TW201400447A - Cocrystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one - Google Patents

Abstract

The present invention is a cocrystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one and a C14-17 fatty acid.

Description

Co-crystallization of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one Field of invention

(cross-reference to related fields)

This case is a priority interest of the Japanese Patent Application No. 2012-075604 filed on March 29, 2012, the entire disclosure of which is incorporated herein by reference.

The present invention relates to a novel co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one which is pharmaceutically useful, and a process for producing the same A pharmaceutical composition containing the same.

Background of the invention

3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one is a compound represented by the following formula (1).

Patent Document 1 describes a compound represented by the formula (1). The long-chain alcohol of cyclohexenone exhibits a nerve growth promoting effect, and is a preventive medicine for the prevention of brain diseases such as dementia. Further, for example, in Patent Document 2, a therapeutic agent for urinary dysfunction represented by prostate hypertrophy is also known.

However, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one itself is a waxy compound at normal temperature due to its low melting point (about 30 Since it is a compound which melt|dissolved easily by °C), when it develops as a pharmaceutical|medicine, it is the [

Generally, co-crystal is defined as a substance in which a host compound and a solid substance at room temperature (guest compound) undergo a certain action, for example, crystallization by hydrogen bonding or intermolecular force, and by ion bonding. The crystallized salt has a clear division (for example, Non-Patent Document 1). The formation of co-crystals makes it possible to express the function or physical properties which cannot be obtained by crystals composed of only a single compound, but in order to form a co-crystal of the host compound with the guest compound, it is known that if it is capable of selectively making, for example, one party acidic It is difficult in the case where the other part has a different compound such as a basic part to interact. That is, there is a high difficulty in predicting the combination of the host compound and the guest compound which can be used to obtain the co-crystal.

In the above-mentioned patent documents and non-patent documents, the crystal polymorphism of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one is not specifically described. Nor does it reveal any content about co-crystallization.

Advanced technical literature Patent literature

Patent Document 1: International Publication WO1999/008987

Patent Document 2: International Publication WO2002/066024

Non-patent literature

Non-Patent Document 1: Chemical & Engineering News, June 18 2007, vol. 85, No. 25, 17-30

Summary of invention

An object of the present invention is to provide 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one which is useful as a medicine and which is excellent in oral absorption. Co-crystallized and its pharmaceutical composition.

The present inventors directed against 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one to obtain a novel crystal having excellent physical properties as a medicine, especially Review for the purpose of obtaining new co-crystals. As a result, a higher melting point co-crystal was found in the combination of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with a specific fatty acid. . Further, it was not unexpectedly observed, and in the drug-dynamic test (PK test) using a rat described later, the well-known 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-ring The hexene-1-one was compared, and it was confirmed that the cocrystal of the present invention has an improvement of _Cmax of about 2 times to 23 times and AUC _0-24hr of about 2 times to 14 times, and the present invention has been completed.

According to one aspect of the present invention, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one and carbon represented by formula (I) are provided. Co-crystallization of fatty acids numbered 14 to 17.

[Chemical 2]

In one embodiment, co-crystals of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with a fatty acid having 14 to 17 carbon atoms are provided.

In other embodiments, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one is provided with leucovoric acid, palmitic acid or myristic acid Co-crystallized.

In other embodiments, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one is provided with pearlescent acid, palmitic acid or myristic acid, The co-crystals constituted by the ratio of the molar ratio of 1:0.5 to 1:2 are formed.

In other embodiments, the composition of the co-crystals may be 1:1.

In other embodiments, a co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid is provided, which is characterized by having the following Any of the peaks, any two, any three, any four, any five or more peaks: 7.7, 12.5, 17.1, 18.8, 22.0, 22.4, 24.2.

In other embodiments, a co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid is provided, characterized by having 7.7 The peaks of 18.8 and 22.4.

In other embodiments, co-crystallisation of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with a fatty acid having 14 to 17 carbon atoms is provided. its In the case where the temperature increase rate at the time of DSC measurement is 2 to 10 ° C / min, the peak value of the endothermic peak measured by differential scanning calorimetry is between about 40 and about 55 ° C.

In other embodiments, co-crystals of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid are provided, which are measured by DSC. When the temperature increase rate was 2 ° C / min, the peak value of the endothermic peak measured by differential scanning calorimetry was about 45.9 ° C.

In another embodiment, a pharmaceutical composition comprising the co-crystal described in any of the above is provided as an active ingredient.

According to the present invention, a co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one and a pharmaceutical composition thereof can be provided. It is a useful drug and is excellent in oral absorption, stability, and the like. The treatment of the co-crystals and pharmaceutical compositions of the present invention in the formulation is easy.

Figure 1 is a powder X-ray diffraction pattern of co-crystallized 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with pearlescent acid.

Figure 2 is a powder X-ray diffraction pattern of co-crystallized 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid.

Figure 3 is a powder X-ray diffraction pattern of co-crystallized 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with myristic acid.

Figure 4 is a DSC chart of co-crystallisation of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with pearlescent acid.

Figure 5 is 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1- A DSC chart of the co-crystallization of a ketone with palmitic acid.

Figure 6 is a DSC chart of co-crystallisation of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with myristic acid.

Figure 7 is a ¹ H-NMR chart of co-crystals of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid.

Figure 8 is a ¹ H-NMR chart of co-crystals of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with myristic acid.

Figure 9 is a ¹ H-NMR chart of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one.

Figure 10 is a ¹ H-NMR chart of palmitic acid.

Figure 11 is a ¹ H-NMR chart of myristic acid.

Form for implementing the invention

In the present invention, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one represented by the formula (1) (hereinafter, reference compound 1) The production method described in Patent Document 1 described above can be used.

The co-crystal of the present invention is a co-crystal of reference compound 1 and a fatty acid having 14 to 17 carbon atoms.

The co-crystal system is composed of the reference compound 1 and the fatty acid having 14 to 17 carbon atoms in a molar ratio of about 1:0.5 to 1:2, particularly about 1:1.

Further, the molar ratio of the reference compound 1 to the fatty acid having 14 to 17 carbon atoms can be determined by the integral ratio of ¹ H-NMR. That is, in the ¹ H-NMR of the cocrystal, the composition ratio of the cocrystals can be calculated from the ratio of the integral ratio of the peaks from the reference compound 1 to the integral ratio of the peaks derived from the fatty acids. The error range of the integral ratio of ¹ H-NMR is due to the error range of the composition ratio of the co-crystals. Therefore, in the range of "1:1 composition ratio", it is possible to include the integral ratio of ¹ H-NMR. The range of errors produced. In Fig. 9 to Fig. 11, ¹ H-NMR of Reference Compound 1, Palmitic Acid, and Myristic Acid is shown, and the composition of the co-crystals can be determined by comparing the patterns of these figures with the co-crystals.

Examples of the fatty acid having 14 to 17 carbon atoms include pearlic acid, palmitic acid, pentadecanoic acid, and myristic acid. Preferably, the fatty acid having a carbon number of 14 to 17 is preferably a fatty acid such as pearlic acid, palmitic acid or meat. Myristic acid.

The co-crystal of the present invention can be obtained by mixing the reference compound 1 with a fatty acid having 14 to 17 carbon atoms in a specific composition ratio, and if necessary, mixing in a solvent and precipitating a co-crystal. By using the reference compound 1 and the fatty acid having a carbon number of 14 to 17 in the absence of a solvent, the composition ratio of the co-crystal can be formed (for example, the reference compound 1 and the fatty acid having a carbon number of 14 to 17 are 1:0.5 to 1). The range of 2: is mixed, and the co-crystal (melting method) is precipitated by cooling after heating. In the case of using a solvent, the reference compound 1 and the fatty acid having 14 to 17 carbon atoms can be dissolved in the solvent at the appropriate ratio as necessary, and the solvent is evaporated, or the reference compound is gradually added. A method such as a solvent (inferior solvent) in which the solubility is lowered, and the co-crystals are precipitated. Examples of the solvent include ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran (THF), diethyl ether and diisopropyl ether; and lower alcohols such as methanol, ethanol, isopropanol and n-butanol; and chloroform; Chlorinated hydrocarbons such as dichloromethane and carbon tetrachloride; esters such as ethyl acetate; hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as benzene and toluene; Oxygen, etc. Suitable solvents are THF and acetone. The solvent may be used singly or in combination of two or more kinds of solvents.

In the co-crystal of the present invention, the peak top value of the endothermic peak measured by differential scanning calorimetry (hereinafter referred to as DSC) is 2 to 10 ° C/min when the DSC is measured. It was detected to be between about 40 and about 55 °C.

Regarding this part, the term "about" means ±5 °C. The peak value of the endothermic peak measured by DSC changes the measured temperature due to the temperature rise per minute, for example, the peak value of the endothermic peak of the reference 1:1 co-crystal of compound 1 and palmitic acid, as in As shown in the experimental example described later, the temperature rise rate was 55 ° C (co-crystallized solvent: acetone) or 53 ° C (co-crystallized solvent: THF) at a temperature increase rate of 10 ° C/min, and the temperature rise rate was 2 ° C / min at 45.9 ° C (cocrystal) Solvent: THF). The peak top value of the endothermic peak of the 1:1 co-crystal of the reference compound 1 and myristic acid was 42.1 ° C (co-crystallized solvent: THF) at a temperature elevation rate of 2 ° C/min. The peak top value of the endothermic peak of the reference 1:1 co-crystal of the reference compound 1 and the pearlescent acid was 48.1 ° C at a temperature increase rate of 2 ° C / min (co-crystallized solvent: none). The co-crystal of the peak top value of each of the above-mentioned co-crystals having a peak top value in the range of "about" is included in the "co-crystal" of the present invention. In addition, the peak value of the endothermic peak varies depending on the solvent in which the co-crystal is precipitated (for example, acetone and THF), and although the crystal form of the co-crystal has some different possibilities, these are also included in the present invention. crystallization".

The co-crystal of reference compound 1 of the present invention and pearlescent acid is characterized by having 2θ of any one, any two, any three, any four, any five or more powders of X-ray diffraction Crests: 13.5, 14.9, 16.3, 19.4, 21.0, 22.9, 24.0.

The co-crystal of reference compound 1 of the present invention and palmitic acid is characterized by having any one, any two, any three, any four, any five or more powder X-ray diffraction 2θ of the following Wave peaks: 7.7, 11.1, 11.8, 12.5, 13.3, 14.6, 17.1, 17.8, 18.8, 19.8, 20.5, 21.2, 22.0, 22.4, 24.2, 29.3. More preferably, the co-crystal of reference compound 1 and palmitic acid is characterized by having any one, any two, any three, any four, any five or more peaks of the following: 7.7, 12.5, 17.1 18.8, 22.0, 22.4, 24.2. Particularly preferred is a co-crystal of reference compound 1 with palmitic acid characterized by having peaks of 7.7, 18.8 and 22.4.

The co-crystal of reference compound 1 of the present invention and myristic acid is characterized by having 2θ of any one, any two, any three, any four, any five or more powders of X-ray diffraction Peaks: 8.2, 12.1, 13.2, 14.3, 16.5, 18.7, 21.5, 22.0, 23.1, 23.6, 24.4.

In addition, the peak value of the powder X-ray diffraction spectrum may cause some errors due to measurement conditions such as measurement equipment or reading conditions of peaks. The peak value in the present specification is a measurement error in the range of about ±0.2° 2θ.

Examples of the powder X-ray diffraction pattern of the reference compound 1 and the co-crystals of pearlescent acid, palmitic acid, and myristic acid are shown in Figs. 1 to 3, and examples of the DSC chart thereof are shown in Figs. 4 to 6.

The present invention provides a pharmaceutical composition comprising the co-crystal of the present invention.

When the co-crystal of the present invention is used as a medicine, it can be used with pharmacy The carrier is used in combination, and various administration forms are used for the purpose of prevention or treatment. As the form, for example, an oral preparation, an injection, a suppository, an ointment, a patch, or the like may be used, and an oral preparation is preferably used. Such administration forms can be produced by a formulation method conventionally known to those skilled in the art.

As a pharmaceutically acceptable carrier, various organic or inorganic carrier materials conventionally used as a material for preparation are used, and a solid preparation such as an excipient, a lubricant, a fixing agent, a cleavage agent, or the like; a solvent, a solubilizing agent, a suspending agent, and a tonicity agent are formulated. Liquid preparations such as buffers, soothing agents, and the like. In addition, preparations such as preservatives, antioxidants, colorants, and sweeteners may also be used as necessary.

In the case of preparing a solid preparation for oral administration, an excipient may be added to the co-crystal of the present invention, and if necessary, a fixing agent, a cracking agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. may be added, and Methods A tablet, a film-coated tablet, a granule, a powder, a capsule, and the like are produced. As such an additive, a general user in the field can be used, and for example, excipients such as lactose, white sugar, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and citric acid can be exemplified; water, ethanol, and c. Alcohol, monosaccharide syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone And other fixing agents; dry starch, sodium alginate, acacia powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose and other cleavage agents; refined talc, stearate, borax Lubricants such as polyethylene glycol; colorants such as titanium oxide and iron oxide; flavors such as white sugar, orange peel, citric acid, and tartaric acid.

In the case of preparing a liquid preparation for oral administration, a flavoring agent, a buffering agent, a stabilizer, a flavoring agent and the like may be added to the co-crystal of the present invention, and an internal liquid preparation, a syrup, an expectorant or the like may be produced by a general method. In this case, the flavoring agent may be the above-mentioned, and the buffering agent may, for example, be sodium citrate or the like, and the stabilizer may, for example, be xanthan gum, gum arabic or gelatin.

In the case of preparing an injection, a pH adjuster, a buffer, a stabilizer, a tonicity agent, a local anesthetic or the like may be added to the co-crystal of the present invention, and a subcutaneous, intramuscular, and intravenous injection may be produced by a general method. The pH adjuster and the buffering agent in this case may, for example, be sodium citrate, sodium acetate or sodium phosphate. Examples of the stabilizer include sodium metabisulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride and lidocaine hydrochloride. As the tonicity agent, sodium chloride, glucose, or the like can be exemplified.

In the case of preparing a suppository, a carrier for the formulation known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., may be added to the co-crystal of the present invention, and further, if necessary, such as TWEEN (landing) After the surfactant or the like of the trademark), it is produced by a general method.

In the case of preparing an ointment, a base, a stabilizer, a moisturizer, a preservative, etc. which are generally used in the co-crystallizing of the present invention may be mixed and formulated by a general method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecanol, and paraffin. Examples of the preservative include methyl p-hydroxybenzoate and ethyl p-hydroxybenzoate. Propyl p-hydroxybenzoate and the like.

In the case of modulating the patch, the ointment, cream, gel, paste, or the like may be applied to a general support by a general method. As the support, a woven fabric made of cotton, staple fiber, chemical fiber, a nonwoven fabric, or a film such as elastic polyvinyl chloride, polyethylene, or polyurethane, or a foam sheet is suitably used.

The amount of the co-crystal of the present invention to be formulated in each of the above-mentioned dosage unit forms is based on the symptoms of the patient to be applied, or according to the dosage form rather than being fixed. Generally, the dosage of the reference compound 1 is in the form of each administration unit. Oral agents are expected to be 0.01 to 200 mg. In addition, the single-dose dosage of the drug having the above-mentioned administration form cannot be determined uniformly depending on the patient's symptoms, body weight, age, sex, etc., but the average adult daily dose is about 0.01 to 2000 mg, preferably 0.01 to 200 mg. However, it is preferred to administer the drug once a day or 2 to 4 times. Further, in the present invention, the co-crystals of the present invention may be used singly or in combination of plural kinds.

Examples of the diseases treatable by administering the agent containing the co-crystal of the present invention include dysuria: for example, no inhibitory neurogenic bladder disorder, reflex neuropathic bladder disorder, type 1 diabetic neuropathic bladder disorder, Type 2 diabetic neurogenic bladder disorder, diabetic neurogenic bladder disorder, autonomic neurogenic bladder disorder, flaccid neuropathic bladder disorder, low-tension bladder disorder, other neurogenic bladder disorders, postoperative bladder function reduction, bladder overactivity Symptoms, non-neurological overactive bladder, detrusor external sphincter ataxia, bladder systolic dysfunction, urinary tract dysfunction, bladder dysfunction, urethral dysfunction, stress urinary incontinence, overflow urinary incontinence, urgency Urinary incontinence, reflex urinary incontinence, etc.; and neurological disorders: for example, spinal cord injury, spinal stenosis, neuropathic pain, neurosensory disturbance, diabetic pain, diabetic sensory disturbance, autonomic dysfunction, autonomic dysfunction , myasthenia gravis, etc.

Example

Hereinafter, the present invention will be described in more detail based on examples and comparative examples.

Examples 1 to 3 and Comparative Examples 1 to 11 were subjected to co-crystallization screening by a melt method.

The reference compound 1 and the guest compound shown in Table 1 were each mixed with a molar ratio of 1:1, and after heating and melting, it was confirmed that a co-crystal was formed by cooling. In the case where the product forms a solid compound, and in the differential scanning calorimetry (hereinafter referred to as DSC), the decrease in the endothermic peak from the reference compound 1 and the confirmation of the new endothermic peak from the co-crystal are judged. There is the possibility of forming co-crystals.

In Table 1 below, the guest compound to be used and its melting point are indicated as ○ in the case where it is judged that co-crystallization with Reference Compound 1, and × in the case where solid compound is not obtained, suggesting partial crystallization The sexual condition is indicated as △.

DSC measurement method

Device: DSC8230 (made by Rigaku Co., Ltd.)

Compound amount: 5~20mg

Heating rate: 2 or 10 ° C / min

Measuring temperature range: from 20 ° C to the melting point of the guest compound + 10 ° C

Reference object: alumina

As shown in Table 1, only the endothermic peak derived from the reference compound 1 was detected from the pearlic acid, palmitic acid and myristic acid of the linear fatty acid having 14 to 17 carbon atoms, suggesting a possibility of uniform crystallization. The powder X-ray diffraction pattern of the pearlescent acid co-crystal is shown in Fig. 1, and the DSC chart is shown in Fig. 4.

On the other hand, in the fatty acid of 20, 18 fatty acids of arachidic acid, stearic acid or ascorbyl palmitate, 1-hexadecanol and 16-hydroxyhexadecanoic acid, a new endothermic peak was detected simultaneously with reference compound 1 Endothermic peaks suggest a possibility of partial co-crystallization.

Other fatty acids such as lauric acid and citric acid having a carbon number of 12 or 10, or The ester was not confirmed to be co-crystallized.

Experimental Example 1 Co-crystallization screening by solvent evaporation

In Example 2, Comparative Examples 2 and 5, palmitic acid, stearic acid, and ascorbyl palmitate suggesting formation of a uniform co-crystal or a partial co-crystal, and reviewing with reference compound 1 by solvent evaporation Crystallization.

In the review, the reference compound 1 and the guest compound (palmitic acid, stearic acid, ascorbyl palmitate) are mixed and dissolved in a solvent at a molar ratio of 1:0.5 to 1:2.0, and the solvent is naturally volatilized while stirring. The way to co-crystallize. As the solvent, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, chloroform and dichloromethane were used.

As a result, it was cured with reference to Compound 1 and palmitic acid (constituting a molar ratio of 1:1) in combination with a THF or an acetone solvent. The fact that the peak of the reference compound 1 was not detected from the DSC measurement of the solidified product and the new endothermic peak was detected suggests a combination of uniform co-crystallization. On the other hand, no uniform co-crystallization is obtained under the combination or solvent conditions with other guest compounds.

Experimental Example 2 Verification experiment of co-crystallization

In Examples 2, 3, and Comparative Examples 2 and 5, palmitic acid, myristic acid, stearic acid, and ascorbyl palmitate co-crystallized with reference compound 1 were suggested as guest compounds, and the experimental examples were examined in more detail. a total of 1 solvent Crystallization.

Reference compound 1 (100 mg, 0.274 mmol) and a guest compound (0.274 mmol) were dissolved in THF at a molar ratio of 1:1, and a co-crystal was obtained by gradually dropping purified water under stirring.

The powder X-ray and DSC were measured for the obtained co-crystals, and the molar ratio of the reference compound 1 to the guest compound was calculated by the proton ratio of ¹ H-NMR, and is shown in Table 3. A powder X-ray diffraction pattern of co-crystallized palmitic acid and myristic acid is shown in Fig. 2 to Fig. 3, and a DSC chart of co-crystallized palmitic acid and co-crystal of myristic acid is shown in Fig. 5 to Fig. 6 The ¹ H-NMR charts of acid co-crystal, myristic acid co-crystal, reference compound 1, palmitic acid, and myristic acid are shown in Fig. 7 to Fig. 11, respectively.

Measuring device: JNM-EX270 (manufactured by JEOL Ltd.)

Determination of solvent: DMSO-d6

The results are shown in Table 3.

As shown in Table 3, when palmitic acid or myristic acid was used as the guest compound, a uniform co-crystal constituting a molar ratio of 1:1 was obtained. In the present specification, the term "homogeneous co-crystal" means that in the graph of DSC and powder X-ray diffraction as shown in the figure, the peaks from the reference compound 1 and the guest compound cannot be visually observed, and can be seen by the naked eye. A peak derived from co-crystallization was obtained, and in the ¹ H-NMR chart, the integral ratio of the peak from the reference compound 1 to the peak from the guest compound was 1:1.

Also on the molar ratio of, for example, in the case of palmitic acid co-crystals, respectively, by comparing Figures 7 lines of FIG. ¹ H-NMR 2.15ppm ~ 2.20ppm vicinity of the peak integral ratio, FIG. 9 of FIG. ¹ H-NMR after calculating the integral ratio of ¹ H-NMR 10 of FIG vicinity of the peak integral ratio 2.16ppm 2.15ppm and the peak in the vicinity of the drawing of 2.20ppm ~.

On the other hand, regarding stearic acid, palmitic acid, and ascorbate, a complex endothermic peak is shown in the DSC chart, and no uniform co-crystal is formed.

Powder X-ray measurement conditions

Measuring device: X'Pert PRO MPD (manufactured by PANalytical)

Scan range (2θ): 2~40°

Scanning speed: 0.2°/s

Tube voltage: 40kV

Tube current: 30mA

Experimental Example 3 Drug Dynamics Experiment (rat)

Weighing Reference Compound 1 and the co-crystal of the present invention (cocrystal of reference compound 1 with palmitic acid, co-crystal of reference compound 1 with myristic acid, and co-crystal of reference compound 1 and pearlescent acid, co-crystallized to form a molar ratio The drug suspension was prepared at 0.5% HPMC with a concentration of 1:1) (reference compound 1 conversion concentration was 3 mg/mL). The number of rats in each group was 4, and each of the drug suspensions was orally administered using a feeding needle (reference compound 1 was 30 mg/kg) to rats (Wistar, female, 6 weeks old). Blood was collected from the jugular vein using a heparin-treated syringe at each blood collection point (0.5, 1, 2, 4, 6, 8, 24 hr). Will take it After centrifugation of blood (13,000 rpm, 2 min, 4 °C), the concentration of Reference Compound 1 in plasma was determined by LC/MS/MS. The measurement results are shown in Table 4.

As shown in Table 4, the co-crystal of the present invention was compared with the reference compound 1, and it was confirmed that the improvement of C _max and AUC _{0 to 24 hr} was about 2 to 23 times and about 2 to 14 times, respectively. In particular, the C _max and AUC _{0 to 24 hr} of the co-crystal of palmitic acid are significantly increased by 20 times or more and 10 times or more respectively, and the C _max and AUC _{0 to 24 hr} of co-crystallized with myristic acid are also meaningful with respect to the reference compound 1. The increase in AUC _0~24hr co-crystallized with pearlescent acid is also a significant increase with respect to reference compound 1, and the co-crystal of the present invention can greatly improve the fact that drug power is dissimilar.

Claims (10)

A co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with a fatty acid having 14 to 17 carbon atoms. A co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with a linear fatty acid having 14 to 17 carbon atoms. A co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with pearlic acid, palmitic acid or myristic acid. a co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with pearlic acid, palmitic acid or myristic acid, 3 -(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with pearlic acid, palmitic acid or myristic acid to form a molar ratio of 1:0.5 The ratio of 1:2. Co-crystallization of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one of claim 4 with pearlic acid, palmitic acid or myristic acid , which constitutes a molar ratio of 1:1. a co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid characterized by having 7.7, 12.5, 17.1, 18.8 Any one of any of 22.0, 22.4, and 24.2, any two, any three, any four, or any five or more peaks. a co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid characterized by peaks of 7.7, 18.8 and 22.4 . 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one Co-crystallized with a fatty acid having 14 to 17 carbon atoms. When the temperature rise rate in the DSC measurement is 2 to 10 ° C/min, the peak value of the endothermic peak measured by differential scanning calorimetry is about 40~. Between about 55 ° C. A co-crystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one with palmitic acid at a rate of 2 ° C in DSC measurement In the case of /min, the peak value of the endothermic peak measured by differential scanning calorimetry was about 45.9 °C. A pharmaceutical composition comprising the co-crystal of any one of claims 1 to 9 as an active ingredient.