using occlusive patches, all 52 subjects were: The score was (0), and there were no adverse reactions of any kind during the course of the study, and no cases of erythema. The test substance formulated according to the present invention, when administered to the skin, is therefore a "non-primary irritant." It is considered "quality".

[0140] Regarding the cumulative irritation and sensitization test (RIPT) for skin irritation / sensitization evaluation, all 52 subjects were The scores at the evaluation points of 0 hours, 24 hours, and 48 hours were zero (0). No adverse reactions of any kind occurred during the course of the experiment. The test substance prepared according to the present invention was, however Therefore, it is considered both a "non-primary irritant" and a "non-primary sensitizer" for human skin.

[0141] The activity of silicon nanoparticles associated with fluorouracil and willow bark extract in vi tro transmission test The nanoparticles according to the present invention are used by varying the amount of fluorouracil and / or willow bark extract. The preparations were made by combining the compounds. Three such formulations were prepared (see Table 1). It contains 5% by weight of fluorouracil, stearyl alcohol, white petrolatum, and polysorbate. Bate 60, propylene glycol, methyl parahydroxybenzoate, and parahydroxybenzoate I used Efudex cream, which contains propyl propyl phosphate and purified water.

[0142] [Table 7]

[0143] In vitro permeability testing (IVPT) was used to determine the permeability of each sample into human skin. Hyperprofile analysis was performed over 24 hours. Table 2 below shows the receptor over time. The amount of fluorouracil detected in the liquid, i.e., the donor chamber and le This shows the amount of fluorouracil that passed through the skin membrane between the scepter chamber and the scepter chamber. Table 2 Odor BLQ is an abbreviation for limit of quantification.

[0144] [Table 8]

[0145] As shown in Table 2, fluorouracil suspended in conventional Efudex cream, It can easily pass through the skin membrane. However, fluorouraci associated with the nanoparticles of the present invention Because the substance is delivered to the skin under even stricter control, it does not pass through the skin in this way. When willow bark is used in association with the nanoparticles of the present invention, delivery to the skin is (Efud (compared to ex) it remains controlled, but the penetration rate into each layer of the skin is, Compared to the nanoparticles of this invention without Nagi bark, the reaction is slightly faster.

[0146] The transmission profiles of each sample were analyzed in each layer of skin after 24 hours. The results are shown in Table 3.

[0147] [Table 9]

[0148] As shown in Table 3, fluorouracil (5) suspended in conventional Efudex cream Fluorouracil (by weight) easily penetrates the skin film without being trapped in any layer of skin. When fluorouracil associates with the nanoparticles of the present invention (S1, 5% by weight of fluorouracil) The release of uracil and fluorouracil is better controlled, and even smaller amounts are released into the epidermis. Therefore, fluorouracil does not reach the receptor solution. Lowering the concentration of fluorouracil When fluorouracil was added (S3, 0.5 wt%), the release of fluorouracil was observed. No. However, when willow bark extract is associated with the nanoparticles of the present invention (S2, 0 (0.5 wt% fluorouracil), controlled release of fluorouracil into the skin layer In each of these, a small amount of fluorouracil flows into the receptor fluid.

[0149] In vitro Franz cell permeability test Conventional Efudex cream (5% by weight fluorouracil) also contains Invitr In the Franz cell permeability test, S2 (10% by weight of willow bark extract, 0.5% by weight of It was compared with fluorouracil. After 24 hours, tissue samples were collected and layers of skin tissue were separated. Then, fluorouracil was extracted, and the drug was biochemically quantified in the layers of skin tissue. The degree of localization of fluorouracil and the degree of drug penetration into skin tissue samples were determined. Tested. The tissue samples included specimens collected from the stratum corneum, epidermis, and dermis.

[0150] In the case of Efudex, fluorouracil is not present in the stratum corneum, epidermis, or dermis. Understood. 3.55% fluorouracil applied to Efudex cream penetrates the skin layer. It was found that it penetrated the entire surface. This means that, in the case of conventional Efudex cream, the stratum corneum In an uncontrolled manner, fluorouracil, which passes through the layer, rapidly passes through the remaining layers of skin. This suggests that...

[0151] In the case of S2, it was found that fluorouracil is not present in the stratum corneum or epidermis. However, 10.13% of the fluorouracil applied in S2 is present in the dermis. It was found that, on the other hand, only 0.73% penetrated the entire skin. This means that When fluorouracil associated with the nanoparticles of the present invention is applied, it is dispersed in the cream base. Conventional creams (such as Efudex) that simply contain suspended molecules of fluorouracil and This suggests that it can pass through the skin using a more superior control method compared to other methods.

Claims

1. A pharmaceutical composition for use in the treatment of superficial basal cell carcinoma, actinic keratosis, actinic keratosis, acne, or scarring, The pharmaceutical composition comprises pharmaceutically suitable nanoparticles and at least 0.5% by weight of fluorouracil. The nanoparticles contain at least 50% by weight of hydrolyzable silicon. The aforementioned nanoparticles are surface-coated with phospholipids, and the coated nanoparticles are associated with fluorouracil. The fluorouracil is electrostatically associated with the surface of the nanoparticles and / or phospholipid bilayer, The aforementioned nanoparticles are associated with willow bark extract in a pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the phospholipid comprises one or more of phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylethanolamine, lecithin components, phosphoinositides, sphingophospholipids, and derivatives thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically suitable nanoparticles are porous.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the phospholipid coating comprises a phosphatidylcholine bilayer.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the nanoparticles are associated with one or more amino acids.

6. The pharmaceutical composition according to claim 5, wherein the one or more amino acids are selected from arginine and glycine.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the aforementioned scar is selected from one or more of keloid scars, hypertrophic scars, and postoperative scars.

8. The pharmaceutical composition according to claim 7, wherein the scar is a hypertrophic scar.

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