WO2013137694A1 - Matière solide pour matériau insoluble dans l'eau enrobé de tensioactif amorphe contenant un acide gras ayant une chaîne alkyle droite - Google Patents

Matière solide pour matériau insoluble dans l'eau enrobé de tensioactif amorphe contenant un acide gras ayant une chaîne alkyle droite Download PDF

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WO2013137694A1
WO2013137694A1 PCT/KR2013/002136 KR2013002136W WO2013137694A1 WO 2013137694 A1 WO2013137694 A1 WO 2013137694A1 KR 2013002136 W KR2013002136 W KR 2013002136W WO 2013137694 A1 WO2013137694 A1 WO 2013137694A1
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surfactant
poorly soluble
barrier
anhydrous
water
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PCT/KR2013/002136
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English (en)
Korean (ko)
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유우영
김학철
권돈선
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한국콜마 주식회사
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Priority claimed from KR1020120027175A external-priority patent/KR101280005B1/ko
Priority claimed from KR1020120027176A external-priority patent/KR101309033B1/ko
Application filed by 한국콜마 주식회사 filed Critical 한국콜마 주식회사
Priority claimed from KR1020130028081A external-priority patent/KR20130105538A/ko
Publication of WO2013137694A1 publication Critical patent/WO2013137694A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention has a variety of uses due to its efficacy when dissolved in water, but a new method and a method for greatly improving the solubility of so-called poorly soluble substances that could not be properly used due to the poorly soluble in water or other solvents, especially water
  • the main content is the new type of objects that appear.
  • the poorly soluble material described herein are first limited to organic compounds in poorly soluble materials. Therefore, any inorganic compound can be considered as a poorly soluble material, which is not a poorly soluble material in the present invention.
  • it refers to a substance that is difficult to dissolve in water as an organic compound, and it is not important how much it is difficult to dissolve in water. This is because the material which is almost insoluble does not have any problem in substituting the technical idea of the present invention.
  • the melting means commonly used in the art means that it is generally dissolved except melting in the emulsified state. This is different from the meaning of "melting" in the following description of the present specification up to being emulsified.
  • Formulations containing poorly soluble drugs were found to be less than 85% average elution for 6 hours of the reference when testing for dissolution under conditions of 50 rpm and pH of 1.2, 4.0, 6.8, and water. Refers to an agent. "
  • the problem to be solved in the present invention is to find a new method to dissolve a poorly soluble substance having various effects as much as possible to greatly improve the effect.
  • the present invention is based on a completely new concept that completely reverses the conventional concept that a poorly soluble material can be used only by dissolving it or that the dissolved form is clear.
  • the present invention is not a concept of dissolution, but if it is possible to delay the recrystallization sufficiently even by emulsifying by changing the general perception, would it be possible to improve the utilization of poorly soluble substances in the human body even by a method other than dissolution or liposome form? I started with what I thought.
  • Another breakthrough inventive element of the present invention is the introduction of the concept of "dissolving insoluble form in water at the time of use by making a solid or solid powder containing the poorly soluble substances".
  • the first feature is that the type of surfactant used must be a surfactant having two or more legs.
  • the term bridge refers to an alkyl chain attached to the hydrophilic portion of the surfactant, which means that at least two such chains must exist. This is an important technical element necessary to achieve this in that the liposomes of the prior art require that the material of the invention is not as formal as possible.
  • the second feature is that the size of the poorly soluble substance attached to the surfactant is preferably in the range of 1 ⁇ 10 ⁇ m, even if you think a little more magnification can be thought of up to 30 ⁇ m, at least 0.5 ⁇ m. Compared to the liposomes of 45-200 nm size, the size of the soluble substance is greatly increased, which greatly increases the amount of soluble substance insoluble and greatly improves its utilization. Analyzing that it could be the cause.
  • the third characteristic is that the homogeneity of the size of the poorly soluble substance to which the surfactant is attached is very high.
  • the average range of products produced is almost ⁇ 30% of the total diameter, and in no case shall the average range exceed ⁇ 200% of the diameter. This is regarded as an important factor for delaying recrystallization, and the higher homogeneity, the greater the effect of delaying recrystallization.
  • the fourth feature is that the material according to the present invention requires that the prior art is not as formal as possible, unlike liposomes. This also contributes significantly to the rate of recrystallization. The higher the degree of amorphousness, the slower the rate of recrystallization. In this case, of course, there may be no complete amorphousness.
  • the material of the present invention may not be referred to as completely amorphous, but the term "amorphous" is used when describing the material of the present invention within the specification in that it is directed to amorphous. Therefore, the meaning of "amorphous" in this specification should be interpreted as such.
  • the point of amorphousness is closely related to the type and amount of the surfactant used and the method of mixing the surfactant and the poorly soluble material.
  • the fifth feature is that the form dissolved in water is aimed at emulsion type.
  • the material which greatly retarded recrystallization by having five characteristics simultaneously was created for the first time.
  • the material of the present invention having the above five characteristics is to be referred to as "absorption interface material (abbreviation of poorly water-soluble substance in which the outside of the water-soluble amorphous phase of the emulsion type is covered with a surfactant). do.
  • the term “bleached material” in the present invention means that the material has the above five concepts.
  • a liquid-free barrier material which is a final use form, is made of a "solid material such as a solid powder which becomes a barrier-free material when it is put in water” and then dissolved in water. Therefore, in the present invention, it can be seen that the development of another new material, "solid material such as a solid powder that becomes a barrier-free material when put into water.” The name of this material is referred to as “anhydrous-free barrier material" in the present invention. It was.
  • the first poorly soluble material and the organic solvent having polarity to the surfactant are added to the fluidized state by adding a mixing aid.
  • the anhydrous barrier-free material generally contains an organic solvent having a polarity such as -OH.
  • the adjuvant adjuvant is usually dissolved in water and mostly dissolved in water to maintain a state that is not attached to most of the barrier-free material.
  • the mixed adjuvant may be an essential component for anhydrous barrier-free materials, but it is difficult to see them in the barrier-free materials.
  • fatty acids with a straight chain are stearic acid, palmitic acid, myristic acid and lauryl acid.
  • the fatty acids used are required to be free of double bonds. This is because, if a double bond is present, there is a high possibility of denaturation such as rancidity due to the reaction.
  • fatty acids which are economical as long as there is no problem in the efficacy of the barrier-free material because the marketing is usually much cheaper than the surfactant. In fact, most fatty acids are generally cheaper than surfactants.
  • the barrier-free material differs from the general dissolution concept.
  • the recrystallization is extremely delayed in the macroscopic aspect (the concept of "melting” used hereafter, unless otherwise described separately) The above concept is included in the above description.
  • the material insoluble insoluble material is made into a solid or a solid powder and dissolved in water at the time of use as an emulsion.
  • Fig. 4 Conceptually depicts the emulsified form of one barrier-free material in water
  • Example 6 is a schematic view of the manufacturing process of Example B
  • Figure 7 a DSC graph of the natural ceramide 3 (comparative) and the ceramide-containing composition of Example 19 of the present invention
  • the temperature at which the phase transition from the crystal form of ceramide to the liquid phase at room temperature is 97.70 °C
  • the temperature at which the phase transition to the liquid phase is 52.08 ° C. shows a significant difference in the phase transition temperature.
  • Figure 9 is a photograph of pure ceramide under a microscope
  • H30S is a ceramide
  • a hydrogen-free lecithin mixture of the concept specified in the present invention to prepare anhydrous barrier-free material in the manner described in the present invention and observed it under a microscope 1000 and 7000 means magnification seen with microscope
  • 10a is a photograph showing the dispersion degree of the ceramide-containing composition prepared by the method
  • 10b is a photograph showing the dispersion degree of the ceramide-containing composition prepared by the method
  • barrier-free materials are based on numerous trials and errors and long periods of research. This can be said to significantly increase the utility value of the poorly soluble material significantly different from the prior art by dramatically increasing the amount of the poorly soluble material dissolved in water. This is a concept that has never existed before.
  • the invention was achieved by specially limiting the type of surfactant, proceeding with a specific manufacturing method in an optimized form, and adjusting the compounding ratio of the surfactant and the poorly soluble material to an appropriate level. In the homogeneity diagram of the structure and size, the new material was created.
  • FIG. 1 Conceptually drawing the material of the present invention is shown in FIG.
  • This new material refers to a state in which water is emulsified in a special method of the present invention, and it is required to have five aspects simultaneously.
  • the first feature is that the type of surfactant used must be a surfactant having two or more legs.
  • the term bridge refers to an alkyl chain attached to the hydrophilic portion of the surfactant, which means that at least two such chains must exist. This is an important technical element in that unlike the liposomes of the prior art, the material of the present invention requires that it is not as formal as possible.
  • the portion attached to the poorly soluble material is an alkyl body, and thus the attached form is relatively simple. Naturally, therefore, it is easy to form a formalized form.
  • the number of the poorly soluble substances and the manner in which the alkyl chains are attached may be relatively diverse, and in particular, various functional groups in the alkyl chain may be attached in the alkyl chain and also bonds between carbons. The angles can also vary, which makes it possible to combine poorly soluble materials in many different forms.
  • the two chains are different from each other in terms of bending angle and various aspects.
  • any surfactant having an alkyl chain having 10 or more carbon atoms can be used.
  • Hydrogenated lecithin is not only suitable for the number of alkyl chains, but also has a considerable difference in the length and shape of the two alkyl chains. Therefore, it can be regarded as one of the suitable materials in terms of difficulty in attaching to a poorly soluble substance in a standard form.
  • Phosphatidylcholine The lecithin used to make a non-surfactant has the same effect as both yolk lecithin and soybean lecithin.
  • Phosphatidylethanolamine (phosphatidylethanolamine) is an emulsifier in which ethanolamine is bonded to phospholipid instead of choline, and it is possible to make a mask-free surfactant.
  • Phosphatidylserine Surfactants of the Cephalin family which also have the structural properties of serine in the choline position, have very similar chemical properties to Lecithin, and make it possible to produce maskless interface materials.
  • Phosphatidyl inositol (Phosphotidyl inositol) It is possible to make a mask-free surface-active substance by inositol ester-bonded to the phosphate group of phosphatidic acid.
  • PEG30 Dipolyhydroxystearate (PEG-30 Dipolyhydroxystearate) It is possible to make a maskless surface-active substance as a nonionic surfactant having two alkyl chains attached to 30 moles of polyethylene glycol which is a hydrophilic group.
  • a maskless surface-active substance as a nonionic surfactant having two chains of alkyl chains in a polyglyceryl chain which is a hydrophilic group of polyglyceryl-2 dipolyhydroxystearate.
  • Polyglyceryl-2 diisostearate (Polyglyceryl-2 diisostearate) It is possible to make a maskless surface-active substance as a nonionic surfactant having two alkyl chains attached to a polyglyceryl chain which is a hydrophilic group.
  • PEG-150 Pentaerythrityl Tetrastearate A non-ionic surfactant with a four-chain alkyl chain attached to the PEG-150 mole chain, which is a hydrophilic group, can make a maskless surfactant.
  • Polyglyceryl-2 triisostearate (Polyglyceryl-2 triisostearate) It is possible to make a maskless surface-active substance as a nonionic surfactant having three chain alkyl chains in a polyglyceryl chain which is a hydrophilic group.
  • the second feature relates to the size of the poorly soluble material to which the surfactant is attached and the size of the barrier-free material.
  • the size is in the range of 1 to 10 ⁇ m on the basis of diameter, and even if it is considered to be larger, a maximum of 30 ⁇ m on the basis of diameter and 0.5 ⁇ m may be considered.
  • the size is tens of times to hundreds of times, and the size of the insoluble material mass contained therein is significantly increased, which is a cause for drastically improving the utilization of insoluble materials. It seems to have been possible.
  • the size of the barrier-free material is of great importance in terms of its ability to dissolve poorly soluble materials. This is because the hydrophobic group of the surfactant is an important factor in determining the amount of poorly soluble substances that can be contained. In the case of liposomes, it is unknown whether the poorly soluble substances are completely dissolved in the vicinity of the hydrophobic group, but since the size of the barrier-free substance is much larger than that of the liposomes, at least the poorly soluble substance inside the individual barrier-free substance is constant. The part may be crystallized internally, but the outside is wrapped in a surfactant, which is emulsified, so it is dissolved in water and its size is so small (very large compared to liposomes) that it is completely dissolved. Even if it is not, it can be said that the invention proceeded from the recognition that there is no harm to the human body (if used in animals) as long as the emulsion state is maintained.
  • the size should be as large as possible to increase the efficiency of use of poorly soluble materials.
  • a barrier-free material having a significant value with a small particle diameter variation and an average particle size of 0.5 ⁇ m or more was produced.
  • the average particle diameter is about 5 ⁇ m.
  • the stability may be a problem, so the maximum value that it is not easy to maintain as a barrier-free material was found through various experiments and worries.
  • the third characteristic is that the homogeneity of the size of the poorly soluble substance to which the surfactant is attached, that is, the barrier-free substance, is very high and the advantage is important.
  • the average range of products tested is almost within ⁇ 30% of the diameter, and in no case shall the average range exceed ⁇ 200% by the diameter. Securing proper homogeneity is considered to be an important factor in delaying recrystallization. The higher the homogeneity, the greater the effect of delaying recrystallization.
  • One of the most surprising aspects of the present invention is the homogeneity of the barrier-free material. Numerous experiments have shown that the tendency of recrystallization of barrier-free materials is significantly slowed down with higher homogeneity. Thus, too many repeated experiments and various attempts have been put into finding ways to increase homogeneity. Of course, increasing the average particle size appropriately and increasing the melting amount of the poorly soluble material required a lot of foresight and inspiration. So what we found is an inline mixer that contains a mixed blade structure with the concept of reparation mixing.
  • Zeta potential is a high density of positive ions attached to the surface of negatively-charged particles, forming a stern layer.
  • the anion and cations are balanced through the diffusion layer. It is defined as the potential difference between the starting point of the diffuse layer and the balance of anions and cations.
  • the double layer repulsion between particles in solution increases exponentially as the distance between particles increases, and the van der Waals attraction increases by the power of the distance. Therefore, as the distance between particles gets closer, the double layer repulsion becomes stronger than the attraction, but when the distance between particles becomes closer than the size of the double layer, the van der Waals attraction becomes dominant.
  • the maximum repulsive force appears when the distance between particles is 1 ⁇ 4nm.
  • the energy size at this time is called Energy Barrier, and the larger the Barrier, the more stable the particle.
  • colloids Finely divided particles dispersed or suspended in a liquid system are called colloids. These colloids have an electrical charge when present in the medium in aqueous solution. Most of these charges result from selective ion adsorption from aqueous solutions.
  • This Zeta-Potential provides a convenient concept for understanding surface behavior and surface interactions in liquid phases.
  • the particles dispersed in the solution are electrically charged to the cathode or the anode by dissociation of the surface polar groups on the particle surface and adsorption of ions.
  • the fourth feature is that the material according to the present invention requires that the prior art is not as formal as possible, unlike liposomes. This also contributes significantly to the rate of recrystallization. The higher the degree of amorphousness, the slower the rate of recrystallization. Of course, there may be no perfect amorphous form in the world. In this regard, the material of the present invention may not be referred to as completely amorphous, but the term "amorphous" is used when describing the material of the present invention within the specification in that it is directed to amorphous. In particular, the amorphous orientation is closely related to the type and amount of the surfactant used and the method of mixing the surfactant and the poorly soluble material.
  • the barrier-free material can be said to be a kind of emulsified type in that it uses a surfactant as a medium to dissolve when dissolved in water.
  • the material dissolved in the amorphous emulsifying type of the present invention is referred to as a barrier-free material. .
  • fatty acids with a straight chain are stearic acid, palmitic acid, myristic acid and lauryl acid.
  • the fatty acids used are required to be free of double bonds. This is because, if a double bond is present, there is a high possibility of denaturation such as rancidity due to the reaction.
  • fatty acids which are economical as long as there is no problem in the efficacy of the barrier-free material because the marketing is usually much cheaper than the surfactant. In fact, most fatty acids are generally cheaper than surfactants.
  • the anhydrous barrier-free material When the anhydrous barrier-free material is made of the surfactant and the poorly water-soluble material, the solidification may be easy, but it may be difficult to solidify too much. In this case, a multi-faceted approach can solve this problem, but there are many problems in terms of cost and process. In this case, when preparing the anhydrous barrier-free material by inserting the fatty acid from the beginning, it is possible to easily secure the appropriate hardness and thus can be easily made into a powder.
  • mixed adjuvant having polarity such as -OH. Because mixed adjuvant is mostly dissolved in water when forming the barrier-free material, it is rarely present in the barrier-free material. However, fatty acids are different in that most of them are combined with the barrier-free material and serve as one of the components of the barrier-free material.
  • the fatty acids are irregularly entangled with the alkyl chain of the surfactant attached to the poorly soluble substance, thereby preventing the surfactant from being formalized, thereby significantly lowering the probability of encountering the poorly soluble substances.
  • the fatty acid plays a synergistic role in reducing the probability of recrystallization pursued by the barrier-free material.
  • the amount of usage tends to be higher than that of poorly soluble substances, which is generally about 2 to 10 times higher than the poorly soluble substances.
  • fatty acids may need to be used as excipients.
  • the barrier-free substance can be dissolved by using 1/10 to 1/30 of the amount of surfactant required per unit of poorly soluble substance compared with the conventional liposome form.
  • the surfactant is preferably used as compared to the 1% of the poorly soluble material. Even when only 0.2 ⁇ 1.0% is used, it is easily soluble in water and does not exceed twice the level even when it is used a lot. Therefore, the amount of surfactant required per unit of poorly soluble substance is 1/10 ⁇ when compared to the conventional liposome form. Dissolution was possible using 1/30.
  • Another breakthrough effect of the present invention is that unlike liposomes that produce a product in the form of water from the beginning, it is produced as a product containing a solid barrier-free material such as powder and emulsified in the water when using it. It is easy to use because it can be used by melting.
  • the resultant object is usually in the form of a solid powder, and the final use form is used by dissolving in a solvent such as water.
  • a solvent such as water.
  • the "obsolete interface material” refers to a substance dissolved in a solvent.
  • anhydrous-free interface material it is necessary to name the solid material in a state that becomes a barrier-free material by adding a solvent such as water, and in the present invention, this is referred to as "anhydrous-free interface material".
  • this may be a powder and may include a powder that is not.
  • Liposomes are prepared in liquid form dissolved in a solvent and are used as is or diluted. Therefore, it is considered for the first time that a product which improves the ease of use of a poorly soluble substance in the form of a powder.
  • the size of one poorly soluble substance with surfactant is 0.5 to 30 ⁇ m, which is about 100 times higher than that of the liposome form.
  • the average particle size is mostly 45 to 200 nm, and in the case of the barrier-free material according to the present invention, the average particle size is 0.5 to 30 ⁇ m.
  • the skin-absorbing agent due to the nano-size is also referred to the harmful effects on the body, so that the barrier-free material is advantageous over the liposome state.
  • the liposome is so stable that even if there is a difference in zeta potential due to the difference in size, there is little possibility of recrystallization. Therefore, if the liposome is kept in a solution that can be applied to the machine before it is added to the micro pull freezer, As a general rule, a homomixer is used.
  • the ratio of the poorly soluble substance and the surfactant is important in order to make the anhydrous barrier-free material. It is generally desirable to use less surfactant than the amount of poorly soluble substances on a weight ratio basis. In addition, the use of too little is also problematic, so it is preferable to use 20 to 100% by weight of the surfactant relative to the amount of poorly soluble material. However, in some cases, 10% by weight or 200% by weight may be used.
  • fatty acids are smaller in size than surfactants, and are entangled with lipophilic portions of the surfactants, thereby adheringly improving the adhesion of the surfactants to the poorly soluble substances.
  • a mixer including an inline mixer including a mixing blade structure having the concept of reparation mixing should be used.
  • the mixed blade structure seems to be essential to make the material pursued by the present invention most efficiently up to now, and many cases of not using it have been tested, but even if the initial emulsification form is maintained, ultimately the armorless we pursue I was not able to make the interface material.
  • Reparation mixing means "10 n or less at regular intervals as shown in Figure 5 to cut and finely homogenize 2 n , 3 n , 4 n , 5 n, etc. or mixtures thereof while changing the direction of the passing liquid.
  • the blades preferably four or less blades, change their direction repeatedly, passing through the pipeline part arranged inside in a fixed manner, so that the solution is conceptually cut every time it passes through each blade unit.
  • a blade that repeatedly changes direction is referred to as a “unit blade.”
  • the mixed blade structure can be regarded as a combination of unit blades.
  • a mixer capable of such compensation mixing is defined as a "compensation mixing mixer.”
  • the liquid mixing mixer only needs to include a structure capable of performing the liquid phase mixing in any part of the mixer, and it is not necessary for all pipelines to have a liquid phase mixing structure.
  • reparation mixing is essential, and any other mixing method may be used in parallel if necessary.
  • the reparation mixing mixer used may be different, but the five conditions to be prepared for the above-mentioned barrier-free material are described, and the size and homogeneity of the particles are also described. Repeat as many times as necessary until the reparation mixture.
  • microhomogenization time within a maximum of 1 hour. Because all the materials introduced are organic substances that can be denatured, it is necessary to properly design the mixing mixture mixer and to adjust the time appropriately within at least 1 hour, particularly preferably within 30 minutes.
  • the temperature must be increased to make the liquid work.
  • the temperature is appropriately adjusted according to the type of material introduced, such as the melting point of the poorly soluble material.
  • the material passing through the liquid phase mixing mixer may be a liquid phase.
  • water can be added to the liquid material to form a barrier-free material.
  • Example 1 Using the composition of Example 1 below to evaluate the homogeneity and dispersibility of the ceramide-containing composition prepared by the method of a that does not include the reparation mixing process and the method of b including the reparation mixing process.
  • Method a Ceramide 3, hydrated lecithin PC (phosphatidyl coline), dipropylene glycol, glyceryl stearate, stearic acid was purchased and used.
  • Example 4 Hydrated lecithin, dipropylene glycol, glyceryl stearate, and stearic acid except for ceramide 3 using a vacuum emulsification tank in a content of the composition of Example 4 was first stirred at 3000 rpm using a general mixer at 75 ° C. for 10 minutes to be completely After dissolving, the ceramide was added to the mixture, followed by homogeneous stirring at 3000 rpm for 10 minutes to complete the process. The following photograph a shows the dispersion degree of the ceramide-containing composition prepared in this way.
  • Test 1 Ceramide Solubility Assessment (Method a and b)
  • Example 1 Using the composition of Example 1, the ceramide solubility of the ceramide-containing compositions prepared by the method of a, b and b was evaluated, respectively.
  • Example 1 In addition to the content of the composition of Example 1 below, when the resultant was stirred with Agitator alone, the result was difficult to disperse in the aqueous phase, and the dispersion degree thereof could not be measured.
  • This embodiment first checks whether the barrier-free material can be composed of only a poorly soluble material and a surfactant, and secondly, a surfactant having a poorly soluble material and two or more alkyl chains, which can be said to be the most essential element in the present invention, and This was done to test the correlation of the adjuvant.
  • the mixing adjuvant is generally a poorly soluble material and the surfactant is often a solid, so that the liquid phase mixture must be in a solution state for this purpose is to put a liquid material to make a mixture of the appropriate viscosity.
  • These solutions evenly transfer heat to poorly soluble materials and surfactants when heated, thus solving the problem of burning if not mixed with these solutions.
  • Such a liquid substance is referred to as "mixing adjuvant" in the present invention.
  • one of the important purposes of this experiment is to define the role of the mixing aid.
  • the strict aspect of the present invention is that the most important thing is that the surfactant is adsorbed amorphously on the surface of the poorly soluble material and thus interferes with the periodicity of the poorly soluble material. To identify.
  • Example 1 (% by weight)
  • Example 2 (% by weight)
  • Example 3 (% by weight) Ceramide 3 40 40
  • Hydrated Lecithin (PC 75%) 20
  • Purified water 40 - - Dipropylene glycol - 40 - ethanol - - 40 10% aqueous solution moisture content 98.9% 93.7% 96.9%
  • Example 2 Example 3 was dispersed in purified water 10% in the table to check the water content using a Karl Fischer (water content meter). This was to confirm the possibility of further increasing the ease of use as a cosmetic raw material or pharmaceutical raw material through freeze drying and powdering of the finished final material.
  • the minimum essential component of the barrier-free material is sufficient only with the poorly soluble material and the aforementioned characteristic surfactant.
  • additional materials may be entered to complement a variety of options at the discretion of the skilled artisan, it can be seen that the fundamental inventive idea of the present invention is a "bodyless material" as will be mentioned above.
  • This embodiment summarizes the contents carried out with various poorly soluble materials and various surfactants.
  • ceramide 3 N-acetylphytosphingosine, ursolic acid and UDCA are poorly soluble substances.
  • PEG-150 Stearate has one alkyl chain as a surfactant.
  • hydrated lecithin and PEG-30 are two alkyl chains.
  • Dipropylene glycol and glyceryl stearate are mixed adjuvant and the like and stearic acid is fatty acid.
  • Example 8 is an example of using a surfactant having one strand of a hydrophilic group and a lipophilic group, in which case it failed to make a barrier-free material.
  • Examples 10 to 12 evaluated the acceptability of ceramide 3 according to the carbon number difference of the higher fatty acids. In Examples 10, 11 and 12, all succeeded. Among these, Example 12 showed the best result in terms of stability.
  • the ceramide content was fixed at 30% by weight, and the content of the surfactant and the solvent was adjusted to prepare the ceramide-containing compositions of Examples 13 to 16 with the compositions shown in [Table 2], and 10% by weight of each composition sample.
  • the degree of water solubility was evaluated using a 100 ml measuring cylinder. .
  • Example 16 Thickness (cm) 3.2 3.1 2.1 2.6
  • the ceramide-containing composition of the present invention was prepared as shown in Table 6, and the DSC graph was analyzed to measure the phase transition temperature.
  • natural ceramide 3 was used as a comparative example.
  • Example 17 (% by weight)
  • Example 18 (% by weight) Ceramide 3 40 30 Hydrated Lecithin (PC 75%)
  • PC 75%) 20
  • Dipropylene glycol 20
  • Glyceryl Stearate 10 Stearic acid 10
  • the first picture of Figure 9 is a SEM photograph of a representative poorly soluble material ceramide was taken at 7000 times, 1000 times magnification.
  • the blue letters are the ceramides themselves, and they appear to be in a very regular array, not disperse in water, and even if they are dissipated by physical force for a moment, recrystallization occurs.
  • looking at the H30S ⁇ 7000 of Figure 9, the result of Example 20 taken with an electron microscope when the shape is changed to an amorphous state, it becomes very easy to disperse, and there is no regular arrangement due to crystallization for a long time (more than 3 years at room temperature) It can be seen that the dispersed state is maintained.
  • Ursodoxycholic acid (UDCA)
  • Propylene glycol was selected and used as a solvent of UDCA.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of UDCA, solvent and unsaturated lecithin was 6.25: 88.75: 5 based on the weight percent.
  • propylene glycol PC content 95% formulation stability is as follows.
  • Propylene glycol was selected and used as a solvent of cyclosporin A.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of cyclosporin A to solvent and unsaturated lecithin was 0.05: 99.45: 5 based on the weight percent.
  • Propylene glycol was selected and used as a solvent of Dercusin.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of Dercusin to solvent and unsaturated lecithin was set to 16.875: 78.125: 5 by weight.
  • Propylene glycol was selected and used as a solvent of Latanoprost.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of Latanoprost to solvent and unsaturated lecithin was set to 0.005: 94.995: 5 by weight.
  • Propylene glycol was selected and used as a solvent for Travoprost.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of Travoprost to solvent and unsaturated lecithin was set to 0.004: 94.996: 5 by weight.
  • Diethylene glycol was selected and used as a solvent of docetaxel.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of docetaxel to solvent and unsaturated lecithin was set to 4.268: 90.732: 5 based on the weight%.
  • Propylene glycol was selected and used as a solvent for bimatoprost.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of bimatoprost to solvent and unsaturated lecithin was set to 0.003: 94.997: 5 by weight.
  • Diethylene glycol was selected and used as a solvent for Amphotericin B.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of amphotericin B to solvent and unsaturated lecithin was set to 14.062: 80.938: 5 based on the weight%.
  • Benzyl alcohol was selected and used as a solvent for Itraconazole.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of Itraconazole, solvent, and unsaturated lecithin was set to 25: 70: 5 by weight.
  • Diethylene glycol was selected and used as a solvent of isoflavone.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of isoflavone to solvent and unsaturated lecithin was set to 16.875: 78.125: 5 by weight.
  • Ethoxy diglycol was selected and used as a solvent of Meloxicam.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • Meloxicam, the solvent and the unsaturated lecithin were set to 3.75: 91.25: 5 by weight.
  • Isostearic acid was selected and used as a solvent of Ibandronate.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of ibandronate to solvent and unsaturated lecithin was 42.188: 56.812: 1 by weight.
  • Ethanol was selected and used as a solvent of Celecoxib.
  • Two types of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of Celcoxib to solvent and unsaturated lecithin was 50: 49: 1 by weight.
  • Propylene glycol was selected and used as a solvent of Ginsenoside Rg1.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of ginsenoside Rg1 to solvent and unsaturated lecithin was 1: 94: 5 based on the weight%.
  • Propylene glycol was selected and used as a solvent for Amlodipine.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of amlodipine to solvent and unsaturated lecithin was 3.125: 91.875: 5 based on weight%.
  • Propylene glycol was selected and used as a solvent of Tacrolimus.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of Tacrolimus, solvent and unsaturated lecithin was 1.25: 93.75: 5 by weight.
  • Propylene glycol was selected and used as a solvent of paclitaxel.
  • Two examples of unsaturated lecithin (PC75%) and unsaturated lecithin (PC95%) were used as surfactants.
  • the ratio of paclitaxel to solvent and unsaturated lecithin was 0.6: 94.4: 5 based on the weight percent.

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Abstract

L'invention porte sur un matériau ayant les cinq caractéristiques suivantes simultanément et ayant de cette manière une recristallisation considérablement retardée. La première caractéristique est que le type de tensioactif qui est utilisé doit être un tensioactif ayant au moins deux queues. La deuxième caractéristique est que la taille d'un matériau insoluble auquel le tensioactif est amené à adhérer est de préférence entre 1 et 10 μm, et même dans une plage étendue, inférieure ou égale à 30 µm et supérieure ou égale à 0,5 µm. La troisième caractéristique est que la taille du matériau insoluble auquel le tensioactif est amené à adhérer est extrêmement homogène. La quatrième caractéristique exige que le matériau, selon la présente invention, ne soit autant que possible pas standardisé, à la différence des liposomes selon les techniques existantes. La cinquième caractéristique est qu'une forme dissoute dans de l'eau est destinée à être sous une forme émulsifiée. La présente invention porte également sur le matériau à l'état solide avant dissolution dans l'eau et qui contient l'acide gras ayant la chaîne alkyle droite.
PCT/KR2013/002136 2012-03-16 2013-03-15 Matière solide pour matériau insoluble dans l'eau enrobé de tensioactif amorphe contenant un acide gras ayant une chaîne alkyle droite WO2013137694A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
KR10-2012-0027176 2012-03-16
KR1020120027175A KR101280005B1 (ko) 2012-03-16 2012-03-16 무수무복계물질
KR10-2012-0027174 2012-03-16
KR20120027177 2012-03-16
KR10-2012-0027177 2012-03-16
KR1020120027176A KR101309033B1 (ko) 2012-03-16 2012-03-16 무복계면물질 및 무수무복계면물질의 제조방법
KR10-2012-0027175 2012-03-16
KR20120027174 2012-03-16
KR1020130028081A KR20130105538A (ko) 2012-03-16 2013-03-15 직쇄 알킬체인을 가진 지방산을 포함하는 무수무복계면물질
KR10-2013-0028081 2013-03-15

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WO2013137694A1 true WO2013137694A1 (fr) 2013-09-19

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WO (1) WO2013137694A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116585304A (zh) * 2023-04-25 2023-08-15 四川大学华西医院 一种急性肝损伤保护药物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10203964A (ja) * 1997-01-16 1998-08-04 Lipotec Sa 難吸収性薬剤の経口生物学的利用能を改善する新しい調剤
KR20000006503A (ko) * 1998-06-27 2000-01-25 윤승원 오일,지방산또는이들의혼합물을함유한난용성약물의고형분산제제
KR20010093154A (ko) * 1998-12-11 2001-10-27 추후제출 물에서 불충분하게 용해되는 약제를 위한 자가-유화용조성물
JP2011057587A (ja) * 2009-09-08 2011-03-24 Sakamoto Yakuhin Kogyo Co Ltd 水系化粧料組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10203964A (ja) * 1997-01-16 1998-08-04 Lipotec Sa 難吸収性薬剤の経口生物学的利用能を改善する新しい調剤
KR20000006503A (ko) * 1998-06-27 2000-01-25 윤승원 오일,지방산또는이들의혼합물을함유한난용성약물의고형분산제제
KR20010093154A (ko) * 1998-12-11 2001-10-27 추후제출 물에서 불충분하게 용해되는 약제를 위한 자가-유화용조성물
JP2011057587A (ja) * 2009-09-08 2011-03-24 Sakamoto Yakuhin Kogyo Co Ltd 水系化粧料組成物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116585304A (zh) * 2023-04-25 2023-08-15 四川大学华西医院 一种急性肝损伤保护药物及其制备方法
CN116585304B (zh) * 2023-04-25 2024-04-05 四川大学华西医院 一种急性肝损伤保护药物及其制备方法

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