ORAL PHARMACEUTICAL COMPOSITION AND METHOD FOR PRODUCING PARTICULATE FORMULATION COMPRISING COMPOSITION

Abstract

Provided is an oral pharmaceutical composition characterized by containing a medicinal ingredient (A), a hydrophobic liquid (B), a water-soluble macromolecular substance (C), and an excipient (D), but not containing a surfactant, wherein: the medicinal ingredient (A) is included in the hydrophobic liquid (B); and the hydrophobic liquid (B) is dispersed in a composition including the water-soluble macromolecular substance (C) and the excipient (D). The oral pharmaceutical composition: allows easy dose-adjustment; has excellent dosability and safety; is biologically equivalent to a standard formulation having established profiles regarding efficacy, safety, etc.; and can be easily produced.

Claims

1. An oral pharmaceutical composition not containing surfactant comprising: 0.1 to 20 parts by mass of an active ingredient (A); 1 to 100 parts by mass of a hydrophobic liquid (B); 100 parts by mass of a water-soluble polymer substance (C); and 1 to 300 parts by mass of an excipient (D), wherein the active ingredient (A) is incorporated in the hydrophobic liquid (B), and this hydrophobic liquid (B) is dispersed in a composition comprising the water-soluble polymer substance (C) and the excipient (D).

2. The oral pharmaceutical composition according to claim 1, wherein the active ingredient (A) is a drug subject to Therapeutic Drug Monitoring (TDM) or an anti-cancer drug.

3. The oral pharmaceutical composition according to claim 2, wherein the active ingredient (A) is one or two or more usable in combination of drugs subject to TDM selected from digoxin, theophylline, procainamide, N-acetylprocainamide, aprindine, disopyramide, lidocaine, pilsicainide, propafenone, mexiletine, flecainide, quinidine, cibenzoline succinate, amiodarone, pirmenol, bepridil, phenobarbital, nitrazepam, primidone, diazepam, phenytoin, carbamazepine, zonisamide, ethosuximide, acetazolamide, clobazam, sodium valproate, trimethadione, clonazepam, sultiame, gabapentin, levetiracetam, topiramate, lamotrigine, gentamicin, amikacin, tobramycin, arbekacin, vancomycin, teicoplanin, voriconazole, cyclosporine, tacrolimus, everolimus, mycophenolate mofetil, salicylic acid, methotrexate, haloperidol, bromperidol, lithium carbonate and imatinib, or one or two or more usable in combination of anti-cancer drugs selected from cyclophosphamide, ifosfamide, melphalan, busulfan, thiotepa, nimustine, ranimustine, dacarbazine, procarbazine, temozolomide, carmustine, streptozocin, bendamustine, cisplatin, carboplatin, oxaliplatin, nedaplatin, fluorouracil, cytarabine, gemcitabine, irinotecan, nogitecan, doxorubicin, etoposide, vinblastine, vincristine, vindesine, vinorelbine, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, gefitinib, erlotinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nintedanib, nilotinib, crizotinib, alectinib, ruxolitinib, tofacitinib, sorafenib, vemurafenib, bortezomib, sirolimus and temsirolimus.

4. The oral pharmaceutical composition according to any one of claims 1 to 3, wherein the hydrophobic liquid (B) is one or two or more selected from propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol monooleate, benzyl benzoate, octyl decyl triglyceride, oleic acid, triethyl citrate, dimethyl polysiloxane, cinnamaldehyde, medium chain mono-diglyceride, medium chain fatty acid triglyceride, triacetin, piperonyl butoxide, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, octyl dodecyl myristate and ethyl butyrate.

5. The oral pharmaceutical composition according to any one of claims 1 to 4, wherein the water-soluble polymer substance (C) is one or two or more selected from gelatin, carrageenan, xanthan gum, locust bean gum and agar.

6. The oral pharmaceutical composition according to any one of claims 1 to 5, wherein the excipient (D) is one or two or more selected from isomalt, erythritol, xylitol, glycerin, sorbitol, maltitol, mannitol, lactitol, reduced palatinose, reduced sugar syrup and powdered reduced maltose syrup.

7. An oral pharmaceutical composition not containing surfactant comprising: 0.00001 parts by mass or more and less than 0.1 parts by mass of an active ingredient (A); 1 to 100 parts by mass of a hydrophobic liquid (B); 100 parts by mass of a water-soluble polymer substance (C); and 1 to 300 parts by mass of an excipient (D), wherein the active ingredient (A) is incorporated in the hydrophobic liquid (B), and this hydrophobic liquid (B) is dispersed in a composition comprising the water-soluble polymer substance (C) and the excipient (D).

8. A method for producing a particulate formulation in powdery or granular form consisting of the oral pharmaceutical composition according to any one of claims 1 to 6, the method comprising: preparing a water-soluble polymer aqueous solution by dissolving 100 parts by mass of the water-soluble polymer substance (C) and 1 to 300 parts by mass of the excipient (D) in water and preparing an active ingredient solution by dissolving or dispersing 0.1 to 20 parts by mass of the active ingredient (A) in 1 to 100 parts by mass of the hydrophobic liquid (B); obtaining a mixed aqueous solution where the hydrophobic liquid (B) comprising the active ingredient (A) is dispersed in said water-soluble polymer aqueous solution by mixing this active ingredient solution into the water-soluble polymer aqueous solution; and shaping this mixed aqueous solution into particles in powdery or granular form by adding dropwise, spraying or discharging the mixed aqueous solution in a cooling medium having no compatibility with said aqueous solution or in the air followed by drying the particles such that their water content is 1 to 20 mass %.

9. The method for producing a particulate formulation in powdery or granular form according to claim 8, wherein the mixed aqueous solution is made into granules with a particle diameter of 0.5 to 10 mm by adding the mixed aqueous solution dropwise in a cooling medium having no compatibility with said aqueous solution followed by shaping.

10. A method for producing a particulate formulation in powdery or granular form consisting of the oral pharmaceutical composition according to claim 7, the method comprising: preparing a water-soluble polymer aqueous solution by dissolving 100 parts by mass of the water-soluble polymer substance (C) and 1 to 300 parts by mass of the excipient (D) in water and preparing an active ingredient solution by dissolving or dispersing 0.00001 parts by mass or more and less than 0.1 parts by mass of the active ingredient (A) in 1 to 100 parts by mass of the hydrophobic liquid (B); obtaining a mixed aqueous solution where the hydrophobic liquid (B) comprising the active ingredient (A) is dispersed in said water-soluble polymer aqueous solution by mixing this active ingredient solution into the water-soluble polymer aqueous solution; and shaping this mixed aqueous solution into particles in powdery or granular form by adding dropwise, spraying or discharging the mixed aqueous solution in a cooling medium having no compatibility with said aqueous solution or in the air followed by drying the particles such that their water content is 1 to 20 mass %.

11. The method for producing a particulate formulation in powdery or granular form according to claim 10, wherein the mixed aqueous solution is made into granules with a particle diameter of 0.5 to 10 mm by adding the mixed aqueous solution dropwise in a cooling medium having no compatibility with said aqueous solution followed by shaping.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0046] FIG. 1 is a micrograph showing the mixed liquid prepared in Example 8.

[0047] FIG. 2 is a micrograph showing the mixed liquid prepared in Example 11A.

[0048] FIG. 3 is a micrograph showing the mixed liquid prepared in Comparative Example 1A.

[0049] FIG. 4 is a micrograph showing the mixed liquid prepared in Comparative Example 7.

[0050] FIG. 5 is a graph showing the results of the dissolution test with a test liquid of pH 1.2.

[0051] FIG. 6 is a graph showing the results of the dissolution test with a test liquid of pH 5.0.

[0052] FIG. 7 is a graph showing the results of the dissolution test with a test liquid of pH 6.8.

[0053] FIG. 8 is a graph showing the results of the dissolution test with water.

DESCRIPTION OF EMBODIMENTS

[0054] The present invention is more specifically described below.

[0055] As described above, the oral pharmaceutical composition of the present invention contains 0.1 to 20 parts by mass of an active ingredient (A), 1 to 100 parts by mass of a hydrophobic liquid (B), 100 parts by mass of a water-soluble polymer substance (C) and 1 to 300 parts by mass of an excipient (D), and contains no surfactant, and is a dispersion of the hydrophobic liquid (B) containing the above active ingredient (A) in the composition containing the above water-soluble polymer substance (C) and the excipient (D).

[0056] There are no particular limitations to the above active ingredient (A) and any drug can be used as long as they are orally-administrable, but it is suitably applicable especially to drugs subject to Therapeutic Drug Monitoring (TDM) and anti-cancer drugs as described above. In this case, there are no particular limitations, but examples of drugs subject to TDM include digoxin, theophylline, procainamide, N-acetylprocainamide, aprindine, disopyramide, lidocaine, pilsicainide, propafenone, mexiletine, flecainide, quinidine, cibenzoline succinate, amiodarone, pirmenol, bepridil, phenobarbital, nitrazepam, primidone, diazepam, phenytoin, carbamazepine, zonisamide, ethosuximide, acetazolamide, clobazam, sodium valproate, trimethadione, clonazepam, sultiame, gabapentin, levetiracetam, topiramate, lamotrigine, gentamicin, amikacin, tobramycin, arbekacin, vancomycin, teicoplanin, voriconazole, cyclosporine, tacrolimus, everolimus, mycophenolate mofetil, salicylic acid, methotrexate, haloperidol, bromperidol, lithium carbonate, imatinib and the like, and one or two or more usable in combination thereof can be used.

[0057] Moreover, examples of anti-cancer drugs include cyclophosphamide, ifosfamide, melphalan, busulfan, thiotepa, nimustine, ranimustine, dacarbazine, procarbazine, temozolomide, carmustine, streptozocin, bendamustine, cisplatin, carboplatin, oxaliplatin, nedaplatin, fluorouracil, cytarabine, gemcitabine, irinotecan, nogitecan, doxorubicin, etoposide, vinblastine, vincristine, vindesine, vinorelbine, mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, gefitinib, erlotinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nintedanib, nilotinib, crizotinib, alectinib, ruxolitinib, tofacitinib, sorafenib, vemurafenib, bortezomib, sirolimus, temsirolimus and the like, and one or two or more usable in combination thereof can be used.

[0058] It is preferable that an amount of this active ingredient (A) to be blended is 0.1 to 20 parts by mass based on 100 parts by mass of the water-soluble polymer substance (C) as described above, more preferably 0.5 to 10 parts by mass, and further preferably 1 to 5 parts by mass. It depends on kind of active ingredient (A), but when the amount of the active ingredient (A) to be blended is less than 0.1 parts by mass, obtaining a sufficient therapeutic effect by adequate dose administering becomes difficult, and it may be less usable as a pharmaceutical. On the other hand, when it exceeds 20 parts by mass, it depends on solubility of the active ingredient (A) to the hydrophobic liquid (B), but the amount of the hydrophobic liquid (B) to be blended increases and formability of the composition decreases, which may cause inconveniences such as, for example, that it may become difficult to shape the composition into a particulate form.

[0059] However, for example, there are no particular limitations, but all vitamins such as alfacalcidol, eldecalcitol, calcitriol and falecalcitriol, clenbuterol hydrochloride, desmopressin acetate hydrate, nalfurafine hydrochloride, fentanyl citrate, beraprost sodium, pergolide mesylate, misoprostol, iodine lecithin, ramosetron hydrochloride, limaprost alfadex, lubiprostone and the like may also be made into formulations of low dosage with a very low content, and in the case of such active ingredients, the amount of the active ingredient to be blended can be less than 0.1 parts by mass, concretely 0.00001 parts by mass or more and less than 0.1 parts by mass, and particularly can be 0.001 parts by mass or more and less than 0.1 parts by mass.

[0060] The above hydrophobic liquid (B) is a hydrophobic liquid that can dissolve or disperse well the above active ingredient (A) and is not a surfactant. In this case, the hydrophobicity of this hydrophobic liquid (B) should disperse as liquid particles containing the active ingredient (A), without dissolving into the water-based composition containing the water-soluble polymer substance (C) and the excipient (D) described below. More specifically, if it is, for example, a liquid at 20 C. and its solubility in water at 20 C. is 10 mass % or less, it can be used as the above hydrophobic liquid (B). When this hydrophobicity is insufficient, it becomes difficult to remain dispersed in the composition while containing the above active ingredient (A), and all or much of the active ingredient (A) becomes contained in the composition as crystals, which makes it impossible to achieve the purpose of the present invention.

[0061] Specifically, examples of this hydrophobic liquid (B) include propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol monooleate, benzyl benzoate, octyl decyl triglyceride, oleic acid, triethyl citrate, dimethyl polysiloxane, cinnamaldehyde, medium chain mono-diglyceride, medium chain fatty acid triglyceride, triacetin, piperonyl butoxide, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, octyl dodecyl myristate, ethyl butyrate and the like, and one or two or more thereof can be suitably used.

[0062] An amount of this hydrophobic liquid (B) to be blended is 1 to 100 parts by mass based on 100 parts by mass of the water-soluble polymer substance (C) as described above, preferably 1 to 50 parts by mass, and more preferably 10 to 30 parts by mass. When the amount of hydrophobic liquid (B) to be blended is less than 1 part by mass, it depends on the amount of the above active ingredient (A) to be blended, but the active ingredient cannot be contained satisfactorily in this hydrophobic liquid (B). As a result much of the active ingredient becomes present directly in the composition, and when it becomes this way, the dissolution properties of the active ingredient decrease. On the other hand, when it exceeds 100 parts by mass, the formability of the composition decreases as described above, and for example, it becomes difficult to shape the composition into a particulate form.

[0063] The above water-soluble polymer substance (C) which serves as base for the oral pharmaceutical composition of the present invention with the above excipient (D) should be able to serve this role and should be selected and be used appropriately. Specifically, there are no particular limitations, but examples include gelatin, carrageenan, xanthan gum, locust bean gum, agar and the like, and one or two or more thereof can be used.

[0064] Moreover, the above excipient (D) can be selected and used appropriately from publicly known materials, and is not particularly limited, but examples include isomalt, erythritol, xylitol, glycerin, sorbitol, maltitol, mannitol, lactitol, reduced palatinose, reduced sugar syrup, powdered reduced maltose syrup and the like, and one or two or more thereof can be used.

[0065] An amount of this excipient (D) to be blended is 1 to 300 parts by mass based on 100 parts by mass of the above water-soluble polymer substance (C), preferably 50 to 200 parts by mass, and more preferably 100 to 170 parts by mass, and should be set appropriately in this range depending on form of the oral pharmaceutical composition and type of the excipient. When the amount to be blended is less than 1 part by mass, inconveniences may occur, such as the formability decreasing, which, for example, makes satisfactorily shaping particles difficult, and low dissolution properties, which may cause not to sufficiently obtain therapeutic effect of the active ingredient (A). On the other hand, when it exceeds 300 parts by mass, fluidity when shaping the composition decreases, the preparation of the composition becomes difficult, or shaping the composition into the desired form becomes difficult depending on shaping method and dosage form.

[0066] For example, when making the oral pharmaceutical composition of the present invention into a particulate formulation in powdery or granular form, no other additives are particularly needed, and it is a particulate formulation typically consisting of the above four components (A) to (D) and water. However, it may be blended with known additives within a range not deviating from the purpose of the present invention depending on dosage form. For example, sweeteners, coloring agents, preservatives, lubricants, thickeners, stabilizers, antioxidants, bleaching agents, flavoring agents, acidulants, seasonings, pH adjusters, and all other agents for production can be blended in appropriate amounts.

[0067] Here, the oral pharmaceutical composition of the present invention is characterized in that it contains no surfactant. In this case, containing no surfactant in the present invention refers to

(1) when no component having a surfactant action is contained in the oral pharmaceutical composition at all, and,
(2) when, even if the oral pharmaceutical composition contains a component having a surfactant action, its amount is less than an amount significantly changing the dispersion state of the hydrophobic liquid (B) in the water-based composition containing the water-soluble polymer substance (C) and the excipient (D).

[0068] The amount significantly changing the dispersion state of the hydrophobic liquid in the above (2) refers, for example, to the amount which changes by 20% or more the maximum diameter of the liquid particles of the hydrophobic liquid (B) compared to when this component is not added, when observing with a microscope the maximum diameter of the liquid particles of the hydrophobic liquid (B) in the mixed aqueous solution prepared by the method described below. Namely, containing no surfactant means that it is acceptable that components having a surfactant action is contained in the oral pharmaceutical composition of the present invention, if it is an amount not significantly changing the dispersion state in the mixed aqueous solution of the hydrophobic liquid (B). In other words, in the present invention, even when containing components having a surfactant action, if its amount is less than the amount necessary to exhibit a substantial surfactant action, such component is not considered as a surfactant.

[0069] More specifically, there are no particular limitations, but if adding pharmaceutical additives the application of which is indicated as surfactant in the Japanese Pharmaceutical Excipients Directory 2016 (Yakuji Nippo, Limited) in effective amounts as surfactant, they fall into category of surfactant in the present invention. This is the case when adding in effective amounts, for example, caprylocaproyl polyoxy glyceride, cholesterol, sucrose fatty acid ester, stearyl alcohol, polyoxyl 40 stearate, cetanol, sorbitan fatty acid ester, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene hardened castor oil 60, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyl 35 castor oil, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monolaurate, sodium lauryl sulfate, lauromacrogol and the like.

[0070] As described above, the oral pharmaceutical composition of the present invention is prepared so that the hydrophobic liquid (B) containing the above active ingredient (A) be dispersed in the composition containing the above water-soluble polymer substance (C) and the excipient (D). There are no limitations to a preparation method of the oral pharmaceutical composition of the present invention, however for example, it is preferable to make a particulate formulation in powdery or granular form by the following method. And according to this method, the particulate formulation in granular form with a particle diameter of 0.5 to 10 mm, in which the dose adjustment is easy and the ingestibility is high, and that is suitable for drugs subject to TDM and anti-cancer drugs, can be produced easily.

[0071] Namely, first, a water-soluble polymer aqueous solution is prepared by dissolving 100 parts by mass of the above water-soluble polymer substance (C) and 1 to 300 parts by mass of the excipient (D) in water and an active ingredient solution is prepared by dissolving or dispersing 0.1 to 20 parts by mass of the active ingredient (A) in 1 to 100 parts by mass of the above hydrophobic liquid (B). Then, this active ingredient solution is mixed with the above water-soluble polymer aqueous solution, and a mixed aqueous solution where the above hydrophobic liquid (B) containing the above active ingredient (A) is dispersed in the water-soluble polymer aqueous solution is obtained. This mixed aqueous solution is shaped into particles in powdery or granular form by adding dropwise, spraying or discharging the mixed aqueous solution in a cooling medium having no compatibility with the aqueous solution or in the air, and then dried shaped particles thus obtained such that their water content becomes 1 to 20 mass %. This method allows a particulate formulation in powdery or granular form consisting of the above oral pharmaceutical composition of the present invention to be obtained. However, if making it a low dosage formulation as described above, the amount of the above active ingredient (A) to be blended can be 0.00001 parts by mass or more and less than 0.1 parts by mass.

[0072] In this production method, by adopting a shaping method that adds dropwise the above mixed aqueous solution in the cooling medium having no compatibility with the aqueous solution, the mixed aqueous solution can easily be made into granules with a particle diameter of 0.5 to 10 mm, preferably 1 to 5 mm and more preferably 2 to 4 mm. As a result, the particulate formulation in which the dose adjustment is easy and the ingestibility is high, and that is suitable for drugs subject to TDM and anti-cancer drugs can easily be obtained.

EXAMPLES

[0073] The present invention is shown more specifically below, by showing Examples and Comparative Examples, but the present invention is not limited to the following examples.

Example 1

[0074] A gelatin aqueous solution (water-soluble polymer aqueous solution) was obtained by adding 2.496 g of gelatin and 2.496 g of lactitol to 7.738 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the lactitol. On the other hand, an active ingredient solution was obtained by adding 0.022 g of sirolimus to 2.247 g of diethyl phthalate, then heating an obtained mixture at 55 to 65 C. to dissolve the sirolimus. A mixed liquid (mixed aqueous solution) was obtained by adding gradually the active ingredient solution into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C. In this mixed liquid, the droplets of diethyl phthalate where sirolimus was completely dissolved were uniformly dispersed in the gelatin aqueous solution.

[0075] The above mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., then solidified into granules and recovered after 5 min. The total mass of the recovered undried particles was 13.5 g. A particulate formulation of an oral pharmaceutical composition was obtained by air drying these undried particles at 10 to 20 C. (relative humidity 20 to 40%) for 16 h. There, the total mass decreased by 5.21 g, which corresponds to 38.6 mass %, due to the above drying treatment, to become 8.29 g. The loss on drying of this particulate formulation was 12.0%, the mass per particle was 20.1 mg on average (water content: about 13.0 mass %), and the particle diameter was 2.6 to 3.3 mm.

Example 2

[0076] 0.011 g of xanthan gum and 0.011 g of locust bean gum were added to 8.672 g of purified water, then heated at 75 to 80 C. to dissolve the xanthan gum and the locust bean gum, and an obtained mixture was allowed to cool at room temperature for 2 h. The gelatin aqueous solution was obtained by adding 2.168 g of gelatin and 2.168 g of lactitol to this aqueous solution, then heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the lactitol. On the other hand, the active ingredient solution was obtained by adding 0.020 g of sirolimus to 1.951 g of propylene glycol monocaprylate, then heating an obtained mixture at 55 to 65 C. to dissolve the sirolimus. The mixed liquid was obtained by adding gradually the active ingredient solution into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C. In this mixed liquid, the droplets of propylene glycol monocaprylate where sirolimus was completely dissolved were uniformly dispersed in the gelatin aqueous solution.

[0077] This mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., then solidified and recovered after 5 min. The total mass of the recovered undried particles was 13.2 g. A particulate formulation of an oral pharmaceutical composition was obtained by air drying these undried particles at 10 to 20 C. (relative humidity 20 to 40%) for 16 h. There, the total mass decreased by 5.98 g, which corresponds to 45.3 mass %, due to the above drying treatment, to become 7.22 g. The loss on drying of this particulate formulation was 11.7%, the mass per particle was 19.5 mg on average (water content: about 12.5 mass %) and the particle diameter was 2.5 to 3.1 mm.

Example 3

[0078] 7.67 g of a particulate formulation was obtained by preparation in the same way as in Example 1, except that in the gelatin aqueous solution of Example 1, 7.181 g of purified water, 2.688 g of gelatin and 3.840 g of reduced sugar syrup were used, and in the active ingredient solution, 0.042 g of carbamazepine and 1.250 g of diethyl phthalate were used. The loss on drying of this particulate formulation was 10.5%, the mass per particle was 21.3 mg on average (water content: about 11.2 mass %), and the particle diameter was 2.8 to 3.4 mm.

Example 4

[0079] 7.83 g of a particulate formulation was obtained by preparation in the same way as in Example 3, except that in the active ingredient solution of Example 3, triethyl citrate was used instead of diethyl phthalate. The loss on drying of this particulate formulation was 10.8%, the mass per particle was 21.0 mg on average (water content: about 11.5 mass %), and the particle diameter was 2.9 to 3.4 mm.

Example 5

[0080] 7.45 g of a particulate formulation was obtained by preparation in the same way as in Example 3, except that in the active ingredient solution of Example 3, oleic acid was used instead of diethyl phthalate. The loss on drying of this particulate formulation was 10.0%, the mass per particle was 20.3 mg on average (water content: about 10.8 mass %), and the particle diameter was 2.8 to 3.3 mm.

Example 6

[0081] 8.41 g of a particulate formulation was obtained by preparation in the same way as in Example 1, except that in the gelatin aqueous solution of Example 1, 7.381 g of purified water, 2.381 g of gelatin and 3.968 g of lactitol were used, and in the active ingredient solution, 0.423 g of cyclosporine and 0.847 g of propylene glycol monocaprylate were used. The loss on drying of this particulate formulation was 12.9%, the mass per particle was 23.9 mg on average (water content: about 12.9 mass %), and the particle diameter was 2.9 to 3.5 mm.

Example 7

[0082] 8.13 g of a particulate formulation was obtained by preparation in the same way as in Example 1, except that in the gelatin aqueous solution of Example 1, 7.254 g of purified water, 2.340 g of gelatin and 3.900 g of lactitol were used, and in the active ingredient solution, 0.430 g of cyclosporine and 1.076 g of oleic acid were used. The loss on drying of this particulate formulation was 11.1%, the mass per particle was 22.8 mg on average (water content: about 11.9 mass %), and the particle diameter was 2.8 to 3.4 mm.

Example 8

[0083] 8.38 g of a particulate formulation was obtained by preparation in the same way as in Example 1, except that in the gelatin aqueous solution of Example 1, 7.122 g of purified water, 2.298 g of gelatin and 3.829 g of lactitol were used, and in the active ingredient solution, 0.438 g of cyclosporine and 1.313 g of triethyl citrate were used. The loss on drying of this particulate formulation was 11.1%, the mass per particle was 22.8 mg on average (water content: about 12.5 mass %) and the particle diameter was 2.8 to 3.4 mm. The micrograph of the above mixed liquid in the preparation of this example is shown in FIG. 1. As shown in FIG. 1, it was confirmed that it was a mixed liquid, wherein the droplets of triethyl citrate where cyclosporine was completely dissolved were uniformly dispersed in the gelatin aqueous solution.

Example 9

[0084] 7.54 g of a particulate formulation was obtained by preparation in the same way as in Example 1, except that in the gelatin aqueous solution of Example 1, 7.529 g of purified water, 2.818 g of gelatin and 4.026 of reduced sugar syrup were used, and in the active ingredient solution, 0.039 g of everolimus and 0.588 g of medium chain fatty acid triglyceride were used. The loss on drying of this particulate formulation was 10.0%, the mass per particle was 19.8 mg on average (water content: about 11.1 mass %), and the particle diameter was 2.8 to 3.3 mm.

Example 10

[0085] 7.31 g of a particulate formulation was obtained by preparation in the same way as in Example 10, except that in the active ingredient solution of Example 9, piperonyl butoxide was used instead of medium chain fatty acid triglyceride. The loss on drying of this particulate formulation was 9.70%, the mass per particle was 19.1 mg on average (water content: about 10.5 mass %), and the particle diameter was 2.8 to 3.2 mm.

Example 11A

[0086] 7.42 g of a particulate formulation was obtained by preparation in the same way as in Example 1, except that in the gelatin aqueous solution of Example 1, 8.757 g of purified water, 2.825 g of gelatin and 2.825 g of powdered reduced maltose syrup were used, and in the active ingredient solution, 0.039 g of tacrolimus hydrate and 0.555 g of triethyl citrate were used. The loss on drying of this particulate formulation was 9.40%, the mass per particle was 18.9 mg on average (water content: about 10.3 mass %) and the particle diameter was 2.9 to 3.2 mm. The micrograph of the mixed liquid in the preparation of this example is shown in FIG. 2. As shown in FIG. 2, it was confirmed that it was a mixed liquid, wherein the droplets of triethyl citrate where tacrolimus hydrate was completely dissolved were uniformly dispersed in the gelatin aqueous solution.

Example 11B

[0087] 7.21 g of a particulate formulation was obtained by preparation in the same way as in Example 11A, except that in the gelatin aqueous solution of Example 11A, 8.280 g of purified water, 2.671 g of gelatin and 2.671 g of powdered reduced maltose syrup were used, and in the active ingredient solution, 0.042 g of tacrolimus hydrate and 1.336 g of triethyl citrate were used. The loss on drying of this particulate formulation was 9.00%, the mass per particle was 19.2 mg on average (water content: about 9.80 mass %), and the particle diameter was 2.9 to 3.2 mm.

Example 12

[0088] 7.37 g of a particulate formulation was obtained by preparation in the same way as in Example 11A, except that in the active ingredient solution of Example 11A, triacetin was used instead of triethyl citrate. The loss on drying of this particulate formulation was 9.50%, the mass per particle was 19.3 mg on average (water content: about 10.7 mass %), and the particle diameter was 2.9 to 3.3 mm.

Example 13

[0089] 7.27 g of a particulate formulation was obtained by preparation in the same way as in Example 11A, except that in the active ingredient solution of Example 11A, butyl phthalyl butyl glycolate was used instead of triethyl citrate. The loss on drying of this particulate formulation was 10.3%, the mass per particle was 19.9 mg on average (water content: about 11.1 mass %), and the particle diameter was 2.8 to 3.3 mm.

Comparative Example 1A

[0090] The gelatin aqueous solution was obtained by adding 2.934 g of gelatin and 2.934 g of powdered reduced maltose syrup to 9.095 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the powdered reduced maltose syrup. The mixed liquid was obtained by adding gradually 0.037 g of tacrolimus hydrate into the gelatin aqueous solution while stirring this gelatin aqueous solution at 55 to 65 C. The micrograph of this mixed liquid is shown in FIG. 3. As shown in FIG. 3, it was confirmed that in this mixed liquid tacrolimus hydrate crystals which were not dissolved were dispersed in the gelatin aqueous solution.

[0091] This mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., then solidified and recovered after 5 min. The total mass of the recovered undried particles was 13.4 g. A particulate formulation of an oral pharmaceutical composition was obtained by air drying these undried particles at 10 to 20 C. (relative humidity 20 to 40%) for 16 h. There, the total mass decreased by 6.58 g, which corresponds to 49.1 mass %, due to the above drying treatment, to become 6.82 g. The loss on drying of this particulate formulation was 10.2%, the mass per particle was 18.9 mg on average (water content: about 11.5 mass %), and the particle diameter was 2.8 to 3.2 mm.

Comparative Example 1B

[0092] The gelatin aqueous solution was obtained by adding 2.929 g of gelatin and 2.929 g of powdered reduced maltose syrup to 9.081 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the powdered reduced maltose syrup. On the other hand, 0.037 g of tacrolimus hydrate was added to 0.023 g of triethyl citrate (corresponding to about 0.8 parts by mass of triethyl citrate based on 100 parts by mass of the above gelatin), then it was heated at 55 to 65 C. for 30 min, but undissolved tacrolimus hydrate was found. A mixed liquid was obtained by adding the dispersion liquid of the tacrolimus hydrate and triethyl citrate into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C. When observing this mixed liquid with a microscope, it was found that both the droplets of triethyl citrate where tacrolimus hydrate was dissolved and the tacrolimus hydrate crystals were dispersed in the gelatin aqueous solution.

[0093] This mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., then solidified and recovered after 5 min. The total mass of the recovered undried particles was 13.5 g. A particulate formulation of an oral pharmaceutical composition was obtained by air drying these undried particles at 10 to 20 C. (relative humidity 20 to 40%) for 16 h. There, the total mass decreased by 6.66 g, which corresponds to 49.3 mass %, due to the above drying treatment, to become 6.84 g. The loss on drying of this particulate formulation was 10.0%, the mass per particle was 19.2 mg on average (water content: about 11.2 mass %) and the particle diameter was 2.7 to 3.2 mm.

Comparative Example 1C

[0094] The gelatin aqueous solution was obtained by adding 2.336 g of gelatin and 2.336 g of powdered reduced maltose syrup to 7.242 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the powdered reduced maltose syrup. On the other hand, the active ingredient solution was obtained by adding 0.048 g of tacrolimus hydrate to 3.037 g of triethyl citrate (corresponding to about 130 parts by mass of triethyl citrate based on 100 parts by mass of the above gelatin), then by heating an obtained mixture at 55 to 65 C. to dissolve the tacrolimus hydrate. A mixed liquid was obtained by adding gradually the active ingredient solution into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C. In this mixed liquid, the droplets of triethyl citrate where tacrolimus hydrate was completely dissolved were uniformly dispersed in the gelatin aqueous solution.

[0095] This mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., then recovered after 60 min, but the particulate formulation could not be obtained since it was not solidified.

Comparative Example 2

[0096] The gelatin aqueous solution was obtained by adding 2.825 g of gelatin and 2.825 g of powdered reduced maltose syrup to 8.757 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the powdered reduced maltose syrup. On the other hand, the active ingredient solution was obtained by adding 0.039 g of tacrolimus hydrate to 0.555 g of polyoxyl 35 castor oil (surfactant), then by heating an obtained mixture at 55 to 65 C. to dissolve the tacrolimus hydrate. The mixed liquid was obtained by adding gradually the active ingredient solution into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C. In this mixed liquid, the droplets of polyoxyl 35 castor oil where tacrolimus hydrate was completely dissolved were uniformly dispersed in the gelatin aqueous solution.

[0097] This mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., but a particulate formulation could not be obtained since the mixed liquid blended with the medium chain fatty acid triglycerides was not solidified as spheres.

Comparative Example 3

[0098] The gelatin aqueous solution was obtained by adding 2.825 g of gelatin and 2.825 g of powdered reduced maltose syrup to 8.757 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the powdered reduced maltose syrup. On the other hand, the active ingredient solution was obtained by adding 0.039 g of tacrolimus hydrate to 0.555 g of polyoxyethylene hardened castor oil 60 (surfactant), then by heating an obtained mixture at 55 to 65 C. to dissolve the tacrolimus hydrate. When gradually adding the active ingredient solution into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C., precipitation of tacrolimus hydrate crystals was confirmed in the mixed liquid. Moreover, this mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., but a particulate formulation could not be obtained since the mixed liquid blended with the medium chain fatty acid triglycerides was not solidified as spheres.

Comparative Example 4

[0099] It was prepared in the same way as in Comparative Example 3, except that polysorbate 80 (surfactant) was used instead of polyoxyethylene hardened castor oil 60 in the active ingredient solution of Comparative Example 3. Precipitation of tacrolimus hydrate crystals were confirmed in the mixed liquid as in Comparative Example 3, and a particulate formulation could not be obtained since the mixed liquid blended with the medium chain fatty acid triglycerides was not solidified as spheres.

Comparative Example 5

[0100] It was prepared in the same way as in Comparative Example 4, except that caprylocaproyl polyoxy glyceride (surfactant) was used instead of polyoxyethylene hardened castor oil 60 in the active ingredient solution of Comparative Example 3. Precipitation of tacrolimus hydrate crystals were confirmed in the mixed liquid as in Comparative Example 3, and a particulate formulation could not be obtained since the mixed liquid blended with the medium chain fatty acid triglycerides was not solidified as spheres.

Comparative Example 6

[0101] The gelatin aqueous solution was obtained by adding 2.825 g of gelatin and 2.825 g of powdered reduced maltose syrup to 8.757 g of purified water, then by heating an obtained mixture at 55 to 65 C. to dissolve the gelatin and the powdered reduced maltose syrup. On the other hand, the active ingredient solution was obtained by adding 0.039 g of tacrolimus hydrate to 0.555 g of propylene glycol (solubility in water at 20 C.: the amount exceeding 10 mass % is uniformly dissolved), then by heating an obtained mixture at 55 to 65 C. to dissolve the tacrolimus hydrate. When gradually adding the active ingredient solution into the gelatin aqueous solution while stirring the gelatin aqueous solution at 55 to 65 C., precipitation of tacrolimus hydrate crystals was confirmed in the mixed liquid.

[0102] This mixed liquid was added dropwise by 25 to 40 mg at a time in 250 mL of medium chain fatty acid triglyceride which was cooled to 10 to 15 C., then solidified and recovered after 5 min. The total mass of the recovered undried particles was 13.8 g. A particulate formulation of an oral pharmaceutical composition was obtained by air drying these undried particles at 10 to 20 C. (relative humidity 20 to 40%) for 16 h. There, the total mass decreased by 6.27 g, which corresponds to 45.4 mass %, due to the above drying treatment, to become 7.53 g. The loss on drying of this particulate formulation was 11.5%, the mass per particle was 20.8 mg on average (water content: about 13.0 mass %) and the particle diameter was 2.6 to 3.3 mm.

Comparative Example 7

[0103] It was prepared in the same way as in Comparative Example 6, except that in the active ingredient solution of Comparative Example 6, macrogol 400 (surfactant) was used instead of propylene glycol. The loss on drying of the obtained particulate formulation was 11.3%, the mass per particle was 21.0 mg on average (water content: about 12.4 mass %) and the particle diameter was 2.7 to 3.2 mm. The micrograph of the mixed liquid in the preparation of this example is shown in FIG. 4. As shown in FIG. 4, a precipitation of tacrolimus hydrate crystals was confirmed in the mixed liquid as in Comparative Example 6.

[0104] As described above in each Examples and Comparative Examples, the state of the active ingredient, the presence or absence of precipitation and the formability in the production of each example were evaluated according to the following method. The results are shown in Tables 1 and 2. Moreover, the dissolution properties were evaluated by performing a dissolution test according to the following method regarding the particulate formulations of the oral pharmaceutical compositions obtained in each example. The results are shown in Tables 1 and 2.

[State of the Active Ingredient]

[0105] In all the above Examples and Comparative Examples, the state of the active ingredient was evaluated by adding and stirring the hydrophobic liquid in the active ingredient during the step of preparing the active ingredient solution, and heating an obtained mixture at 55 to 65 C. for 30 min, then observing visually if the active ingredient had been dissolved. The results are shown in Tables 1 and 2. The meaning of the evaluation symbols in the tables is as follows.

: Dissolved.

[0106] x: Insoluble matter was found.
-: The active ingredient solution was not prepared.

[Presence or Absence of Precipitation]

[0107] In all the above Examples and Comparative Examples, it was observed by microscope whether there was a precipitation of active ingredient regarding the mixed liquid. The results are shown in Tables 1 and 2. The meaning of the evaluation symbols in the tables is as follows.

: No precipitation of the active ingredient was confirmed.
x: A precipitation of the active ingredient was confirmed.

[Formability]

[0108] In all the above Examples and Comparative Examples, it was determined whether the particulate formulation was shapable from the mixed liquid in the preparation of the particulate formulation. The results are shown in Tables 1 and 2. The meaning of the evaluation symbols in the tables is as follows.

: It was shapable.
x: It could not be shaped.

[Dissolution Properties]

[0109] Regarding the particulate formulations obtained in the above Examples 1 to 13, Comparative Examples 1A and 1B, and Comparative Examples 6 and 7, a dissolution properties test was performed under the following conditions depending on an active ingredient, and it was observed visually whether the formulation and the active ingredient in the vessel remained within a predetermined time period. The results are shown in Tables 1 and 2. The meaning of the evaluation symbols in the tables is as follows.

: No residue of the particulate formulation and the active ingredient was found.
x: A residue of the particulate formulation and the active ingredient was found.
-: The dissolution properties test could not be performed since the particulate formulation could not be prepared.

Test Conditions

Examples 1 and 2 (Component: Sirolimus)

[0110] Test method: Dissolution test method 2 (Paddle method)
Test liquid: Aqueous solution of sodium lauryl sulfate 0.4%, 500 mL, 37 C.
Number of revolutions: 100 rpm
Input amount: 1 mg (as sirolimus)
Evaluation time: 60 min

Examples 3 to 5 (Component: Carbamazepine)

[0111] Test method: Dissolution test method 2 (Paddle method)
Test liquid: Water, 900 mL, 37 C.
Number of revolutions: 75 rpm
Input amount: 200 mg (as carbamazepine)
Evaluation time: 45 min

Examples 6 to 8 (Component: Cyclosporine)

[0112] Test method: Dissolution test method 2 (Paddle method)
Test liquid: Water, 900 mL, 37 C.
Number of revolutions: 50 rpm
Input amount: 50 mg (as cyclosporine)
Evaluation time: 45 min

Examples 9 to 10 (Component: Everolimus)

[0113] Test method: Dissolution test method 2 (Paddle method)
Test liquid: Water, 900 mL, 37 C.
Number of revolutions: 50 rpm
Input amount: 10 mg (as everolimus)
Evaluation time: 60 min

Examples 11A to 13, Comparative Examples 1A and 1B, and Comparative Examples 6 and 7 (Component: Tacrolimus Hydrate)

[0114] Test method: Dissolution test method 2 (Paddle method)
Test liquid: Water, 900 mL, 37 C.
Number of revolutions: 100 rpm
Input amount: 5 mg (as tacrolimus)
Evaluation time: 45 min

TABLE-US-00001 TABLE 1 Examples Composition 1 2 3 4 5 6 7 8 9 10 11A 11B Active Sirolimus 0.022 0.020 ingredients Carbamazepine 0.042 0.042 0.042 Cyclosporine 0.423 0.430 0.438 Everolimus 0.039 0.039 Tacrolimus 0.039 0.042 hydrate Water- Gelatin 2.496 2.168 2.688 2.688 2.688 2.381 2.340 2.298 2.818 2.818 2.825 2.671 soluble Xanthan gum 0.011 polymer Locust bean 0.011 substances gum Excipients Lactitol 2.496 2.168 3.968 3.900 3.829 Reduced sugar 3.840 3.840 3.840 4.026 4.026 syrup Powdered 2.825 2.671 reduced maltose syrup Hydrophobic Diethyl phthalate 2.247 1.250 liquids Propylene glycol 1.951 0.847 monocaprylate Triethyl citrate 1.250 1.313 0.555 1.336 Oleic acid 1.250 1.076 Medium chain fatty acid 0.588 triglyceride Piperonyl 0.588 butoxide Triacetin Butyl phthalyl butyl glycolate Other liquids Polyoxyl 35 used for castor oil dissolving Polyoxyethylene the active hardened castor ingredient oil 60 Polysorbate 80 Caprylocaproyl polyoxy glyceride Propylene glycol Macrogol 400 Water Purified water 7.738 8.672 7.181 7.181 7.181 7.381 7.254 7.122 7.529 7.529 8.757 8.280 Total (g) 14.999 15.001 15.001 15.001 15.001 15.000 15.000 15.000 15 000 15.000 15.001 15.000 Evaluation State of the results active ingredient Presence or absence of precipitation Formability Dissolution properties The units for the amounts blended are all in g.

TABLE-US-00002 TABLE 2 Examples Comparative Examples Composition 12 13 1A 1B 1C 2 3 4 5 6 7 Active Sirolimus ingredients Carbamazepine Cyclosporine Everolimus Tacrolimus hydrate 0.039 0.039 0.037 0.037 0.048 0.039 0.039 0.039 0.039 0.039 0.039 Water-soluble Gelatin 2.825 2.825 2.934 2.929 2.336 2.825 2.825 2.825 2.825 2.825 2.825 polymer Xanthan gum substances Locust bean gum Excipients Lactitol Reduced sugar syrup Powdered reduced 2.825 2.825 2.934 2.929 2.336 2.825 2.825 2.825 2.825 2.825 2.825 maltose syrup Hydrophobic Diethyl phthalate liquids Propylene glycol monocaprylate Triethyl citrate 0.023 3.037 Oleic acid Medium chain fatty acid triglyceride Piperonyl butoxide Triacetin 0.555 Butyl phthalyl butyl 0.555 glycolate Other liquids Polyoxyl 35 castor oil 0.555 used for Polyoxyethylene 0.555 dissolving hardened castor oil 60 the active Polysorbate 80 0.555 ingredient Caprylocaproyl 0.555 polyoxy glyceride Propylene glycol 0.555 Macrogol 400 0.555 Water Purified water 8.757 8.757 9.095 9.081 7.242 8.757 8.757 8.757 8.757 8.751 8.757 Total (g) 15.001 15.001 15.000 14.999 14.999 15.001 15.001 15.001 15.001 15.001 15.001 Evaluation State of the active x results ingredient Presence or absence x x x x x x x of precipitation Formability x x x x x Dissolution properties x x x x The units for the amounts blended are all in g.

[0115] As shown in the above Tables 1 and 2, according to the oral pharmaceutical composition of the present invention, particulate formulations having 0.5 to 10 mm particle diameter can be easily obtained, and the obtained particulate formulations of the oral pharmaceutical composition was confirmed to have excellent dissolution properties of the active ingredient.

[Dissolution Test of the Particulate Formulation Blended with Tacrolimus Hydrate]

[0116] A dissolution test was performed under the following conditions regarding each particulate formulation of the above Example 11A, Comparative Example 1A and Comparative Example 7 blended with tacrolimus hydrate as the active ingredient and a standard formulation (Astellas Pharma Inc.'s Prograf Capsules 5 mg). The results are shown in FIGS. 5 to 8. For Comparative Example 1A and Comparative Example 7, the dissolution test was performed only with water.

<Test Conditions>

[0117] Test liquid: 900 mL, 37 C. for each test liquid

[0118] (1) pH 1.2 (Japanese Pharmacopoeia Dissolution test liquid 1)

[0119] (2) pH 5.0 (diluted McIlvaine buffer solution)

[0120] (3) pH 6.8 (Japanese Pharmacopoeia Dissolution test liquid 2)

[0121] (4) Water

Number of revolutions: 50 rpm
Input amount: 5 mg (as tacrolimus)
Test method: After starting the dissolution test under the above conditions according to the Dissolution test method 2 (Paddle method), the test liquid was collected at 15, 30, 60 and 120 min, and filtered with a membrane filter having 0.45 m pore size. Excluding the first filtrate of 1 mL, the next filtrate of 1 mL was collected and this was diluted twice with ethanol, to obtain the sample solution.

<Analysis Conditions>

High-Speed Liquid Chromatograph: Shimadzu Prominence

[0122] Detector: UV absorption photometer (measurement wavelength: 220 nm)

Column: YMC-Triart C18 (5 m) 1504.6 mm I.D.

[0123] Column temperature: 50 C.
Mobile phase: Water/2-propanol/tetrahydrofuran mixture (5:2:2)
Flow rate: 0.725 mL/min
Injection amount: 40 L

[0124] As shown in FIGS. 5 to 8, the particulate formulation of tacrolimus consisting of the oral pharmaceutical composition of the present invention was confirmed to have excellent dissolution properties that are not inferior to the standard formulation.