Preparation method of pharmaceutical composition containing pranlukast and pharmaceutical composition prepared by preparation method

Abstract

The invention discloses a preparation method of a pharmaceutical composition containing pranlukast and the pharmaceutical composition prepared by the preparation method.

Description

Technical Field

[0001] This invention relates to a method for preparing a pharmaceutical composition containing pranlukast and the pharmaceutical composition prepared by said method. More specifically, it relates to a method for preparing a pranlukast-containing pharmaceutical composition and the pharmaceutical composition prepared by said method that can solve the following problems: When preparing a pranlukast-containing pharmaceutical composition, a binder and a solubilizer are added to a solvent used to dissolve the binder, and the mixture is left to stand overnight (12-16 hours). Then, before use the next day, the evaporated solvent is weighed and corrected. Then, the mixture is kneaded in a high-speed mixer. In this process, the solubilizer precipitates out, and the kneaded mixture becomes viscous in a short time, resulting in uneven mixing and kneading. When the prepared kneaded mixture is dried, pulverized, and then compressed into tablets after a post-mixing process, adhesion and fragmentation occur. Background Technology

[0002] Prenstar

[0003] This invention uses prenstar as the active ingredient.

[0004] Represented by the following chemical formula 1, with the chemical name 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate, prancelast is a new drug developed by Ono Pharmaceutical Co., Ltd. of Japan.

[0005] Chemical Formula 1

[0006] Prunust is a medication used to treat asthma and allergic rhinitis. It works by blocking leukotrienes, an inflammatory mediator that triggers asthma and rhinitis, thus inhibiting allergic reactions.

[0007] For example, when a foreign object enters the body, it may trigger an immune allergic reaction, potentially leading to asthma or allergic rhinitis.

[0008] Asthma is a disease caused by substances such as pollen and dust mites, which cause swelling and inflammation of the bronchial mucosa and contraction of the muscles around the airways, leading to narrowing of the airways and difficulty breathing.

[0009] Based on the period of exposure to the antigen, allergic rhinitis can be divided into seasonal allergic rhinitis, which occurs only in specific seasons, such as spring pollen and autumn ragweed pollen, and perennial allergic rhinitis, which is caused by substances such as indoor dust, mites, mold and animal dander. Allergic reactions occur on the nasal mucosa, resulting in symptoms such as sneezing, runny nose and nasal congestion.

[0010] Prunster is a medication used to treat this type of asthma and allergic rhinitis, and it helps improve symptoms.

[0011] Existing formulations

[0012] We have attempted to formulate prunustraz into various dosage forms, including tablets, dispersants, dry syrups, and capsules.

[0013] Among them, the early marketed oral solid dosage forms of pransil were Onon capsules (each capsule contains 112.5 mg of pransil, 2 capsules per dose, Dong-A ST), Pranair capsules (each capsule contains 112.5 mg of pransil, 1 capsule per dose, SKCHEMICAL), Prakanon tablets (each tablet contains 75 mg of pransil, 1 tablet per dose, Yuhan-Yanghaeng), and Citus tablets (each tablet contains 50 mg of pransil, 1 tablet per dose, Sam-A Pharmaceutical).

[0014] Studies have shown that the maximum absorption site of oral prolansta is the upper small intestine. As a drug belonging to class II of the Biopharmaceutics Classification System (BCS), it has strong adhesiveness and cohesiveness and very low solubility (1.2 μg / ml). Therefore, compared with other drugs, it has the problem of lower bioavailability when administered orally.

[0015] In this regard, because Onon capsules failed to address the issue of pramuximab during the formulation stage, the approach of increasing the pramuximab content was ultimately adopted. Calculations show that a single dose of 225mg pramuximab is required for adults to achieve significant therapeutic efficacy for the target disease. However, the large single dose leads to poor cost-effectiveness, may reduce patient compliance, and high doses may cause side effects.

[0016] To address the shortcomings of the aforementioned Onon capsules, Korean Patent Publication No. 10-0389606 discloses a spray-dried particulate material for improving the adhesion and cohesiveness of prenstard. In this patent, sugars, binders, and surfactants are dissolved in purified water, and prenstard is suspended in the water to prepare the spray-dried particulate material. However, while the spray-dried particulate material disclosed in Korean Patent Publication No. 10-0389606 improves the adhesion and cohesiveness of prenstard, it fails to improve its solubility. This results in delayed dissolution and extremely low dissolution rate, ultimately limiting its bioavailability.

[0017] Korean Patent Publication No. 10-1332223 discloses a prencal nanoparticle solid dispersion that can improve the low solubility of prencal and increase its bioavailability. The prencal nanoparticle solid dispersion in this patent has a structure in which prencal exists in a carrier composed of polyethylene glycol and poloxamer, which enables the drug to maintain a stable nanoscale particle size while improving bioavailability.

[0018] However, the preparation of the nano-solid dispersion described in Korean Patent Publication No. 10-1332223 requires mixing, thermal melting, and solvent evaporation processes, resulting in high manufacturing costs and complex processes. Furthermore, the use of methanol / dichloromethanol as a co-solvent leaves organic solvent residues in the solid dispersion, which also causes environmental pollution.

[0019] Korean Patent Publication No. 10-1446129 discloses a mixture comprising pranceloin and polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone and vinyl acetate. In this patent, the solubility and dissolution rate of pranceloin are improved by simply mixing it with a hydrophilic polymer. However, the proportion of the hydrophilic polymer to the main component is high, there is a lack of in-vivo experimental data, and no data is provided to prove whether the actual bioavailability is improved.

[0020] Korean Patent Publication No. 10-1086254 discloses a solid dispersion composition of pransil, characterized in that it is formed by heating and melting polyvinylpyrrolidone-vinyl acetate copolymer relative to pransil at a weight ratio of 0.2:1 to 10:1. This patent relates to Pranair capsules (each capsule contains 112.5 mg of pransil, one capsule per dose, SK CHEMICAL).

[0021] However, the solid dispersion disclosed in Korean Patent Publication No. 10-1086254, compared to the existing reference drug Onon capsules, can be considered to have doubled the bioavailability of prenroximate. However, because it cannot use the preparation equipment commonly used in the pharmaceutical industry (emphasizing a hot-melting method), it suffers from high equipment investment and complex preparation processes. Furthermore, since converting a drug into an amorphous form through hot melting can be considered a thermodynamically unstable state, there is a limitation that the drug may revert to a stable crystalline form within the product's shelf life, thus potentially leading to changes in solubility and bioavailability.

[0022] Korean Patent Publication No. 10-0981751 discloses a granule containing pramucoid, the granule comprising a drug coating layer on a granule core. The patent is characterized by preparing the granules by coating the granule core with a suspension of pramucoid, a binder, and a surfactant, and then processing them into tablets. This patent relates to Prakanon tablets (each tablet containing 75 mg of pramucoid, taken once daily, Yuhan-Yanghaeng).

[0023] However, the spray-dried granules disclosed in Korean Patent Publication No. 10-0981751 require a vigorous suspension process to suspend pransilate in a solvent. The spray-drying process introduces various process variables, and its complexity may increase manufacturing costs. Furthermore, while this patent improves the bioavailability of pransilate, reducing the single-dose dose to one-third compared to the existing control drug Onon capsules, the current single-dose dose is 75 mg. Further improvements in bioavailability and dose reduction are needed to improve patient compliance and reduce side effects caused by high-dose administration.

[0024] Korean Patent Publication No. 10-2363727 is the inventor's prior art, disclosing a wet granule form of pramux. Although the method employs a conventional wet granulation process rather than a hot-melt method, it is characterized by significantly improving the bioavailability of pramux through a combination of specific diluents, binders, and surfactants, successfully reducing the single-dose dose to 50 mg. This patent relates to Citus tablets (each tablet containing 50 mg of pramux, one tablet per dose, Sam-A Pharmaceutical), and is listed in the Korean Ministry of Food and Drug Safety's pharmaceutical patent list.

[0025] However, the aforementioned patent literature completely ignores the problems that occur when preparing formulations containing prenroxith (such as the precipitation of solubilizers and the phenomenon that the kneaded mixture becomes viscous in a short time, resulting in uneven mixing and kneading of the mixture, as well as sticking and chipping during tableting), and does not propose any solutions.

[0026] Therefore, there is an urgent need to develop a new method for preparing a pransilate-containing formulation that can solve the above problems.

[0027] Existing technical documents

[0028] Patent documents

[0029] Patent Document 1: Korean Patent Publication No. 10-0389606

[0030] Patent Document 2: Korean Patent Publication No. 10-1332223

[0031] Patent Document 3: Korean Patent Publication No. 10-1446129

[0032] Patent Document 4: Korean Patent Publication No. 10-1086254

[0033] Patent Document 5: Korean Patent Publication No. 10-0981751

[0034] Patent Document 6: Korean Patent Publication No. 10-2363727 Summary of the Invention

[0035] Technical issues

[0036] The purpose of this invention is to solve the above-mentioned problems. In the preparation method of the pharmaceutical composition containing prenroximate of this invention, in order to improve the problems existing in the prior art when standing overnight, the dissolution temperature and dissolution time of the solubilizer, the dissolution time of the binder and the usage time of the binder after mixing are adjusted so that the mixture is uniformly mixed and kneaded, thereby solving the interference with tableting.

[0037] Furthermore, by adjusting the particle size during the sieving process after kneading, suitable process results can be ensured, the uneven mixing in the post-mixing stage can be improved, and appropriate dissolution can be ensured.

[0038] At the same time, by adjusting the kneading / tableting conditions, optimal process results can be ensured, thereby improving the solubility of prenstar.

[0039] Technical solution

[0040] In this specification, "premnaste" may refer to premnaste, its hydrate, its solvate, or its salts. Therefore, in this specification, "pharmaceutical composition containing premnaste" may refer to a pharmaceutical composition containing premnaste, its hydrate, its solvate, or its salts.

[0041] Unless otherwise specified in this specification, the term "percentage by weight" refers to the mass ratio of a particular component to the total pharmaceutical composition to which it is added.

[0042] The present invention will now be described in detail.

[0043] The present invention solves the above problems through the following solution.

[0044] 1. A method for preparing a pharmaceutical composition containing prencalfloxacin, comprising: step (S1), dissolving a solubilizer at 50-60°C for 30-60 minutes, adding the resulting solution to a solution containing a binder, and then stirring to prepare a mixed solution containing a solubilizer and a binder; step (S2), mixing prencalfloxacin, its hydrate, its solvate, or its salt with a pharmaceutical additive; step (S3), adding the mixed solution from step (S1) to the mixture from step (S2), and then kneading it into granules; step (S4), drying the granules from step (S3) to prepare dried granules; step (S5), sieving the dried granules from step (S4) and mixing them with the pharmaceutical additive to prepare a final mixture; and step (S6), compressing the final mixture from step (S5) into tablets.

[0045] 2. The method for preparing the pharmaceutical composition containing prenroximate according to 1 above is characterized in that, after dissolving the solubilizer at 50-60°C for 30-60 minutes, the solution containing the solubilizer is used within 1 hour.

[0046] 3. The method for preparing the pharmaceutical composition containing prenroximate according to 1 above, characterized in that the solution containing the binder in step (S1) is obtained by adding the binder to the adhesive solvent and stirring for 20 to 50 minutes, and is used within 5 hours.

[0047] 4. The method for preparing the pharmaceutical composition containing prenroximate according to 1 above is characterized in that a solution containing a solubilizer is added to a solution containing a binder, and then dissolved for 15 to 45 minutes to obtain the mixed solution in step (S1).

[0048] 5. The method for preparing the pharmaceutical composition containing prenstar according to 1 above, characterized in that the solubilizer in step (S1) is any one of polyoxyethylene 15-hydroxystearate, poloxamer 407, or a mixture thereof.

[0049] 6. The method for preparing the pranoxetine-containing pharmaceutical composition according to 1 above, characterized in that the binder in step (S1) is selected from one or more of the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyethylene glycol, and polyvinyl alcohol.

[0050] 7. The method for preparing the pharmaceutical composition containing prenroximate according to 1 above, characterized in that the content of the added solubilizer is 1 to 20% by weight relative to the total weight of the pharmaceutical composition, and the content of the added binder is 1 to 5% by weight.

[0051] 8. The method for preparing the pharmaceutical composition containing prenroximate according to 1 above, characterized in that the pharmaceutical additive in step (S2) is one or more selected from the group consisting of diluent, sweetener and binder.

[0052] 9. The method for preparing the pranoxetine-containing pharmaceutical composition according to 8 above, characterized in that the diluent in step (S2) is xylitol, mannitol, isomaltitol, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, maltotriitol, microcrystalline cellulose, croscarmellose sodium, carboxymethylcellulose calcium, hydroxypropyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose, gelatinized starch. The sweetener is any one or more of starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silica or crystalline cellulose, and is anti-curing sugar powder.

[0053] 10. The method for preparing the pharmaceutical composition containing pranoxetine according to 1 above, characterized in that the mixing in step (S2) is carried out for 1 to 5 minutes at a stirrer speed of 110 to 130 rpm and a chopper speed of 1800 to 2200 rpm.

[0054] 11. The method for preparing the pranoxetine-containing pharmaceutical composition according to 8 above, characterized in that the binder in step (S2) is selected from any one or more of the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol and polyvinyl alcohol.

[0055] 12. The method for preparing the pharmaceutical composition containing pransildenafil according to 1 above, characterized in that the sieving in step (S5) is performed on the dried particulate matter using a sieve with a mesh size of 710-850 μm.

[0056] 13. The method for preparing the pharmaceutical composition containing prenroximate according to 1 above, characterized in that the pharmaceutical additive in step (S5) is one or more selected from the group consisting of diluents, disintegrants, pH adjusters, sweeteners, flavorings and gliding agents.

[0057] 14. The method for preparing the pharmacopoeia containing prolansta according to 13 above, characterized in that the diluent is any one or more of xylitol, mannitol, isomaltitol, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabinitol, galactitol, lactitol, maltotriol, microcrystalline cellulose, croscarmellose sodium, carboxymethyl cellulose calcium, hydroxypropyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicate, or crystalline cellulose.

[0058] 15. The method for preparing the pranoxetine-containing pharmaceutical composition according to 13 above, characterized in that the disintegrant is any one of crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), or a mixture thereof.

[0059] 16. The method for preparing the pharmaceutical composition containing prenroximate according to 13 above, characterized in that the pH adjuster is citric acid hydrate.

[0060] 17. The method for preparing the pharmaceutical composition containing prenroximate according to 13 above, characterized in that the sweetener is selected from any one of the group consisting of white sugar, glucose, mannitol, sorbitol, aspartame, acesulfame potassium and sucralose.

[0061] 18. The method for preparing the pranoxetine-containing pharmaceutical composition according to 13 above, characterized in that the gliding agent is any one of colloidal silica, sodium stearyl fumarate, magnesium stearate, or a mixture thereof.

[0062] 19. The method for preparing the pranoxetine-containing pharmaceutical composition according to 1 above, characterized in that, in the tableting step (S6), the rotation speed of the turret is 20-30 rpm, the tableting position is 16.5-18 mm, and the tableting pressure is a pre-compression of 25-35 kgf / cm². 2 Main pressure 30-40 kgf / cm 2 The tablets are then compressed to adjust the hardness to 5–12 kPa.

[0063] 20. A pharmaceutical composition, characterized in that it is prepared by the method for preparing the pharmaceutical composition containing pranoxetine as described in any one of 1 to 19 above.

[0064] 21. The pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is an oral solid dosage form.

[0065] 22. The pharmaceutical composition according to 21 above, characterized in that the dosage form of the oral solid dosage form is any one of granules, capsules, chewable tablets, single-layer tablets, multi-layer tablets, tablet cores, microparticles or mini tablets.

[0066] 23. The pharmaceutical composition according to 20 above, characterized in that the content of pranoxetine per unit dosage form of the pharmaceutical composition is 26-74.2 mg.

[0067] 24. The pharmaceutical composition according to 20 above is characterized in that, when the pharmaceutical composition is dissolved in a solution at pH 6.8 using the second dissolution method (paddle method) of the Korean Pharmacopoeia, the concentration of praniste reaches more than 80% at a time point of 30 to 45 minutes.

[0068] 25. The pharmaceutical composition according to claim 20, characterized in that, when the pharmaceutical composition is administered to a human body, the time required for pranstar to reach the maximum blood concentration is within 3 hours.

[0069] The effects of the invention

[0070] Regarding the preparation method of the present invention, when preparing a pharmaceutical composition containing prenroximate, by adjusting the process of adding the binder and solubilizer to the solvent used to dissolve the binder, the following phenomena can be solved: the inability to mix and knead evenly; and the adhesion and fragmentation phenomena that occur when the prepared kneaded mixture is dried, pulverized, and then compressed into tablets after a post-mixing process.

[0071] The dissolution of prenlast prepared according to the present invention is improved, and its bioavailability is also significantly improved compared with existing commercially available dry syrup formulations. Even when taking only 53.0-148.4 mg of prenlast daily, it can exhibit clinical efficacy equivalent to or better than existing syrup formulations (prenlast 50, 75, 100, 140 mg / packet, one packet twice daily, Sam-A Pharmaceutical).

[0072] The pharmaceutical compositions prepared according to the present invention, even when taken twice daily at a dose of 26.5-74.2 mg each time, exhibit the same therapeutic effect as when taken twice daily at a dose of 50-140 mg Citus dry syrup.

[0073] The effects of the present invention are not limited to those mentioned above, and may include various effects as will be apparent to those skilled in the art from the following description. Attached Figure Description

[0074] Figure 1 The results of the dissolution test of the chewable tablets (test substance, Citus chewable tablets, 74.2 mg of prunus peroxide hydrate) and dry syrup (Sam-A Pharmaceutical, 140 mg of Citus dry syrup, control substance) of Example 1 are shown in a dissolution solution containing a mixture of pH 6.8 solution and 0.2% PSB solution.

[0075] Figure 2 The results of the dissolution test of chewable tablets (test substance, Citus chewable tablets, 74.2 mg of prunus peroxide hydrate) of Examples 1, 4 and 5 are shown in a dissolution solution mixed with pH 6.8 solution and 0.2% PSB solution.

[0076] Figure 3 The results of the in vivo pharmacokinetic test (in vivo bioequivalence test results) of the chewable tablets (test substance, Citus chewable tablets, 74.2 mg of progesterone hydrate) and dry syrup (Sam-A Pharmaceutical, 140 mg of Citus dry syrup, control substance) of Example 1 of the present invention are shown. Detailed Implementation

[0077] The following is a more detailed description of this instruction manual.

[0078] The specific explanation is as follows. The terminology used in this specification has been selected from widely used general terms as much as possible, taking into account its function in this invention. This may be changed based on the intent of those skilled in the art, convention, or the emergence of new technologies. Furthermore, in certain cases, there may be terms arbitrarily chosen by the applicant; in such cases, their meanings will be described in detail in the description of the corresponding invention. Therefore, the terminology used in this invention should be defined based on its meaning and the overall content of the invention, rather than simply its name.

[0079] Unless otherwise defined, all terms used herein, including technical or scientific terms, shall have the same meaning as commonly understood by one of ordinary skill in the art. Terms as defined in commonly used dictionaries shall be interpreted as having the same meaning as they have in the context of the relevant art, and shall not be interpreted as having an idealized or overly formal meaning unless expressly defined in this specification.

[0080] The numerical range includes the values ​​defined within the specified range. For all maximum numerical limits given throughout this specification, all lower numerical limits are included because lower numerical limits have been explicitly stated. For all minimum numerical limits given throughout this specification, all higher numerical limits are included because higher numerical limits have been explicitly stated. For all numerical limits given throughout this specification, all better numerical ranges within a wider numerical range are included because narrower numerical limits have been explicitly stated.

[0081] It is noted that each description and embodiment disclosed in this invention can be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed in this invention are within the scope of this invention. Furthermore, the scope of this invention should not be considered as limited to the following specific description.

[0082] As used in this specification, expressions such as “comprising” should be understood as open-ended terms, covering the possibility of including other embodiments.

[0083] The inventors of this invention, while developing a method for preparing a pharmaceutical composition containing pransil, discovered that when preparing existing pharmaceutical compositions containing pransil, the binder and solubilizer are added to the solvent used to dissolve the binder, and the mixture is left to stand overnight (12-16 hours). The evaporated solvent is then weighed and corrected before use the next day. The mixture is then kneaded in a high-speed mixer. However, in the above process, the solubilizer precipitates out, and the kneaded mixture becomes viscous in a short time, resulting in uneven mixing and kneading. When the prepared kneaded mixture is dried, pulverized, and then compressed into tablets after a post-mixing process, adhesion and breakage occur.

[0084] Therefore, in order to solve the problems mentioned above, the inventors of the present invention conducted careful observations and confirmed that by adjusting the dissolution temperature and dissolution time of the solubilizer, the dissolution time of the adhesive, and the usage time of the adhesive after mixing, the mixture can be uniformly mixed and kneaded, thereby solving the interference with tableting.

[0085] Furthermore, by adjusting the particle size during the sieving process after kneading, suitable process results can be ensured, the uneven mixing in the post-mixing stage can be improved, and suitable dissolution can be ensured. At the same time, by adjusting the kneading / tableting conditions, optimal process results can be ensured, thereby improving the solubility of prenstar, thus completing the present invention.

[0086] The present invention will now be described in detail.

[0087] Preparation method of pharmaceutical compositions containing pransildenafil

[0088] definition

[0089] This invention uses prencalactus as the active ingredient, and there are no particular limitations on its main component. For example, the main component of commercially available prencalactus is prencalactus hydrate. However, because this invention is characterized by overcoming the limitations of the physicochemical properties of prencalactus itself through a novel formulation design, even using a salt compound containing a pharmaceutically acceptable salt (non-hydrate) as the main component exhibits the same expected effect. Therefore, it should be noted that "prencalactus" in this specification can be used to encompass prencalactus, its hydrate, its solvate, or its salts.

[0090] Preparation method of chewable tablets

[0091] This invention discloses an oral solid dosage form, as described in Korean Patent Publication No. 10-2363727 (the inventor's prior art), which improves the bioavailability of prencalfalcone and reduces dosage. This solid dosage form is prepared by blending a disintegrant with wet granules containing prencalfalcone, a surfactant, a binder, and a diluent. Specifically, in an example, prencalfalcone, lactose, and microcrystalline cellulose are mixed in a high-speed rotary mixer, then a binder solution prepared by stirring a solvent, binder, and surfactant is added. After kneading, granulation and sieving are performed to obtain wet granules. Next, these granules are mixed with a disintegrant and a glidant, then compressed and coated to prepare tablets.

[0092] This method can reduce the dose of each pranstard tablet to 50 mg, and therefore can be considered the optimal formulation design for improving bioavailability.

[0093] The inventors first attempted to design and manufacture chewable tablets using the above dosage form, which is an example of a pharmaceutical composition. Typically, when preparing chewable tablets, the physicochemical properties, taste, or aroma of the main components are considered when blending binders, excipients, and sweeteners. Therefore, the inventors attempted to blend the above formulation by changing the types of sweeteners and flavorings.

[0094] In this invention, the key to preparing formulations containing pranoxetine lies in the solubilization process of poorly soluble pranoxetine. Since the most suitable solubilizer and dosage have been found in existing inventions, the type and content of the solubilizer adopt the methods in existing inventions.

[0095] However, as is known from existing inventions, the lack of research on dissolution and blending methods for solubilizers has led to numerous problems during large-scale production. The biggest problem is that when using the commonly used binder dissolution method—the overnight dissolution method—to dissolve the solubilizer and binder in a suitable solvent for preparation and use, frequent adhesion or breakage occurs during the kneading and tableting processes. Therefore, the inventors have carefully studied the order of addition of the binder and solubilizer in the preparation method, the dissolution time, and the post-dissolution usage time, and have invented an optimal dissolution method.

[0096] No problems were found in the kneading, drying, and tableting processes when the solubilizer and binder were weighed and added in the following order.

[0097] The solubilization method and the type of binder are the same as in existing inventions. The solubilization temperature and time are key factors in the preparation method. The optimal solubilization temperature and time are 55±5℃ and 45±15 minutes, respectively. When the solubilization temperature is below 50℃, not only will the solubilization time of the solubilizer be prolonged, but the solubilization of the main component will also be affected. When heating to above 60℃, although the solubilization time can be shortened, it can cause adhesion or breakage during tableting. Furthermore, when the solubilization time is less than 30 minutes, the solubilization of the main component cannot be adequately guided; when it exceeds 60 minutes, it causes interference with tableting, similar to when the temperature exceeds 60℃.

[0098] In addition, the process of preparing the binder after dissolving the solubilizer also affects the successful completion of the formulation, leading to problems in the kneading and tableting processes.

[0099] It is known that when adhesives and solubilizers are added to the solvent used to dissolve the adhesives and left to stand overnight (12-16 hours), the evaporated solvent is weighed and calibrated before use the next day. Then, the mixture is kneaded in a high-speed mixer. In this process, the solubilizer precipitates out, and the kneaded mixture becomes viscous in a short time, resulting in uneven mixing and kneading. When the kneaded mixture is dried, pulverized, and then compressed into tablets after a post-mixing process, adhesion and breakage occur.

[0100] Although the exact cause of this phenomenon is unclear, it is speculated that it may be due to subsequent processes being carried out without the solubilizer and binder being uniformly mixed with the mixture.

[0101] To address this issue, the inventors not only carefully studied the dissolution time of the solubilizer, but also the dissolution time of the adhesive, the mixing time of the solubilizer and the adhesive, and the appropriate time for the adhesive to be used after mixing.

[0102] The results indicate that the solubilizer dissolution conditions should meet the above requirements, and the dissolution time of the adhesive and the mixing time between the adhesive and the solubilizer should be within 35 to 95 minutes. Furthermore, the dissolved adhesive should be used within 5 hours to avoid interfering with the kneading and tableting processes.

[0103] Furthermore, when prepared in this manner, the characteristic bitterness of pregnenstat is very pronounced, ultimately resulting in a prolonged bitter taste in the mouth.

[0104] Even with precise dissolution methods and usage time for solubilizing and binding, a slight bitterness still exists. This bitterness is caused by the main ingredients and solubilizers. To overcome this problem, we have tried to use a variety of sweeteners and flavorings to reduce the bitterness. The sweeteners can be one or more selected from the group consisting of white sugar, glucose, mannitol, sorbitol, aspartame, acesulfame potassium, and sucralose.

[0105] In addition, the contents of the solubilizer and the binder also need to be adjusted. Specifically, the contents of the solubilizer relative to the total weight of the pharmaceutical composition can be 1 to 20% by weight, preferably 1 to 10% by weight; the contents of the binder relative to the total weight of the pharmaceutical composition can be 1 to 5% by weight, preferably 1 to 3% by weight.

[0106] This invention also demonstrates that, in addition to the preparation conditions of the solubilizer and binder mentioned above, the conditions of the preparation equipment such as the high-speed mixer and tablet press also have a very important impact on the interference phenomena on the kneading and tableting processes that have not been resolved in the prior art.

[0107] Place the mixture containing the main components into a high-speed mixer and start the agitator and chopper. The preferred speed for this is 120±10 rpm for 3±1 minutes. A slower speed will result in poor mixing; a faster speed may cause separation, also leading to poor mixing. Once fully mixed, the binder should be added slowly to ensure good mixing of the solubilizer and main components. The agitator and chopper speeds should ideally match the mixing speed, and a kneading time of 5±1 minutes is optimal. A shorter kneading time will result in uneven mixing of the binder; a longer kneading time will cause the mixture to become viscous instantly, potentially leading to adhesion or breakage during tableting.

[0108] These problems are not common when preparing tablets using conventional wet granulation methods. However, when preparing poorly soluble drugs by solubilization, as in this invention, conventional formulation preparation methods often result in the inability to proceed, or even if preparation is possible, the quality is difficult to guarantee.

[0109] As described in this invention, prunoxetine is a drug with extremely low solubility and poor absorption. Therefore, not only its composition but also its preparation process can be considered as one of the key factors affecting the drug's performance.

[0110] In this invention, the individual or combined action of the main components and the components used for solubilization can produce a very bitter taste. Masking the bitterness is crucial when developing chewable tablets as shown in this invention.

[0111] As a method to mask bitterness, it is common to reduce bitterness by mixing sugars. However, prannis and solubilizing polyoxyl 15-hydroxystearate have the characteristic of bitterness gradually appearing after being taken and chewed, so the choice of sweetener is crucial.

[0112] In this invention, when using sweetness to mask bitterness, a weakly acidic organic acid (pH adjuster) is added in order to more effectively mask the bitterness, and sucralose and aspartame are appropriately mixed in as sugars, so as to completely mask the bitterness of the main component prancetta and the solubilizing polyoxyethylene 15-hydroxystearate.

[0113] Specifically, aspartame and sucralose can be added in a weight ratio of 1 to 2:1, preferably 1.1 to 1.3:1.

[0114] In this invention, lactose hydrate and microcrystalline cellulose may be included as diluents. This is an additive combination disclosed in the inventor's prior art (Korean Patent Publication No. 10-2363727), which significantly improves the bioavailability of pranstar and reduces the dosage. This combination reduces the daily dose of pranstar by a total of 26.5-74.2 mg, for example, 26.5 mg, 37.1 mg, 53 mg, and 74.2 mg, while still having the same effect as the 50 mg, 70 mg, 100 mg, and 140 mg dry syrup doses. Therefore, this diluent combination is a convenient chewable tablet form that can be taken without water and is optimized to improve bioavailability.

[0115] Conventional tablet preparation methods

[0116] The present invention can be prepared by mixing the above-described chewable drug delivery system with progesterone that has undergone a solubilization process.

[0117] At this point, prunust is first wet-granulated together with diluent and surfactant to improve bioavailability.

[0118] When preparing granules according to the present invention, diluents commonly used in the pharmaceutical field can be used. For example, one or more of the following can be selected: xylitol, mannitol, isomaltitol, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabinitol, galactitol, lactitol, maltotriol, microcrystalline cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicate, or crystalline cellulose. In particular, to achieve the desired effects of the present invention, microcrystalline cellulose, lactose, or mixtures thereof are preferred. To achieve the desired effects of the present invention, preferably, the diluent accounts for 20-60% of the total weight of the pharmaceutical composition.

[0119] When preparing granules according to the present invention, binders commonly used in the pharmaceutical field can be used. For example, one or more selected from polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, etc., can be used. In particular, to achieve the desired effects of the present invention, one or more selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, and hydroxypropyl methylcellulose are preferred, with polyvinylpyrrolidone being the most preferred. To achieve the desired effects of the present invention, preferably, the binder accounts for 2-10% of the total weight of the pharmaceutical composition.

[0120] When preparing granules according to the present invention, one or more surfactants (solvents) may be selected as surfactants (solvents), including polyethylene glycol-15-hydroxystearate (e.g., Kolliphor® HS 15), polyoxyethylene natural or hydrogenated castor oil (e.g., Kolliphor® RH 40), polyoxyethylene-polyoxypropylene copolymers (e.g., poloxamers), polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate esters), sodium lauryl sulfate, and glycerol fatty acid esters (e.g., glyceryl monostearate). In particular, to achieve the desired effects of the present invention, one or more surfactants (solvents) selected from the group consisting of polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene sorbitan fatty acid esters, and sodium lauryl sulfate are preferred. To achieve the desired effects of the present invention, preferably, the surfactant (solvent) accounts for 5-20% of the total weight of the pharmaceutical composition.

[0121] When preparing particles according to the present invention, alcohol solvents are preferably used instead of purified water as solvents. In this case, to achieve the desired effects of the present invention, C1-C6 alcohols are preferred as alcohol solvents. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, and butanol can be used. In particular, the bioavailability of prenstar is significantly improved when ethanol is used.

[0122] The pharmaceutical compositions of the present invention may comprise solid particles of the above-mentioned pransildenafil and a pharmaceutically acceptable carrier.

[0123] Pharmaceutically acceptable carriers include known diluents, disintegrants, and flow aids. In this invention, diluents that can be used as carriers include xylitol, mannitol, isomaltitol, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabinitol, galactitol, lactitol, maltodextrin, microcrystalline cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silica or crystalline cellulose, and mixtures thereof. Disintegrants include sodium carboxymethyl starch glycolate, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, etc. Flow aids include sodium stearate fumarate, magnesium stearate, stearic acid, colloidal silica, etc.

[0124] The pharmaceutically acceptable carrier can be flexibly adjusted according to the total weight of the composition and can be appropriately selected and used according to the final dosage form.

[0125] Dissolution and pharmacokinetic (PK) conditions

[0126] The purpose of this invention is to solubilize and prepare a chewable dosage form of progesterone preparations taken twice daily at a dose of 50-140 mg, thereby achieving equivalent effects by taking it twice daily at a dose of 26.5-74.2 mg, for example, 26.5 mg, 37.1 mg, 53.0 mg or 74.2 mg.

[0127] In this invention, the inventors disclose for the first time the dissolution and clinical trial PK conditions required to achieve the following objective: to prepare chewable tablets containing prenroximate, which, when taken twice daily at a dose of 26.5–74.2 mg, instead of twice daily doses of 50–140 mg, for example, 50 mg, 70 mg, 100 mg, or 140 mg (as in existing dry syrup administration), achieve the same effect as existing commercially available formulations.

[0128] The pharmaceutical composition of the present invention is characterized in that, by using a second dissolution method (paddle method), after dissolving in a pH 6.8 + 0.2% PSB solution for 30 to 45 minutes, the concentration of pranoxetine reaches more than 80%.

[0129] Furthermore, the pharmaceutical composition of the present invention is characterized in that, when administered to beagle dogs, the time required for pranlast to reach maximum plasma concentration is within 3 hours. When the above-described non-clinical clinical trial PK conditions are met, the pranlast formulation is equivalent to existing syrup formulations.

[0130] The formulation design of this invention satisfies the above-mentioned dissolution and PK conditions, and the reagent is a formulation that ultimately ensures equivalence to syrup.

[0131] The following are embodiments of the invention. However, it is hereby stated that the scope of the invention should not be limited to the following embodiments.

[0132] Preparation of chewable tablets

[0133] Examples 1-3 and Comparative Example 1

[0134] For the chewable tablets of Examples 1-3 and Comparative Example 1, the preparation methods and process variables were carried out in the same manner, except for the composition described in Table 1 below, and are described in detail below (for compositions containing lactose hydrate or microcrystalline cellulose as diluents, solubilizers, sweeteners and flavorings were added).

[0135] Preparation method

[0136] Process 1. Preparation of adhesive solution (ethanol, ... polyoxy Solvents of 15-hydroxystearate, povidone, and poloxamer (Solution and dispersion)

[0137] To solubilize prenstar, which has extremely low solubility, the solubilizers polyoxymethylene 15-hydroxystearate and poloxamer were dissolved at 55±5°C, more preferably 60°C, for 30–60 minutes. Next, the binder polyvinylpyrrolidone (PVP K-30) was slowly added to the binder solvent ethanol, and the mixture was stirred for 35±15 minutes until completely dissolved. After confirming that there were no lumps or undissolved residues, the previously dissolved solubilizers polyoxymethylene 15-hydroxystearate and poloxamer were slowly added, and the mixture was stirred for 30±15 minutes to homogenize and disperse the mixture.

[0138] Process 2. Mixing of praseodymium hydrate, lactose hydrate, and anti-curing sugar powder

[0139] Add praseodymium hydrate, lactose hydrate and anti-curing sugar powder to a high-speed mixer and mix for 3 minutes at a stirrer speed of 120±10 rpm and a chopper speed of 2000±200 rpm.

[0140] Process 3. Granulate the semi-finished product from Process 2 together with the binder solution from Process 1.

[0141] Slowly add the binder solution (dissolved solubilizer and binder solution) from Process 1 to the semi-finished product from Process 2. The stirring and chopping speeds are the same as in the mixing step. Knead for 5 minutes, as the kneading time affects the properties of the kneaded product.

[0142] Process 4. Use a corn mill to process the semi-finished product from Process 3 ( kneading Granulation

[0143] After kneading, the mixture is granulated using a corn mill at 300–900 rpm.

[0144] Process 5. Drying of the semi-finished product from Process 4

[0145] Drying is carried out using a preheated plate dryer. After spreading the granules to a thickness of approximately 1 cm, they are dried at 50°C until the LOD value reaches below 2.0%. Preferably, it is 0.4% to 1.0%, more preferably about 0.8%.

[0146] Process 6. Use an oscillator (No. 18 sieve, 850μm) to screen the semi-finished product from Process 5.

[0147] The dried particles were sieved using an oscillator (18-mesh sieve, 850 μm screen size) and then transferred to a bin blender.

[0148] Process 7. Add D-mannitol, crospovidone, citric acid hydrate, aspartame to the semi-finished product from Process 6. After mixing sucralose, strawberry flavor powder, and colloidal silica, sodium stearate is added for final mixing.

[0149] Next, add D-mannitol, crospovidone, citric acid hydrate, aspartame, sucralose, strawberry flavor powder, and colloidal silica to a hopper mixer and mix at 10 rpm for 10 minutes. Then, finally add sodium stearate fumarate and mix at 10 rpm for another 5 minutes.

[0150] Process 8. Compress the semi-finished product from Process 7 into tablets using a rotary tablet press.

[0151] The final mixture (semi-finished product from process 7) is tableted using a rotary tablet press. During tableting, the rotary table speed is set to 20–30 rpm, preferably 23–27 rpm; the tableting position is set to 16.5–18 mm; and the tableting pressure is set to a pre-compression of 30 ± 5 kgf / cm². 2 Main pressure 35±5 kgf / cm 2 .

[0152] Examples 4-5

[0153] For the chewable tablets of Examples 4 and 5, except for the composition described in Table 1 below, the preparation methods and process variables were carried out in the same manner and are described in detail below.

[0154] Preparation method

[0155] Process 1. Preparation of adhesive solution (ethanol, ... polyoxy Solvents of 15-hydroxystearate, povidone, and poloxamer (Solution and dispersion)

[0156] To solubilize prenstar, which has extremely low solubility, the solubilizers polyoxymethylene 15-hydroxystearate and poloxamer were dissolved at 55±5°C, more preferably 60°C, for 30–60 minutes. Next, the binder polyvinylpyrrolidone (PVP K-30) was slowly added to the binder solvent ethanol, and the mixture was stirred for 35±15 minutes until completely dissolved. After confirming that there were no lumps or undissolved residues, the previously dissolved solubilizers polyoxymethylene 15-hydroxystearate and poloxamer were slowly added, and the mixture was stirred for 30±15 minutes to homogenize and disperse the mixture.

[0157] Process 2. Prunustrazine hydrate, lactose hydrate, isomaltitol, anti-curing sugar powder, and hydroxypropyl cellulose Mix

[0158] Add prannister hydrate, lactose hydrate, isomaltitol, anti-curing sugar powder and hydroxypropyl cellulose to a high-speed mixer and mix for 3 minutes at a stirrer speed of 120±10 rpm and a chopper speed of 2000±200 rpm.

[0159] Process 3. Granulate the semi-finished product from Process 2 together with the binder solution from Process 1.

[0160] Slowly add the binder solution (dissolved solubilizer and binder solution) from Process 1 to the semi-finished product from Process 2. The stirring and chopping speeds are the same as in the mixing step. Knead for 5 minutes, as the kneading time affects the properties of the kneaded product.

[0161] Process 4. Drying of semi-finished products from Process 3

[0162] Drying is carried out using a preheated fluidized bed dryer, drying the semi-finished particles from process 3 at 50–55°C until the LOD value reaches below 2.0%. Preferably, it is 0.4–1.0%, more preferably about 0.8%.

[0163] Process 5. Use an oscillator (No. 18 sieve, 850μm) to screen the semi-finished product from Process 4.

[0164] The dried particles were sieved using a vibrator (No. 18 sieve, sieve size: 850μm) and then transferred to a hopper mixer.

[0165] Process 6. Add D-mannitol, crospovidone, citric acid hydrate, and low-substituted hydroxypropyl to the semi-finished product from Process 5. After mixing cellulose, aspartame, sucralose, strawberry flavoring powder, and colloidal silica, stearic acid and stearic acid were added. Sodium fumarate (Example 4) or sodium stearate fumarate (Example 5) were then used for the final mixing.

[0166] Next, D-mannitol, crospovidone, citric acid hydrate, low-substituted hydroxypropyl cellulose, aspartame, sucralose, strawberry flavor powder, and colloidal silica were added to a hopper mixer and mixed at 10 rpm for 10 minutes. Then, sodium stearate fumarate (Example 4) or sodium stearate fumarate (Example 5) was added and mixed at 10 rpm for another 5 minutes.

[0167] Process 7. Compress the semi-finished product from Process 6 into tablets using a rotary tablet press.

[0168] The final mixture (semi-finished product from process 6) is tableted using a rotary tablet press. During tableting, the rotary table speed is set to 20–30 rpm, preferably 23–27 rpm; the tableting position is set to 16.5–18 mm; and the tableting pressure is set to a pre-compression of 30 ± 5 kgf / cm². 2 Main pressure 35±5 kgf / cm 2 .

[0169] Table 1

[0170] Preparation of conventional tablets

[0171] Example 6

[0172] The tablets of Example 6 were prepared using the ingredients described in Table 2 below and by the following preparation method.

[0173] Process 1. Preparation of adhesive solution (ethanol, ... polyoxy Solvents of 15-hydroxystearate, povidone, and poloxamer (Solution and dispersion)

[0174] To solubilize prenstar, which has extremely low solubility, the solubilizing agents polyoxymethylene 15-hydroxystearate and poloxamer were dissolved in a constant-temperature water bath at 60°C for 10–30 minutes. Next, the binder polyvinylpyrrolidone (PVP K-30) was slowly added to the binder solvent ethanol, and the mixture was stirred for 60 ± 30 minutes until completely dissolved. After confirming that there were no lumps or undissolved residues, the previously dissolved solubilizing agents polyoxymethylene 15-hydroxystearate and poloxamer were slowly added, and the mixture was stirred for 120 ± 30 minutes to homogenize and disperse the mixture.

[0175] Process 2. Mixing of prunustrazine hydrate, lactose hydrate, and microcrystalline cellulose

[0176] Add prannister hydrate, lactose hydrate and microcrystalline cellulose to a high-speed mixer and mix for 3 minutes at a stirrer speed of 120±10 rpm and a chopper speed of 1800±200 rpm.

[0177] Process 3. Granulate the semi-finished product from Process 2 together with the binder solution from Process 1.

[0178] Slowly add the binder solution (dissolved solubilizer and binder solution) from Process 1 to the semi-finished product from Process 2. The stirring and chopping speeds are the same as in the mixing step. Knead for 5 minutes, as the kneading time affects the properties of the kneaded product.

[0179] Process 4. Use a corn mill to granulate the semi-finished product from Process 3.

[0180] After kneading, the mixture is granulated using a corn mill at 300–900 rpm.

[0181] Process 5. Drying of semi-finished products from Process 4

[0182] Drying is carried out using a preheated flatbed dryer. After spreading the granules to a thickness of approximately 1 cm, they are dried at 50°C until the LOD value reaches 2.0%. Preferably, it is 0.8% to 1.2%, more preferably about 1%.

[0183] Process 6. Use an oscillator (No. 18 sieve, 850μm) to screen the semi-finished product from Process 5.

[0184] The dried particles were sieved using a vibrator (No. 18 sieve, 850 μm) and then transferred to a hopper mixer.

[0185] Process 7. Add crospovidone, crospovidone sodium carboxymethyl cellulose, and colloidal silica to the semi-finished product from Process 6. After mixing, magnesium stearate is added for final mixing.

[0186] Next, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and colloidal silica are added to a hopper mixer and mixed at 10 rpm for 10-15 minutes. Then, magnesium stearate is added and mixed at 10 rpm for another 5 minutes.

[0187] Process 8. Compress the semi-finished product from Process 7 into tablets using a rotary tablet press.

[0188] The final mixture (semi-finished product from process 7) is tableted using a rotary tablet press. During tableting, the rotary table speed is set to 20–30 rpm, preferably 23–27 rpm; the tableting position is set to 14.0–17.5 mm; and the tableting pressure is set to a pre-compression of 25–40 kgf / cm³. 2 Main pressure 30-45 kgf / cm 2 .

[0189] The tablet hardness is preferably 5-12 kp, more preferably compressed to 5-10 kp, and even more preferably compressed to 6-8 kp.

[0190] Process 9. Coating the semi-finished product from Process 8.

[0191] The semi-finished tablets from process 8 are coated by preparing a coating solution.

[0192] Table 2

[0193] Experimental Example

[0194] Experimental Example 1. Confirm the effects of dissolving methods and times of solubilizers and binders on kneading / tableting processes. Should it be sent? Interference phenomenon

[0195] As can be seen in this invention, interference can occur during the kneading process or tableting depending on the dissolution method and time of the solubilizer and binder. Therefore, although the inventors could not accurately determine the specific cause, it was foreseeable that the solubilizer might have an effect. Thus, the dissolution method, dissolution time, and shelf life after dissolution were studied, and the optimal conditions for the kneading and tableting processes were established, thereby completing this invention.

[0196] When dissolving the solubilizer, the dissolution temperature was set to 50℃, 55℃, 60℃, 65℃ and 70℃ respectively, and the dissolution time was set to 30 minutes and 60 minutes respectively.

[0197] Table 3 shows the interference of solubilizer dissolution temperature and dissolution time on the kneading and tableting processes under various conditions, taking Example 1 as a typical example. Table 4 shows the interference of adhesive dissolution time and shelf life on the process.

[0198] Table 3

[0199] Table 4

[0200] This invention discloses for the first time the dissolution time and shelf life of the adhesive. Although the exact mechanism is unclear, it is presumed to be influenced by the solubilizing agents polyoxyethylene 14-hydroxystearate and poloxamer 407 used in this invention for solubilizing pralidoxime. To elucidate this phenomenon, the inventors attempted to clarify the mechanism by changing the types of adhesive and other poorly soluble drugs. In this invention, as shown in Tables 3 and 4, preferably, the preparation time is 30 minutes to 90 minutes, and the shelf life does not exceed 5 hours. More preferably, the adhesive and solubilizer need to be used in production immediately after complete dissolution and swelling to prevent the mixture from becoming viscous in a short time during the kneading process or from severely sticking together during the tableting process, thereby reducing production efficiency.

[0201] Experimental Example 2. Formulation suitability testing based on sieve size

[0202] Evaluation methods

[0203] Prepared according to the sieve size and evaluated after tableting.

[0204] Test results

[0205] If a tablet meets the following criteria for hardness, friability, flowability, disintegration and dissolution, it is considered suitable. Table 5 below shows the results based on the sieve size.

[0206] Evaluation criteria

[0207] Hardness: 4-8 KP

[0208] Friability: Less than 0.5% after 20 pieces are rotated 100 times.

[0209] Flowability: Angle of repose below 43°

[0210] Disintegration rate: within 15 minutes (visually confirmed); Sample quantity: 6 samples of each type.

[0211] Dissolution rate: over 30% within 10 minutes, over 70% after 30 minutes

[0212] Table 5

[0213] Evaluation results

[0214] As shown in Table 5, when using a sieve size of less than 700 μm, specifically 500–600 μm, to prepare particles containing prenstar, unsuitable results were confirmed in the flowability and disintegration tests. This confirms that as the sieve size decreases, the time increases, and the amount of fine particles generated also increases, thus affecting the flowability.

[0215] However, when preparing granules containing prenroximate using a sieve of 710–850 μm according to the present invention (an 850 μm sieve was used in Example 1), it can be confirmed that not only is the sieving time short, but formulations (chewable tablets, tablets) with suitable hardness, friability, flowability, disintegration test, dissolution, etc. can also be prepared.

[0216] Experimental Example 3. Evaluation of the masking effect of chewable tablets

[0217] Evaluation methods

[0218] This invention develops a chewable tablet containing prenrofloxacin hydrate. For formulations intended for oral chewing, the taste and odor must not be unpleasant to the patient. Therefore, the inventors blended various sweeteners and flavorings and conducted sensory tests on the taste, chewing sensation, and other aspects.

[0219] Specifically, the chewable tablets prepared in Examples 1-4 and Comparative Example 1 were subjected to a (simple) sensory evaluation of bitterness, sweetness, and chewiness, and the results are shown in Tables 6-9.

[0220] Table 6

[0221] Table 7

[0222] Table 8

[0223] Table 9

[0224] Evaluation results

[0225] Referring to Table 9, it was confirmed that the chewable tablets of Examples 1 to 4 all received good / very good evaluations in terms of bitterness, sweetness, and chewing texture. However, the chewable tablet of Comparative Example 1 failed to mask the bitterness and was not sweet enough, resulting in inconvenience in taking it.

[0226] Experimental Example 4. Dissolution Evaluation of Chewable Tablets

[0227] Evaluation methods

[0228] According to the second dissolution test method in the Korean Pharmacopoeia, the dissolution of one chewable tablet (test substance, Citus chewable tablet, 74.2 mg of prunoxetine hydrate) and dry syrup (Sam-A Pharmaceutical, Citus dry syrup, control substance) prepared in Example 1 were compared.

[0229] Specifically, 900 mL of a solution containing a pH 6.8 solution and a 0.2% PSB solution were added to the dissolution apparatus. The mixture was stirred at 50 rpm while maintaining a temperature of 37 ± 0.5 °C, and the dissolution rate was measured. Approximately 5 mL of the dissolution solution was collected at each time point (0 min, 10 min, 15 min, 30 min, and 45 min), filtered through a 0.45 μm filter membrane, and analyzed by high-performance liquid chromatography (HPLC). The results are as follows: Figure 1 As shown.

[0230] In addition, a comparative dissolution test was performed on one chewable tablet (test substance, Citus chewable tablet, 74.2 mg of prunoxetine hydrate) prepared in Examples 1, 4, and 5, according to the second dissolution test method in the Korean Pharmacopoeia. The comparative dissolution method was the same as that described above, and the results are as follows. Figure 2 As shown.

[0231] Evaluation results

[0232] Figure 1 The dissolution test results, confirmed by comparing the chewable tablets of Example 1 of the present invention (test substance, Citus chewable tablets, 74.2 mg of prunoxetine hydrate) with the control drug dry syrup (Sam-A Pharmaceutical, 140 mg of Citus dry syrup), are shown. Figure 1 It can be confirmed that the concentration of pranoxetine in the chewable tablets (test substance) of Example 1 of the present invention reaches a dissolution rate of over 75% after 30 to 45 minutes. Therefore, it can be confirmed that the chewable tablets of Example 1 of the present invention, taken twice daily at a dose of 26.5-74.2 mg each time, can exhibit the same therapeutic effect as taking Citus dry syrup twice daily at a dose of 50-140 mg each time.

[0233] Furthermore, the chewable tablet (test substance, Citus chewable tablet) of Example 1 of the present invention was pulverized ( Figure 1 The sample was pulverized (74.2 mg), and the dissolution results of the pulverized tablets were confirmed to be equivalent to those of the control drug.

[0234] Figure 2This demonstrates whether the chewable tablets (test substance, Citus chewable tablets, prenstar hydrate 74.2 mg) of Examples 4 and 5 exhibit the same or similar dissolution behavior as the chewable tablets (test substance, Citus chewable tablets, prenstar hydrate 74.2 mg) of Example 1. Figure 2 It can be confirmed that the concentration of prencalactone in the chewable tablets (test substance) of Examples 4 and 5 reached a dissolution rate of over 75% after 30 to 45 minutes, which is the same as that of the chewable tablets (test substance) of Example 1. Therefore, it can be confirmed that, in addition to the chewable tablets of Example 1 of the present invention, the chewable tablets of Examples 4 and 5 also only require twice-daily administration of 26.5-74.2 mg each time to exhibit the same therapeutic effect as twice-daily administration of Citus dry syrup at a dose of 50-140 mg each time.

[0235] Experimental Example 5. Bioequivalence Test of Chewable Tablets

[0236] Evaluation methods

[0237] The human biokinetics of the chewable tablets (Example 1) prepared according to the present invention and the commercially available formulation Citus dry syrup (Sam-A Pharmaceutical, 140 mg) were evaluated.

[0238] Evaluation results

[0239] Reference Figure 3 It can be confirmed that the chewable tablets of Example 1 prepared by the preparation method of the present invention exhibit the same clinical efficacy even when taken at a dose (74.2 mg / tablet) much lower than that of the commercially available Citus dry syrup (each containing 140 mg of progesterone).

[0240] While specific portions of the invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions are merely preferred examples and do not limit the scope of the invention. Therefore, the actual scope of the invention will be defined by the appended claims and their equivalents.

Claims

1. A method for preparing a pharmaceutical composition containing pransildenafil, characterized in that, include: Step (S1): After dissolving the solubilizer at 50-60°C for 30-60 minutes, add the resulting solution to the solution containing the adhesive, and then stir to prepare a mixed solution containing the solubilizer and the adhesive. Step (S2): Mix pramlast, its hydrate, its solvate or its salt with the pharmaceutical additive; Step (S3): After adding the mixed solution from step (S1) to the mixture from step (S2), the mixture is kneaded to form granules. Step (S4) involves drying the particles from step (S3) to prepare dried particulate matter. Step (S5) involves sieving the dried particulate matter from step (S4) and mixing it with the pharmaceutical additive to prepare the final mixture; and Step (S6) involves compressing the final mixture from step (S5) into tablets.

2. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, Dissolve the solubilizer at 50–60°C for 30–60 minutes, and use the solution containing the solubilizer within 1 hour.

3. The method for preparing the pharmaceutical composition containing pranoxetine according to claim 1, characterized in that, The solution containing the adhesive in step (S1) is obtained by adding the adhesive to the adhesive solvent and stirring for 20 to 50 minutes, and is used within 5 hours.

4. The method for preparing the pharmaceutical composition containing pransildenafil according to claim 1, characterized in that, The solution containing the solubilizer is added to the solution containing the adhesive, and then dissolved for 15 to 45 minutes to obtain the mixed solution in step (S1).

5. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, The solubilizer in step (S1) is any one of polyoxy 15-hydroxy stearate, poloxamer 407, or a mixture thereof.

6. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, The adhesive used in step (S1) is selected from one or more of the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol.

7. The method for preparing the pharmaceutical composition containing pranoxetine according to claim 1, characterized in that, The amount of solubilizer added is 1 to 20% by weight relative to the total weight of the pharmaceutical composition, and the amount of binder added is 1 to 5% by weight.

8. The method for preparing the pharmaceutical composition containing pransildenafil according to claim 1, characterized in that, The drug additive in step (S2) is one or more selected from the group consisting of diluents, sweeteners and binders.

9. The method for preparing the pharmaceutical composition containing pransildenafil according to claim 8, characterized in that, The diluent in step (S2) is any one or more of xylitol, mannitol, isomaltitol, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabinitol, galactitol, lactitol, maltotriol, microcrystalline cellulose, croscarmellose sodium cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium cellulose, carboxymethyl cellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silica, or crystalline cellulose, and the sweetener is anti-curing sugar powder.

10. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, The mixing in step (S2) is carried out for 1 to 5 minutes at a stirrer speed of 110 to 130 rpm and a chopper speed of 1800 to 2200 rpm.

11. The method for preparing the pharmaceutical composition containing pranoxetine according to claim 8, characterized in that, The adhesive used in step (S2) is selected from one or more of the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol.

12. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, The sieving in step (S5) is performed on the dried particulate matter using a 710–850 μm sieve.

13. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, The drug additive in step (S5) is one or more selected from the group consisting of diluents, disintegrants, pH adjusters, sweeteners, flavorings and gliding agents.

14. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 13, characterized in that, The diluent is any one or more of xylitol, mannitol, isomaltitol, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabinitol, galactitol, lactitol, maltotriol, microcrystalline cellulose, croscarmellose sodium cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose sodium cellulose, carboxymethyl cellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silica, or crystalline cellulose.

15. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 13, characterized in that, The disintegrant is any one of crospovidone, low-substituted hydroxypropyl cellulose, or a mixture thereof.

16. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 13, characterized in that, The pH adjuster is citric acid hydrate.

17. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 13, characterized in that, The sweetener is selected from any one of the following groups: white sugar, glucose, mannitol, sorbitol, aspartame, acesulfame potassium, and sucralose.

18. The method for preparing the pharmaceutical composition containing pranoxetine according to claim 13, characterized in that, The gliding agent is any one of colloidal silica, sodium stearate fumarate, magnesium stearate, or a mixture thereof.

19. The method for preparing the pranoxetine-containing pharmaceutical composition according to claim 1, characterized in that, In the tableting step (S6), the rotary table speed is 20–30 rpm, the tableting position is 16.5–18 mm, and the tableting pressure is a pre-compression of 25–35 kgf / cm². 2 Main pressure 30-40 kgf / cm 2 The tablets are then compressed to adjust the hardness to 5–12 kp.

20. A pharmaceutical composition, characterized in that, It is prepared by the method of any one of claims 1 to 19 for preparing a pharmaceutical composition containing pranoxetine.

21. The pharmaceutical composition according to claim 20, characterized in that, The pharmaceutical composition is an oral solid dosage form.

22. The pharmaceutical composition according to claim 21, characterized in that, The dosage form of the oral solid dosage form is any one of granules, capsules, chewable tablets, single-layer tablets, multi-layer tablets, tablet cores, microparticles, or mini tablets.

23. The pharmaceutical composition according to claim 20, characterized in that, The pharmaceutical composition contains 26-74.2 mg of pranoxetine per unit dosage form.

24. The pharmaceutical composition according to claim 20, characterized in that, When the drug composition is dissolved in a solution at pH 6.8 using the second dissolution method of the Korean Pharmacopoeia, namely the paddle method, the concentration of pranlast reaches more than 80% at a time point of 30 to 45 minutes.

25. The pharmaceutical composition according to claim 20, characterized in that, When the pharmaceutical composition is administered to the human body, the time required for pranstar to reach maximum blood concentration is within 3 hours.

Images