WO2013137694A1

WO2013137694A1 - Solid matter for water-insoluble material coated with amorphous surfactant containing fatty acid having straight alkyl chain 직쇄 알킬체인을 가진 지방산을 포함하는 무수무복계면물질

Info

Publication number: WO2013137694A1
Application number: PCT/KR2013/002136
Authority: WO
Inventors: 유우영; 김학철; 권돈선
Original assignee: 한국콜마 주식회사
Priority date: 2012-03-16
Filing date: 2013-03-15
Publication date: 2013-09-19

Abstract

A material having the following five characteristics simultaneously and thereby has significantly delayed recrystallization has been created for the first time. The first characteristic is that the type of a surfactant which is used must be a surfactant having at least two tails. The second characteristic is that the size of a insoluble material to which the surfactant is adhered is desirably between 1-10μm, and even at an extended range, no more than 30μm and no smaller than 0.5μm. The third characteristic is that the size of the insoluble material to which the surfactant is adhered is extremely homogenous. The fourth characteristic requires that the material, according to the present invention, is not standardized as much as possible, unlike liposomes according to existing techniques. The fifth characteristic is that a form dissolved in water is intended to be in an emulsified form. The present invention relates to the material in a solid state before dissolving in the water, and which contains the fatty acid having the straight alkyl chain. 다음과 같이 다섯 가지의 특징을 동시에 가짐으로서 재결정화를 크게 지연시킨 물질이 최초로 창작되었다. 첫째 특징은 사용되는 계면활성제의 종류가 반드시 2개 이상의 다리를 가진 계면활성제라야 한다는 것이다. 둘째 특징은 계면활성제가 부착된 난용성물질의 크기가 바람직하기는 1~10 ㎛ 범위에 속하는 것이 좋고 좀 더 확대하여 생각한다고 해도 최대 30㎛, 최소 0.5㎛ 를 생각할 수 있다. 셋째 특징은 계면활성제가 부착된 난용성물질의 크기의 균질도가 대단히 높다는 것이다. 넷째 특징은 본 발명에 의한 물질은 종래기술이 리포좀과는 달리 최대한 정형화하지 않을 것을 요구하고 있다. 다섯째 특징은 물에 용해된 형태가 유화타입을 지향하고 있다는 점이다. 본 발명은 상기의 물질의 물에 용해하기 전 고체 상태의 물질로서 직쇄 알킬체인을 가진 지방산을 보유하고 있는 물질이다.

Description

Anhydrous barrier-free materials containing fatty acids with straight chain alkyl chains

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.

Prior to the present invention there was, of course, the recognition that the use of surfactants is useful for dissolving poorly soluble materials. But the concept was in the form of liposomes. Liposomes also come in various forms, but looking at the representative ones, such as those shown in Figures 1, 2, and 3. This method of dissolving poorly soluble substances in the form of liposomes is a method of increasing the solubility by enclosing the drug in the hydrophobic inner center, which may protect the drug against a biological environment (e.g., low PH, enzyme), and especially small size (10 ~ 100 nm) polymer has been widely used in the pharmaceutical field because of the advantages such as easy to target the drug and reduce side effects of chemotherapy.

However, the method of utilizing poorly soluble substances in the form of these liposomes had a critical problem. Only a very small amount can be used to melt poorly soluble substances. For example, in the case of poorly soluble substance ceramide, only 0.1 to 1.0% by weight (which can contain ceramide) can be dissolved using liposome method, so even if expensive soluble substance is used in food, cosmetics or medicine It was difficult to make a product that many people could use cheaply.

In the description of the present invention, it is necessary to clearly define the poorly soluble material. This is because the concept is widely used, but the meaning is different depending on the user. The poorly soluble materials 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. Second, 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. And third, 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.

In this regard, the definition of medically insoluble substances is as follows.

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. "

Now, the present invention will be described in earnest.

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. In other words, 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.

Of course, it might be thought that the poorly soluble material could be refined and used as a surfactant. However, it was recognized that it is generally not applicable until now because recrystallization of poorly soluble substances occurs so quickly that crystallization occurs before reaching the destination to which the substance should act.

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.

And another way to increase the utilization is that it is difficult because the amount of the poorly soluble substance that can be dissolved is too small, such as liposomes, so is there a way to reduce the amount of surfactant and take a large amount of poorly soluble substance? I was worried.

However, to implement it as the present invention had to suffer a lot of trial and error and frustration, and to enter a number of ingenious ideas.

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".

This is different from the liposomes that are made in liquid form in terms of solid form, but the more essential aspect is that the effect is remarkable in terms of the breakthrough convenience in terms of user use. The idea of dissolving liquid materials in liquid form to make them easier to use and dissolving them in water may be consequently seen, but it is hard to do such an idea early.

Finally, based on countless trials and errors and long periods of research, it was possible to find new materials and new ways to make them available, with much higher amounts of poorly soluble materials available. This is a concept that has never existed before. It is an invention that could be achieved only by specially limiting the type of surfactant, adjusting the mixing ratio of the surfactant and the poorly soluble material to an appropriate level, and proceeding with a specific manufacturing method in an optimized form. The created material is a new material as having the characteristics of the invention that has not existed conventionally in terms of homogeneity of structure and size.

In other words, it is not a single pure substance, but a substance with a newly created binding relationship in terms of structure between chemicals applicable to various poorly soluble substances.

These new materials have the following five characteristics simultaneously when dissolved in water.

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 ㎛, even if you think a little more magnification can be thought of up to 30㎛, at least 0.5㎛. 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. In practice, 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. 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. Therefore, the meaning of "amorphous" in this specification should be interpreted as such. In particular, 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.

As mentioned above, the material which greatly retarded recrystallization by having five characteristics simultaneously was created for the first time. Considering a term that can define this substance in one word, it is difficult to find a suitable term, and it is difficult to find a suitable term as mentioned above, and it is necessary to newly rename the name. Therefore, in the present specification, 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. In other words, even if the expression of "borderless material" does not properly imply the above five characteristics, the term "bleached material" in the present invention means that the material has the above five concepts.

In addition, another key element of the present invention is the fact that 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.

In order to make such an anhydrous barrier-free material, 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. Unlike the barrier-free material, the anhydrous barrier-free material generally contains an organic solvent having a polarity such as -OH. In addition, 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.

Therefore, 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.

The above five characteristics are essential. However, in addition to these additional components, there is an important component that has a significant synergistic effect on the final product. This is important in that it is not necessarily necessary, but it is synergistic in terms of economics and effects. It is the addition of "fatty acids with a straight chain" as a component of the anhydrous barrier-free material. Currently used fatty acids are stearic acid, palmitic acid, myristic acid and lauryl acid. Preferably 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.

As another factor, there is no technical problem, but it may be a good way to adopt and include 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 biggest effect of the barrier-free material is, among other things, that only a very small amount is dissolved in water, so it is possible to dissolve and use up to tens of times a poorly soluble substance, which had a limited effect even though there were various effects. have. Of course, the expression "melted" here encompasses both the case of dissolution, the form of liposomes, and the case-free interface. Strictly speaking, the barrier-free material differs from the general dissolution concept. However, in this specification, for convenience, in other words, when using a poorly soluble substances in foods or pharmaceuticals, it means that 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.

Another breakthrough effect of the present invention is that "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."

1 Example of Liposomes

Another Example of Liposomes

Figure 3 Another Example of Liposomes

Fig. 4 Conceptually depicts the emulsified form of one barrier-free material in water

5 is an embodiment of an inline mixer including a mixing blade structure having the concept of phase mixing

6 is a schematic view of the manufacturing process of Example B

Figure 7a DSC graph of the natural ceramide 3 (comparative) and the ceramide-containing composition of Example 19 of the present invention

Figure 7b DSC graph of the ceramide-containing composition of natural ceramide 3 (comparative) and Example 19 of the present invention

8a in the case of natural ceramide 3, the temperature at which the phase transition from the crystal form of ceramide to the liquid phase at room temperature is 97.70 ℃

8b In the case of the ceramide-containing composition of Example 20 of the present invention, 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 Y30 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

Fig. 11a Experimental results of ceramide precipitation using slide glass immediately after the article manufactured by different mixing methods

11b Experimental results of ceramide precipitation using the slide glass immediately after the article manufactured by different mixing methods

100 poorly soluble substances

200 surfactants

Hydrophilic Part of 201 Surfactant

202 Alkyl Chain Part of Surfactants

Alkyl chain portion of 301 fatty acid

Carboxylic Acid Part of 302 Fatty Acids

The concept of barrier-free materials is 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.

Conceptually drawing the material of the present invention is shown in FIG.

Of course, this is not a single pure substance, but a substance with a consistently new concept that can be applied to various poorly soluble substances.

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.

In the case where one chain of the alkyl chain forming the surfactant is attached to the poorly soluble material, 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. However, in the case of having two or more alkyl chains, in general, 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.

Of course, this is only a possibility. Generally, the bonds between the same organic or inorganic materials tend to be formalized (including the concept of crystallization in the present invention), and thus only the alkyl chain of the surfactant is unformulated. It's hard to see that you can make it. Therefore, the present invention introduces a new mixing method that can sufficiently overcome the tendency to formalize such organic materials. It will be explained again below.

While minimal conditions require surfactants with multiple alkyl chains, there are other conditions suitable for use. First, the longer the length of the alkyl chain was analyzed to be more preferable. And it is considered that it is more preferable to include a functional group of another form in the alkyl body, but when the size of the functional group is large, there is an undesirable aspect by making the size of the entire surfactant too large. And when the length of the plurality of alkyl chains is not the same can be said to be more preferable. In addition to the length, the two chains are different from each other in terms of bending angle and various aspects.

It is inferred that, after all, whether these are desirable is determined by how good it is to create an unstructured form, and how well they can interfere with each other's movements to recrystallize while still in the emulsion. Doing.

However, it was experimentally demonstrated that in principle, any surfactant having an alkyl chain having 10 or more carbon atoms can be used.

One of the surfactants found for this is hydrogenated lecithin. 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.

If you look more closely at this: It is obvious that the following is an example only and is not limited to those listed here unless expressly expressed.

1) Lecithin Series

Phosphatidylcholine: The lecithin used to make a non-surfactant has the same effect as both yolk lecithin and soybean lecithin.

[Revision under Rule 91 03.05.2013]

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.

[Revision under Rule 91 03.05.2013]

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.

[Revision under Rule 91 03.05.2013]

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.

2) Nonionic Surfactant Series

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.

It is possible to make 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. Preferably, the size is in the range of 1 to 10 μm on the basis of diameter, and even if it is considered to be larger, a maximum of 30 μm on the basis of diameter and 0.5 μm may be considered. Compared to liposomes using nano-units of the prior art, 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.

In principle, the smaller the size, the smaller the size, the smaller the recrystallization can be seen. However, as long as there is no problem in the present invention, the size should be as large as possible to increase the efficiency of use of poorly soluble materials. Using this method, a barrier-free material having a significant value with a small particle diameter variation and an average particle size of 0.5 µm or more was produced. In general, the average particle diameter is about 5㎛. However, if the average particle size is more than 30㎛, 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. In practice, 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.

The exact mechanism of why high homogeneity delays recrystallization is not yet fully understood. However, it is estimated that some of the zeta potential is working.

Zeta potential is a high density of positive ions attached to the surface of negatively-charged particles, forming a stern layer. When a layer is accumulated, 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. In general, 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. Normally, 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.

[Revision under Rule 91 03.05.2013]

In other words: 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.

Therefore, in order to neutralize the interfacial charges, excessively opposite ions and small amounts of eastern ions are diffusely distributed around the particles, and the electrical potential is gradually decreased from the interface with a gentle potential gradient. do.

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.

Numerous experiments have shown that surfactants adhere to the surface of poorly soluble masses, but are reluctant to recrystallize if they are attached as chaotic as possible. Although the mechanism is not known precisely, it is assumed that the amorphous bond itself strongly interferes with the direction of crystallization. In addition, such an amorphous bond is not generally shown, and the mixing method by the "in-line mixer including a mixing blade structure having the concept of compensation mixing" found after a long trial and error of the present invention is greatly contributed. Reasoning. Of course, the use of a surfactant having two or more alkyl chains seems to have an important relationship.

Fifth feature is that 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. However, in order to distinguish it from an emulsified state having a conventionally known bonding structure in terms of having a completely different bonding structure from a conventionally known emulsifying type, the material dissolved in the amorphous emulsifying type of the present invention is referred to as a barrier-free material. .

The above five characteristics are essential. However, in addition to these additional components, there is a synergistic effect on the final product. This is important in that it is not necessarily necessary, but it is synergistic in terms of economics and effects. It is the addition of "fatty acids with a straight chain" as a component of the anhydrous barrier-free material. Currently used fatty acids are stearic acid, palmitic acid, myristic acid and lauryl acid. Preferably 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.

The reason for using these fatty acids can be explained in various ways.

First, it is possible to make the product with higher hardness when making anhydrous barrier-free material, so that it can be easily handled and powdered.

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.

Second, since fatty acid dissolves poorly soluble substances in the molten state, it is estimated that adding poorly soluble substances in the mixed state with surfactants helps to increase the dispersion and homogeneity of the poorly soluble substances.

This is also important to the essential effects of the present invention. These phenomena are most likely to dissolve in water in the future to form a barrier-free substance, while most of the fatty acids are present between the surfactant and the poorly soluble substance, and the alkyl side is strongly entangled with the alkyl chain of the surfactant to the poorly soluble substance. We believe the tendency to position in the water direction will be strong. Therefore, it is experimented that the alkyl chain of fatty acid should have a straight chain form and the length of the chain is also similar to or slightly shorter than the length of alkyl chain of surfactant.

This is presumed that if the length of the fatty acid alkyl chain is too short, the role of entanglement is insufficient, and if the length of the alkyl chain of the fatty acid is too long, there is a possibility that the alkyl chain of fatty acid may stick out of the surfactant.

This is distinguished from 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.

In this way, 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. This can be said that the fatty acid plays a synergistic role in reducing the probability of recrystallization pursued by the barrier-free material.

In general, 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.

In conclusion, especially if you need to use fatty acids can be summarized as follows.

First, if the solubility of poorly soluble substances is extremely low, it should be almost used.

Secondly, when it is not used, if the hardness of the anhydrous non-cemented interface material is low and there is a considerable difficulty in solidification, the use of fatty acid is almost essential to improve the hardness by increasing the density.

Third, when it is necessary to control the amount of poorly soluble substances, fatty acids may need to be used as excipients.

More specifically with respect to the above-described inventive material of the present invention.

As a result, it is concluded that 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. In the case of conventional liposomes, 5 to 10% of the surfactant is used to accept 1% of the poorly soluble material. However, in the case of the barrier-free material according to the present invention, 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.

However, excessive use of surfactants does not prevent the insoluble matter from being dissolved. However, when excessively used, the ratio of dissolved amount of the poorly soluble substance is lowered compared to the amount of the surfactant, so the efficiency is significantly lowered.

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.

In other words, while adding water from the beginning of the manufacturing process (some solvents, such as the initial entry, but to lower the viscosity to be put in the mixer, and ultimately to solidify and commercialize it in the aspect of the present invention in terms of dissolving in the present invention) The concept of dissolving is inherently poorly soluble (meaning poorly soluble in water), which leads to considerable manufacturing difficulties. There is a significant difference from liposomes in this respect.

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. The "obsolete interface material" refers to a substance dissolved in a solvent.

Therefore, 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". Of course, this may be a powder and may include a powder that is not.

In this respect, there is a remarkable difference from liposomes. 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, that is, the size of the barrier-free material, is 0.5 to 30 μm, which is about 100 times higher than that of the liposome form. In the case of liposomes, 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 μm. In addition, it is pointed out that 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.

Since the amount of surfactant used in the barrier-free material is extremely small, there is a possibility that recrystallization may occur due to the large size of poorly soluble substances due to the difference in zeta potential, and the small size of poorly soluble substances combined. Therefore, it was necessary to introduce a mixing method that can ensure a uniform degree of uniformity that can maintain a balance such that the difference in zeta potential is not large and the attraction and repulsive forces are not combined.

This also shows a considerable difference from the prior art. In the case of liposomes, it is introduced that the concept of recrystallization is fundamentally blocked by not meeting each other with poorly soluble substances. However, in the case of a barrier-free material, it is possible to meet solid insoluble materials at room temperature, but it is possible to prevent recrystallization by preventing the regular movement of the poorly soluble materials by alkyl groups of surfactants irregularly bonded to the poorly soluble materials. It is theoretically inferred that it is adopted.

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.

Hereinafter, a method of producing anhydrous non-compound interface materials will be described.

In the present invention, 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.

Of course, you can add fatty acids. It is understood that 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.

In addition, it is possible to put various organic solvents that can adjust the viscosity for the smooth operation of the mixer, which is called a mixing aid and is usually adopted as an organic solvent having a polarity, especially -OH group. This is generally adopted based on common knowledge among those skilled in the art to facilitate mixing.

This is mixed through a mixer. A mixer including an inline mixer including a mixing blade structure having the concept of reparation mixing should be used. Of course, many machines will come out in the future, and there is virtually any possibility that a machine can emerge that can make the barrier-free material easier for the present invention. However, 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. In this case, a blade that repeatedly changes direction is referred to as a “unit blade.” Thus, the mixed blade structure can be regarded as a combination of unit blades.

In the present invention, a mixer capable of such compensation mixing is defined as a "compensation mixing mixer." Of course, 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.

In order to implement the present invention, reparation mixing is essential, and any other mixing method may be used in parallel if necessary.

In the case of reparation mixing time, 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.

However, it is preferable to perform the 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.

Of course, 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.

When the product is finally made, it is common to cool it, solidify it, and grind it to fine powder.

In some cases, of course, the material passing through the liquid phase mixing mixer may be a liquid phase. In this case, water can be added to the liquid material to form a barrier-free material.

The following experiment was conducted to confirm that the introduction of reparation mixture is necessary.

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.

[b method]: Ceramide 3, hydrated lecithin PC, dipropylene glycol, glyceryl stearate and stearic acid were purchased and used. Example 1 Using a vacuum emulsification tank in the content of the composition added hydrous lecithin, dipropylene glycol, glyceryl stearate, stearic acid and ceramide except for ceramide 3 and stirred homogeneously for another 10 minutes at 3000rpm in a general mixer Finished the process. The result was passed three times through an in-line mixer containing a mixing blade structure. Dispersion of the ceramide-containing composition prepared in this way also shows the following picture b.

Test 1: Ceramide Solubility Assessment (Method a and b)

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.

2 (a) of Figure 2 is photographed whether or not precipitated by spreading 0.2 g of the ceramide-containing composition prepared by the method of a (using a vacuum emulsification tank) on a slide glass, the following (b) is a method of b (In- Line column mixer) 0.2g of the ceramide-containing composition prepared by the same method as above was taken.

As shown in FIG. 11, the precipitation of ceramide was not observed in both the a method and the b method immediately after the dissolution. There was no significant difference in solubility, and both were judged to have excellent solubility. This test assesses the uniform dissolution of the various ingredients contained in a simple barrier-free material, so the difference between Homogenizer and liquid phase mixing mixer is not clearly distinguished.

However, as can be seen in Figure 10 showing the dispersion degree (a) shows the dispersion degree of the ceramide-containing composition prepared by the method of a, (b) is the dispersion of the ceramide-containing composition prepared by the method of b As shown in the figure, the average particle size of the ceramide-containing composition prepared by the method of a was 2 μm, and the average particle size of the ceramide-containing composition prepared by the method of b was 1 μm. At that time, it was found that the prepared by the method of Example B is excellent in homogeneity and dispersibility.

Test 2: Long-term stability measurement with time

After hydrating the resultant prepared by the method of a, after confirming the colloidal stability in a 4, 20, 38, 50 ℃ thermostat to confirm long-term stability, when the 15 days at 38, 50 ℃ evaporated fine water surface It was confirmed to float. This suggests that there is a serious problem in long-term stability due to changes over time. Consequently, no barrier-free material was formed.

On the contrary, when the resultant prepared by the method b using the phase mixing mixer was hydrated, stable results were obtained even after 60 days in a constant temperature bath at 4, 20, 38, and 50 ° C. It can be seen that having a reparation mixing process is a necessary element for the production of a barrier-free material.

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.

All the examples below are cases where the reparation mixing method is adopted.

EXAMPLE 1, 2, 3

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.

Here, 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.

In other words, 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.

The reason for this is clear, if the liquid solvent material is not used, when warmed for melting the poorly soluble substance and the surfactant, a phenomenon occurs that the poorly soluble substance and the surfactant burn out before reaching their own melting point. Therefore, the necessity of a liquid medium was strongly required as a method for evenly transferring the temperature to the two materials. Therefore, the completeness of the present invention was improved by using a liquid mixing aid. It was carried out according to Table 1 below.

Table 1

ingredient	Example 1 (% by weight)	Example 2 (% by weight)	Example 3 (% by weight)
Ceramide 3	40	40	40
Hydrated Lecithin (PC 75%)	20	20	20
Purified water	40	-	-
Dipropylene glycol	-	40	-
ethanol	-	-	40
10% aqueous solution moisture content	98.9%	93.7%	96.9%

In addition, in order to see if the solvent can be collected separately, 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.

As a result of the test according to the table, including the embodiment 1, which is a ceramide-containing composition prepared by the method of b including the reparation mixing process, all were found to be water-soluble and carried out containing purified water, dipropylene glycol, ethanol Examples 1, 2, and 3 were dispersed in water at a concentration of 10%, and then, after centrifugation at 10000 rpm for 15 minutes using a centrifuge, the clear supernatant was taken and water content was determined as shown in the above table. As can be seen from this experiment, it is inferred that the solvent acts as an adjuvant that can be easily submerged in water and can be remixed by simply mixing poorly soluble substances.

Through the above embodiments, it can be seen that the minimum essential component of the barrier-free material is sufficient only with the poorly soluble material and the aforementioned characteristic surfactant. Of course, although 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.

[Example 4 to Example 9]

This embodiment summarizes the contents carried out with various poorly soluble materials and various surfactants.

In the table below, ceramide 3, N-acetylphytosphingosine, ursolic acid and UDCA are poorly soluble substances.

PEG-150 Stearate has one alkyl chain as a surfactant. On the other hand, hydrated lecithin and PEG-30 (Dipolyhydroxystearate) are two alkyl chains. Dipropylene glycol and glyceryl stearate are mixed adjuvant and the like and stearic acid is fatty acid.

Except for Example 8 it was possible to make all of the barrier-free material in the following examples. 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.

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TABLE 2

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TABLE 3

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.

[Example 13 to Example 16]

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. Was contained in a round flask containing 90% by weight purified water, sealed, and dispersed at 70 ° C. for 30 minutes using a magnetic stirrer. The degree of water solubility (degree of expansion of ceramide) was evaluated using a 100 ml measuring cylinder. .

The results are shown in the following [Table 5].

Table 4

ingredient	Example 13 Weight%	Example 14 Weight%	Example 15 Weight%	Example 16 weight%
Ceramide
3	30	Left	Left	Left
Hydrated Lecithin (PC 75%)	20	-	-	-
Hydrated Lecithin (PC 80%)	-	20	-	-
Hydrated Lecithin (PC 50%)	-	-	20	-
Dipropylene glycol	30	Left	Left		50
Glyceryl Stearate	10	Left	Left	Left
Stearic acid
	10	Left	Left	Left

Table 5

Classification	Example 13	Example 14	Example 15	Example 16
Thickness (cm)	3.2	3.1	2.1	2.6

As a result of the evaluation, it was found that the degree of solubility was different according to the phospholipid (PC) content of lecithin. However, when the phospholipid content is 75% and 80%, the difference in water solubility was not significant even through repeated experiments. Therefore, if the phospholipid content is more than 75% in hydrated lecithin, it can be applied to the product safely. Could evaluate.

[Examples 17-18]

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. For comparison, natural ceramide 3 was used as a comparative example.

Table 6

ingredient	Example 17 (% by weight)	Example 18 (% by weight)
Ceramide 3	40	30
Hydrated Lecithin (PC 75%)	20	20
Hydrated Lecithin (PC 80%)	-	10
Dipropylene glycol	20	20
Glyceryl Stearate	10	10
Stearic acid	10	10

First, the DSC graphs of the natural ceramide 3 (comparative example) and the ceramide-containing composition of Example 17 of the present invention are shown in FIGS. 7A and 7B.

As shown in Figure 7a and 7b, in the case of natural ceramide 3 (Fig. 7a), the temperature of the phase transition to the liquid phase of the ceramide in the crystalline form at room temperature is 97.70 ℃, the ceramide-containing composition of Example 17 of the present invention ( In the case of FIG. 7B), the temperature of the phase transition to the liquid phase was 45.54 ° C., whereby a significant difference in the phase transition temperature occurred.

8A and 8B, in the case of natural ceramide 3 (FIG. 8A), the temperature at which phase transition of the crystalline ceramide to liquid phase at room temperature is 97.70 ° C., whereas in the case of the ceramide-containing composition of Example 18 of the present invention ( 8b) the temperature of the phase transition to the liquid phase is 52.08 ℃, it was confirmed that a significant difference in the phase transition temperature occurs.

That is, in general, in order to increase the solubility of the natural ceramide 3 in the manufacturing process of the ceramide-containing composition, the process temperature is maintained around 80 ℃, natural ceramide 3 is easy to precipitate as crystals because the phase transition temperature is higher than the process temperature, In the case of the ceramide-containing composition according to the embodiment of the invention it was found that the solubility is very excellent because the phase transition temperature is significantly lowered.

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. However, 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.

[Examples 19-35]

In the above examples, in the process of making a barrier-free material, unlike in the past, the poorly soluble material was able to dissolve a large amount significantly, and also made the anhydrous barrier-free material to significantly improve the ease of use. Many experiments have been conducted since then to make sure that these phenomena can be generally applied to poorly soluble materials, and as a result, the present invention is equally applicable to other poorly soluble materials.

Example 19

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.

In this way, the method for producing a barrier-free material described in the above detailed description was applied.

In both cases, it was possible to produce a stable molten barrier-free material.

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Among these, propylene glycol PC content 95% formulation stability is as follows.

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TABLE 7

Example 20

Cyclosporin A

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.

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Table 8

PC Content 95% Formulation Stability in Propylene Glycol

Example 21

Dercusin

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.

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Table 9

PC Content 95% Formulation Stability in Propylene Glycol

Example 22

Latanoprost

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.

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Table 10

PC Content 95% Formulation Stability in Propylene Glycol

Example 23

Travoprost

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.

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Table 11

PC Content 95% Formulation Stability in Propylene Glycol

Example 24

Docetaxel

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%.

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Table 12

PC Content 95% Formulation Stability in Diethylene Glycol

Example 25

Bimatoprost

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.

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Table 13

PC Content 95% Formulation Stability in Propylene Glycol

Example 26

Amphotericin B

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%.

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Table 14

PC Content 95% Formulation Stability in Diethylene Glycol

Example 27

Itraconazole

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.

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Table 15

PC Content 95% Formulation Stability in Benzyl Alcohol

Example 28

Isoflavone

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.

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Table 16

PC Content 95% Formulation Stability in Diethylene Glycol

Example 29

Meloxicam

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.

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Table 17

PC Content 95% Formulation Stability in Ethoxydiglycol

Example 30

Ibandronate

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.

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Table 18

Formulation of PC Content 95% in Isostearic Acid

Example 31

Celecoxib

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.

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Table 19

PC Content 95% Formulation Stability in Ethanol

Example 32

Ginsenoside Rg1

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%.

[Revision under Rule 91 03.05.2013]

Table 20

PC content 95% formulation stable in propylene glycol

Example 33

Amlodipine

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%.

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Table 21

PC Content 95% Formulation Stability in Propylene Glycol

Example 34

Tacrolimus

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.

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Table 22

PC Content 95% Formulation Stability in Propylene Glycol

Example 35

Paclitaxel

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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Table 23

PC Content 95% Formulation Stability in Propylene Glycol

Claims

If dissolved in water,

Poorly soluble substances; and

Including surfactants having two or more alkyl chains attached to the hydrophilic moiety,

The amount of the surfactant is 10% to 200% by weight of the poorly soluble material,

The surfactant is in the form of being surrounded by an amorphous surrounding the poorly soluble material in an adhesive form is dissolved in water as an emulsion type,

The anhydrous non-surfacting material producing a non-surfacting material, characterized in that the average diameter of the poorly soluble material with the surfactant is 0.5 ~ 30㎛ and the average range of the size is within ± 200% of the diameter.
If dissolved in water,

Poorly soluble substances;

Surfactants having two or more alkyl chains attached to the hydrophilic moiety; And

Include fatty acids with straight chain alkyl chains,

The amount of the surfactant is 10% to 200% by weight of the combined amount of the poorly soluble substance and fatty acid,

The surfactant is bonded around the outer surface of the poorly soluble material in an amorphous form, the fatty acid is present in the form between the surfactant and the poorly soluble material is dissolved in water as an emulsion type,

The anhydrous non-surfacting material producing a non-surfacting material, characterized in that the average diameter of the poorly soluble material with the surfactant is 0.5 ~ 30㎛ and the average range of the size is within ± 200% of the diameter.
The anhydrous barrier-free material according to any one of claims 1 to 2, further comprising a mixed adjuvant which is an organic solvent having a polarity.
The anhydrous barrier-free material according to claim 3, wherein the admixture aid is an organic solvent having an -OH group.
The anhydrous barrier-free material according to claim 4, wherein when the anhydrous barrier-free material including the admixture aid is dissolved in water, the admixture aid is dissolved in water and separated from the barrier-free material.
6. The anhydrous barrier-free material according to any one of claims 4 to 5, wherein the amount of the surfactant is 20% by weight to 100% by weight relative to the poorly soluble material.
The anhydrous barrier-free material according to any one of claims 4 to 5, wherein an average diameter of the poorly soluble substance to which the surfactant is attached is 1.0 to 10 µm.
The anhydrous barrier-free material according to any one of claims 4 to 5, wherein the homogeneity of the size of the barrier-free material is within an average range of ± 100% on a diameter basis.
According to claim 2, The fatty acid is an anhydrous non-surfactant, characterized in that the fatty acid having a straight chain alkyl chain without a double bond.
6. The anhydrous unwashed interface material according to any one of claims 2 to 4, wherein the fatty acid is used in an amount of 2 to 10 times the weight-soluble poorly soluble material.
The anhydrous non-surfactant according to any one of claims 2 to 4, wherein the fatty acid is a substance or mixture of any one or more of stearic acid, palmitic acid, myristic acid and lauryl acid.
The anhydrous barrier-free material according to any one of claims 2 to 4, wherein the surfactant is any one of lecithin-based egg yolk lecithin and soy lecithin.
The anhydrous unwashed interface material according to any one of claims 2 to 4, wherein the PC content of the surfactant is 70% or more.
The anhydrous non-surfacing interface material according to any one of claims 2 to 4 or 5, wherein the surfactant is hydrogenated lecithin.
The anhydrous barrier-free material according to any one of claims 2 to 4 or 5, wherein the surfactant is any one of a series of nonionic surfactants.
The method according to any one of claims 2 to 4 or 5, wherein the surfactant is PEG30 Dipolyhydroxystearate, Polyglyceryl-2dipolyhydroxystearate. 2 Dipolyhydroxystearate, polyglyceryl-2 diisostearate, PEG-150 Pentaerythrityl Tetrastearate and polyglyceryl-2 triisostearate Anhydrous non-compound interface material.