Sirolimus-containing granular preparation and method for producing the same

Abstract

To provide a sirolimus-containing powder granule formulation that ensures bioavailability and has improved stability. [Solution] A sirolimus-containing granular preparation containing sirolimus and tocopherol, but not containing hydroxypropylcellulose, and a method for producing a sirolimus-containing granular preparation, characterized by comprising the steps of (1) mixing a solution containing sirolimus and tocopherol with core particles that form the core of the granular preparation in the absence of hydroxypropylcellulose, and (2) drying the mixture obtained in step (1).

Description

Technical Field

[0001] The present invention relates to a sirolimus-containing granule preparation and a method for producing the same.

Background Art

[0002] Sirolimus (also known as rapamycin) is a metabolite of the actinomycete St reptomyces hygroscopicus isolated from the soil of Easter Island, and was discovered as a macrolide antibiotic in the 1970s. Subsequently, sirolimus was found to have an immunosuppressive effect, and in September 1999 in the United States and in March 2001 in Europe, it was approved and used for "prevention of organ rejection in kidney transplant patients". In Japan, it was approved in July 2014 for the efficacy of "lymphangioleiomyomatosis" and is clinically applied as an oral preparation. However, currently known

[0003] oral preparations containing sirolimus as an active ingredient are only tablets. However, for elderly patients in particular, it is desirable to make a

[0004] powder preparation that is easy to take and allows for easy adjustment of the dosage. Here, since sirolimus is poorly soluble in water, simply making it into a

[0005] granule preparation alone makes it difficult to be absorbed by the body after administration, and sufficient drug efficacy cannot be obtained. Tablets and the like have been disclosed. However, in a comparison of absorption using dogs, compared to commercially available tablets, It does not show excellent absorption in stages. Furthermore, the manufacturing method described in the same document involves adding sirolimus. Because this method involves spraying a heated, molten liquid onto particles, it requires special equipment and lacks versatility. It is considered low. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Special table number 2008-532953 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Oral preparations containing sirolimus are used in patients of a wide range of ages, including the elderly, making them easier to take. It is preferable to use it in the form of a granular formulation, which is easy to administer and allows for easy dosage adjustment. However, Sirolimus has extremely poor solubility in water and poor stability (for example, oxidation, etc.). (It is broken down by vibration). Furthermore, if sirolimus is simply made into a granular preparation, it will not be absorbed by the body after administration. It is poorly absorbed and does not provide sufficient therapeutic effect. Therefore, in the design of granular formulations... Therefore, it is necessary to overcome these problems.

[0008] This invention has been made in view of the above circumstances, and relates to the bioabsorption of sirolimus and sirolimus. The objective is to provide a sirolimus-containing granular formulation in which the stability of sirolimus has been improved. That is the case. [Means for solving the problem]

[0009] As a result of diligent research, the present inventors have found that in a sirolimus-containing granular formulation, sirolimus is present in the particles. It contains tocopherol and is widely used as a binder in granular formulations. By not containing hydroxypropylcellulose, the bioabsorption of sirolimus and We discovered that the stability of lorimus is improved in both cases, thus completing the present invention.

[0010] Tocopherol (vitamin E), like ascorbic acid, is known as an antioxidant. It is a compound that is present. In other words, by incorporating tocopherol, the antioxidant effect is Although this was expected, it was completely unknown that it would affect bioabsorption. The antioxidant effect of tocopherol is not particularly superior compared to other antioxidants. In sirolimus-containing granular formulations, tocopherol is particularly superior compared to other antioxidants. It was not at all anticipated that it would also have the effect of improving stability. In addition, in granular formulations Hydroxypropylcellulose, which is commonly used as a binder, is used in sirolimus-containing preparations. It was also not known that it would affect qualitative results. Contrary to these conventional findings, we Tocopherol is incorporated into a granular preparation containing lorimus, and further hydroxypropyl cellulose By creating a dosage form that does not contain sirolimus, the bioavailability of sirolimus is improved, and further safety We have completed this invention by discovering that it is also possible to improve qualitative results.

[0011] In other words, the present invention contains sirolimus and tocopherol in its constituent particles, and hydro This is a sirolimus-containing granular preparation that does not contain xypropylcellulose.

[0012] Furthermore, the present invention relates to (1) a solution containing sirolimus and tocopherol, and the core of a granular formulation. The process involves mixing the core particles in the absence of hydroxypropylcellulose, and (2 ) A step of drying the mixture obtained in step (1), characterized in that it comprises, sirolimus A method for producing a sirolimus-containing granule preparation.

Advantages of the Invention

[0013] According to the present invention, it is possible to provide a sirolimus-containing granule preparation with ensured bioabsorbability and improved stability. It becomes possible to provide.

Brief Description of the Drawings

[0014] [Figure 1] Figure 1 is a diagram showing the change over time of the sirolimus concentration in whole blood in each test subject administered with the sample.

Modes for Carrying Out the Invention

[0015] Hereinafter, embodiments of the present invention will be described in detail.

[0016] One embodiment of the present invention is a sirolimus-containing granule preparation containing sirolimus and tocopherol and not containing hydroxypropyl cellulose. Since the sirolimus-containing granule preparation according to the present invention has the above-described configuration, it has high stability of sirolimus after long-term storage and exhibits excellent effects such as high elution and bioabsorbability of sirolimus after administration.

[0017] In a preferred embodiment, the granule preparation according to the present invention is composed of particles obtained by binding sirolimus and tocopherol to core particles. Here, the state of "binding" includes, for example a state in which both of the binding substances are adjacent and integrated. For example, when sirolimus and / or tocopherol form a granule preparation in a state of contacting or adhering to the particles , it can be said that sirolimus and / or tocopherol are bound to the particles. Also, the particles The shape is preferably approximately spherical. The particle size is such that it can pass through a 1 mm sieve. It is preferable that this be the case.

[0018] In this invention, the term "core particle" refers to each particle constituting the granular formulation according to the present invention. This refers to the particle located near the center of the particle, which acts as the nucleus. In this invention, the core particle has the property of disintegrating in the mouth. Preferably, the particles contain sirolimus and / or tocopherol used during manufacturing. In a solution containing ferrols, the solvent is insoluble or practically insoluble. It is preferable to use particles. Specifically, when the solvent is ethanol, sucrose and / or Particles with mannitol as the main component can be used. The main component of the core particles is as described above. While not particularly limited as long as the conditions are met, mannitol is used as preferred. This is possible. Furthermore, the shape of the core particles is not particularly limited, but substantially spherical particles are preferred. It can be used as such. The closer the particle shape is to spherical, the more sirolimus and tocopherols are present. This allows for uniform bonding of the material, resulting in stable quality.

[0019] In one embodiment of the present invention, the tocopherol content in the granular formulation is relative to sirolimus. It is preferable that the mass ratio is equal to or greater than 1:1 and at least 0.2% by mass of the total granular formulation. The upper limit is This can be set as the permissible upper limit for oral administration formulations, for example, sirolimus containing 0.2% by mass. In the case of a granular formulation containing sirolimus, if the maximum daily usage is set at 2g, the quality of sirolimus This can be approximately 2.5 times the amount, or 0.5% by mass of the entire granular formulation.

[0020] In one embodiment of the present invention, the content of sirolimus in the granular formulation is an effective amount of sirolimus. The amount should be in a volume that is easy to handle for administration, and is not particularly limited. Usually, 0 It can be used by adjusting as appropriate within the range of 0.05 to 1.0% by weight. Here, "effective amount "A manageable volume for taking sirolimus" means a volume that is appropriate for taking the medication. This means that if the sirolimus content in the granular preparation is too high, the granular preparation The overall volume of the drug decreases, while if the sirolimus content in the granular formulation is too low, The overall volume of the granular preparation increases, making it difficult to take.

[0021] In one embodiment of the present invention, the granular formulation does not impair the effects or performance of the granular formulation according to the present invention. Unless otherwise specified, it may contain pharmaceutically acceptable additives.

[0022] Another embodiment of the present invention is (1) a solution and granules containing sirolimus and tocopherol. A process of mixing core particles that form the core of a granular formulation in the absence of hydroxypropylcellulose. This is a method for producing a sirolimus-containing granular preparation, characterized by containing the following: For example, step (2) may include a step of drying the mixture obtained in step (1). Using this manufacturing method, core particles formed by binding sirolimus and tocopherol are placed in the center of each particle. This allows for the production of granular formulations that do not contain hydroxypropylcellulose.

[0023] In the above manufacturing method, the solvent of the solution containing sirolimus and tocopherol is sirolimus. The solvent is not particularly limited as long as it can dissolve limus and tocopherol. The solvent can be, for example, ethanol, acetone, propanol, etc., and preferably Ethanol can be used.

[0024] The tocopherol and sirolimus content of the granular formulation obtained by the above manufacturing method, and the core particle content The embodiments, such as shape and type, are the same as those in the granular formulations described above. For example, In a solution containing sirolimus and tocopherol, the tocopherol content is equal to the sirolimus content. The mass ratio to the s can be equal to or greater than 1 to 2.5 times. The particles can be particles mainly composed of sucrose and / or mannitol. The particles can be approximately spherical in shape.

[0025] The above manufacturing method involves, for example, mixing sirolimus with the above solvent to prepare a sirolimus solution. The process involves dissolving tocopherol in the sirolimus solution, and then dissolving the obtained sirolimus and tocopherol. A step of adding a solution containing copherol to the particulate component, sirolimus and tocopherol The process includes drying a mixture with particulate components to prepare a solid, and sieving the solid. You can stay like that.

[0026] In one embodiment of the present invention, tocopherol is α-, β-, γ-, or δ-tocopherol. Includes rolls.

[0027] The embodiments of the present invention have been described above, but these are merely examples of the present invention, and other embodiments are also possible. Various configurations can be adopted. Furthermore, combinations of embodiments can also be used. ru. [Examples]

[0028] The present invention will be described below with reference to specific embodiments, but the present invention is not limited to these embodiments. These are not intended to be modified, and various changes and modifications therein may be made by those skilled in the art, as per the attached patent application. It may be carried out without departing from the scope or spirit of the present invention as defined in the scope of the request. It will be understood.

[0029] Test Example 1: Examination of differences in stability due to various additives (1) Sample For 100g of sirolimus ethanol solution (1% by mass), add each additive (polyoxyethylene) Green hydrogenated castor oil (manufactured by Nikko Chemicals Co., Ltd., NIKKOL® HCO-6) 0), Poloxamer 188 (manufactured by BASF Japan Ltd., Kolliphor (registered trademark) (Standard) 188), Hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., HPC-SL ), tocopherol (manufactured by BASF Japan Ltd., DL-ALPHA-Tocopherol) The amount of rol)) listed in Table 1 was added and dissolved. This solution was stirred in a mixer. Then, the amount of mannitol listed in Table 1 was added. This was then transferred to a fluidized bed dryer and heated to the temperature of the supply. The material was dried at 70°C until the loss on drying was 0.4% or less. The resulting solid was then placed in a mesh opening of 1 The samples were separated using a mm sieve to obtain each granular formulation sample.

[0030] [Table 1] *Anhydrous ethanol is removed by drying and is therefore not included in the total mass.

[0031] (2) Test method Weigh 30g of each sample prepared in (1) above and transfer it to a glass bottle, plus The containers were sealed with plastic stoppers. Each sample was placed in a stability tester and kept at 40°C and 75% RH. It existed.

[0032] At the start of the test, after 2 weeks of storage, and after 7 weeks of storage, the following conditions were met: By HPLC, the sirolimus content (residual amount) (%) and the degradation product, secoshi, were determined. The lorimus content (%) was quantified.

[0033] (HPLC conditions) Detector: UV absorbance spectrophotometer (measurement wavelength: 280 nm) Column: A 5μm liquid chromatograph in a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm. Packed with octadecylsilylated silica gel for use in Column temperature: Constant temperature around 40°C Mobile phase: Add water to 6 mL of acetic acid (100) to make 1000 mL, then add triethylamine. Add to adjust the pH to 3.6. Add 600 mL of 1,4-dioxane to 400 mL of this solution. Add and mix. Flow rate: The shortest retention time among the sirolimus isomer peaks on the chromatogram. Adjust so that the holding time for the item is approximately 15 minutes.

[0034] (3) Results The stability measurement results are shown in Table 2. Sample 1 (no additives) and Sample 2 (polyoxyethylene) In the case of (containing hydrogenated castor oil), the sirolimus content rapidly decreases with the passage of storage time. This indicates that sufficient sirolimus stability cannot be obtained. Samples 1 and 2 In the preserved samples, secorsirolimus was not detected, but the sirolimus content was Because it was decreasing rapidly, although secorsirolimus was produced by decomposition, further division As the solution progressed, it was determined that the substance was no longer detected.

[0035] Sample 3 (containing poloxamer 188), Sample 4 (containing hydroxypropyl cellulose), and And sample 6 (containing polyoxyethylene hydrogenated castor oil and hydroxypropyl cellulose) Although it showed a greater inhibitory effect on degradation than samples 1 and 2, after 7 weeks of storage, sample 3 showed odor A decrease in content of 15% or more was confirmed, and in samples 4 and 6, a decrease of 6% or more in seco The occurrence of sirolimus was confirmed, and it was determined that the stability-enhancing effect was insufficient.

[0036] On the other hand, in sample 5 (containing tocopherol), the decrease in sirolimus content was suppressed. In addition, it was confirmed that the production of secorsirolimus was also effectively suppressed.

[0037] [Table 2]

[0038] Test Example 2: Examination of differences in elution and stability with various additives (1) Sample For 100g of sirolimus ethanol solution (1% by mass), add each additive (hydroxypropyl The amounts of pyrucellulose, tocopherol, and ascorbic acid listed in Table 3 were dissolved. This liquid was added to the amount of mannitol listed in Table 1 while stirring in a mixer. Then, it was transferred to a fluidized bed dryer and dried at an air supply temperature of 70°C until the drying loss was 0.4% or less. The obtained solid material was sieved using a sieve with a mesh size of 1 mm to obtain each granular formulation sample.

[0039] Furthermore, regarding dissolution properties, commercially available sirolimus tablets (rapalimus (registered)) were used as a comparison. Experiments were also conducted using (trademark) tablets (manufactured by Nobel Pharma Co., Ltd.).

[0040] [Table 3] *Anhydrous ethanol is removed by drying and is therefore not included in the total mass.

[0041] (2) Dissolution Test method: The paddle method (solvent: water, test solution volume: 900 mL, rotation speed: 100 rpm) was used. Ta. Results: The results of the dissolution measurement are shown in Table 4. Sample 9 (granular formulation without tocopherol) In all granular formulations except for this one, dissolution is compared to sirolimus tablets (tablets in Table 4). It was confirmed that the quality had improved.

[0042] [Table 4]

[0043] (3) Stability Test method: Weigh 30g of each sample prepared in (1) above and transfer it to an aluminum bag. And, an oxygen absorber (PharmaKeep® KD-20, manufactured by Mitsubishi Gas Chemical Company, Inc.) The samples were packaged and sealed by heat sealing. Each sample was placed in a stability tester at 40°C for 7 It was stored under conditions of 5% RH.

[0044] At the start of the test, after 2 weeks of storage, and after 4 weeks of storage, the same procedure as in Test Example 1 was followed. By HPLC under these conditions, the sirolimus content (residual amount) (%) and the major degradation products were determined. The secosirolimus content (%) was quantified. Furthermore, for sample 10, after 8 weeks, For samples 9 and 12, data was also obtained after 8 weeks and 3 months.

[0045] Results: The results of the stability tests are shown in Table 5. Samples 7, 8, 10, and 11 (Hydroxypropylcellulose is mixed with tocopherol and / or ascorbic acid) In the combined granules, compared to sample 9 (without additives), the sirolimus content increased over time during storage. A significant decrease in quantity was confirmed. Also, in samples 7, 8, 10, and 11 Therefore, compared to sample 9, the amount of secorsirolimus produced over time during storage was also higher. Confirmed. Therefore, these formulations cannot improve the stability of sirolimus. It was confirmed that this was the case.

[0046] On the other hand, in sample 12 (granules containing tocopherol), compared to sample 9, the amount of white syrup was also low. The decrease in mucus content is suppressed, and the amount of secorsirolimus produced is less than 0.5%. The occurrence of secorsirolimus was sufficiently suppressed, similar to sample 9.

[0047] Based on these results, tocopherol was added to the granular formulation, and hydroxypropyl cellulose was used. It has been confirmed that the stability of sirolimus can be improved by using a dosage form that does not contain serochloride. It was done.

[0048] [Table 5]

[0049] Test Example 3: Examination of differences in dissolution and stability depending on the amount of tocopherol used. (1) Sample The same method as in Test Example 1 was used, except that tocopherol was added as an additive in the amount shown in Table 6. Each granular sample was prepared using the following method.

[0050] [Table 6] *Anhydrous ethanol is removed by drying and is therefore not included in the total mass.

[0051] (2) Test method Weigh 30g of each sample prepared in (1) above, transfer it to a glass bottle, and stopper it. It was placed in a stability tester. It was stored under conditions of 30°C and 75% RH.

[0052] At the start of the test, after 2 weeks of storage, after 4 weeks of storage, and after 8 weeks of storage, The sirolimus content (remaining amount) (%) was determined by HPLC under the same conditions as in Test Example 1, and The secosirolimus content (%) was quantified (however, for sample 15, after 4 weeks) At that point, the secorsilolimus content exceeded 1%, so quantitative analysis was not performed after 8 weeks. ).

[0053] Furthermore, the elution properties of the sample at the start of the test were confirmed using the same method as in Test Example 2.

[0054] (3) Results The quantitative results for sirolimus content and secorsirolimus content are shown in Table 7. Furthermore, in samples with a tocopherol content of 0.2% by mass or more (Sample 13, Sample 14), sirolim The sulfate content is reduced and the formation of secorsirolimus is suppressed, demonstrating sufficient stability. This was confirmed. From these results, it was determined that a granular formulation containing 0.2% by mass of sirolimus has odor Therefore, if the tocopherol content is at least 0.2% by mass, the stability will be sufficiently improved. It was confirmed to be effective.

[0055] [Table 7]

[0056] The results of the dissolution measurement are shown in Table 8. As shown in this table, at least tocopherol 0 For samples containing 0.2% by mass or more (Sample 13, Sample 14), it was confirmed that they possessed sufficient elution properties. It was acknowledged. [Table 8]

[0057] Based on these results, the amount of tocopherol should be at least equal to or greater than that of sirolimus. It was confirmed that stability can be improved while maintaining dissolution properties.

[0058] Test Example 4: Examination of Bioabsorption (1) Sample Using the same method as in Test Example 1, 1g contains 2mg of sirolimus and 2mg of tocopherol. A granular formulation was prepared (same composition as sample 14; designated as sample 16).

[0059] For comparison, commercially available sirolimus-containing tablets (Rapalimus® Tablets 1mg, No The product used was manufactured by Bellpharma Co., Ltd. (hereinafter referred to as the "control formulation").

[0060] (2) Test method Ten healthy adults aged 20-39 were divided into two groups of five, and each group received 16 samples (granular). The preparation consists of 1.0g (2mg as sirolimus) and 2 tablets of the control preparation (2mg as sirolimus). The sample was administered orally with 150 mL of water. The sample administration period for each subject was 10 hours. This was done after fasting.

[0061] 1 hour before administration, 30 minutes after administration, 1 hour, 1 hour 30 minutes, 2 hours, 4 hours, 8 hours, 12 hours after administration Blood samples were taken at 1 hour, 18 hours, 24 hours, 48 ​​hours, and 72 hours. The obtained blood samples were... For each pull sample, analysis was performed using LC-MS / MS under the following conditions, and the sirolimus concentration in whole blood was determined. The degree was measured.

[0062] LC conditions Column: ZORBAX(registered trademark) XDB-CN (inner diameter 2.1mm, length 50mm) Agilent Technologies, Inc. Column temperature: 50℃ Mobile phase: 0.1% aqueous acetic acid solution and 0.1% acetonitrile acetate solution in the proportions shown in Table 9. mixture Flow rate: 0.45mL / min

[0063] [Table 9]

[0064] ·MS / MS conditions Measurement mode: Positive ESI Gas temperature: 350℃ Gas flow rate: 10 L / min Nebulizer pressure: 50 psi Capillary voltage: 4000V

[0065] (3) Results The results are shown in Figure 1. As shown in this figure, sample 16 showed a blood saturation level compared to the control formulation. The sirolimus concentration was significantly higher. From this result, it was determined that the core particles contained sirolimus and To create a granular formulation that contains copherol and does not contain hydroxypropylcellulose. This demonstrated that the bioabsorption of sirolimus can be improved. [Industrial applicability]

[0066] The sirolimus-containing granule formulation of the present invention is, for example, used for the treatment of lymphangioleiomyomatosis or mTOR(m Uses such as the inhibition of the ammalian target of rapamycin It is usable.

Claims

1. The constituent particles contain sirolimus and tocopherol, and hydroxypropylcellulose A sirolimus-containing granule preparation that is easy to take and does not contain syrup.

2. A decrease in sirolimus content of 10% or less, measured by HPLC, after 7 weeks to 3 months of storage. The sirolimus-containing granular preparation according to claim 1.

3. Claim that the tocopherol content is equal to or greater than the mass ratio of sirolimus. A sirolimus-containing granular preparation as described in 1 or 2.

4. The tocopherol content is 0.2% by mass or more of the total granular formulation, according to claims 1 to 3. A sirolimus-containing granular preparation as described in item one.

5. Each particle constituting the granular formulation has a core particle at its center, according to claims 1 to 4. A sirolimus-containing granular preparation as described in any one of the items.

6. In each particle constituting the granular formulation, sirolimus and tocopherol are bound to the core particle. The sirolimus-containing granular preparation according to claim 5.

7. The core particles are particles mainly composed of sucrose and / or mannitol, as described in claim 5. A granular preparation containing sirolimus.

8. The sirolimus-containing material according to any one of claims 5 to 7, wherein the core particles are substantially spherical particles. Granular formulation.

9. (1) A solution containing sirolimus and tocopherol, and core particles that form the core of the granular formulation. A step of mixing the two in the absence of hydroxypropylcellulose, and (2) A step of drying the mixture obtained in step (1), A method for producing an easy-to-administer sirolimus-containing granular preparation, characterized by containing the following:

10. Sirolimus-containing granule preparations can be tested for sirolimus by HPLC after 7 weeks to 3 months of storage. The manufacturing method according to claim 9, wherein the decrease in musu content is within 10%.

11. The solvent in the solution containing sirolimus and tocopherol is ethanol, claim The manufacturing method described in item 9 or 10.

12. The tocopherol content in a solution containing sirolimus and tocopherol is The mass ratio to rims is equal to or greater than the amount described in any one of claims 9 to 11. Manufacturing method.

13. Claims 9 to 12, wherein the tocopherol content is 0.2% by mass or more of the total granular formulation. The manufacturing method described in any one of the items.

14. Claims 9-1, the core particles are particles mainly composed of sucrose and / or mannitol. The manufacturing method described in any one of item 3.

15. The manufacturing method according to any one of claims 9 to 14, wherein the core particles are substantially spherical particles.

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