TWI326601B - Granule formulation - Google Patents

Description

1326601 A7 _____B7 V. INSTRUCTIONS (丨) BACKGROUND OF THE INVENTION SINGULAIR® is recognized as a white-triad receptor agonist for the treatment of adult asthma and 2-year-old children. The drug is currently being studied for the treatment of seasonal allergic rhinitis and for possible use by young children up to 6 months of age. M〇ntelukast sodium is currently used as a tablet for 1 〇 mg of coated film for adults and 4 mg and 5 mg for children. SUMMARY OF THE INVENTION The present invention is directed to a novel formulation of montelukast sodium in the form of a granulated powder which can be ingested directly or in combination with other foods. Seven, mixed with food or other foods. The novel formulations are suitable for patients who are unsuitable or unacceptable for swallowing or inhaling lozenges. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a flowable or dispersible pharmaceutical composition comprising: a composition comprising a substrate coated with montelukast sodium and a lubricant. The granules of the present compositions can be prepared by coating a substrate with an aqueous solution of montelukast sodium, optionally condensed with a pharmaceutically acceptable 'cleaning agent'. The resulting drug granules are dried and blended with a pharmaceutically acceptable lubricant to form a flowable and dispersible composition suitable for packaging. In the present invention, the substrate may be any pharmaceutically acceptable person; sugars such as mannitol, sucrose, lactose, xylitol and the like are usually used. The preferred form of substrate used is in the form of a free-flowing form which is characterized by a unit dose bag which assists in the accurate sale of the final product granules into the market. If the substrate is not free to flow, then I paper size ^ National Standard (CNS) A4 specification (·2ι〇χ297 mm/----- 1326601 A7 B7 V. Description of invention (2) Need to separate individual particles into Larger particles. In one specific example, the substrate is spray-dried mannitol, which can be prepared by using a conventionally processed, spray-dried aqueous solution of mannitol. Commercially available spray-dried mannitol (e.g., PEARLITOL® SD 200 from Roquette Freres, France). Spray-dried mannitol, such as PEARLITOL® SD 200, is typically a single particle that imparts free-flowing properties to the material. Mannitol, because of its sweetness, cold taste and non-absorbency. The substrate generally comprises from about 95 to about 98 wt% of the composition. When the substrate itself is extremely free flowing, it can be further agglomerated Manufacture of pharmaceutical granules or, where appropriate, coagulation of the substrate with a pharmaceutically acceptable binding agent. Suitable pharmaceutically acceptable binding agents are, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, B Cellulose and poly Vinylpyrrolidone. The agglomeration of the substrate particles is carried out by applying an aqueous solution of the binder to the substrate, for example by spraying a solution of the binder onto the fluid bed of the substrate. The composition is about 2 to about 5%. The resulting agglomerated substrate particles are dried and used in the next step. The substrate particles are coated with Monferruca by, for example, spraying a pharmaceutical aqueous solution directly onto the fluid bed of the substrate. Montellukast, manufacturing pharmaceutical granules. The granulation process obtains granules coated with the medicinal material, followed by drying the sizing to obtain granules of less than about 850 microns. The sized granules are blended with the lubricant. The final product container. The montelukast is a known compound, and is disclosed in, for example, U.S. Patent Nos. 5,565,473 and 5,614,632. The Chinese National Standard (CNS) A4 specification (210X) is applied to the paper scale. 297 mm)

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Line -5 - 1326601 A7 _ B7___ V. INSTRUCTION DESCRIPTION ( ) ' " 3 The application of the present invention uses an aqueous solution of montelukast sodium in a granulation process. Montelukast> generally comprises from about 0% to about 5% of the composition, such that each unit dose package contains from about 2 mg to about 20 mg per dose of Montiel Lucas (montelukast). Those skilled in the art will appreciate that other inert ingredients may also be added to the composition to impart the desired properties, such as taste or appearance, to the final product; for example, sweeteners such as sweeteners, flavoring compounds, and food colors may be used. The dried and sized medical particles are melt blended with the lubricant to assist in the flow of the product during the filling operation of the unit dose formation and to avoid the combination of moving metal components during the operation. Suitable lubricants are pharmaceutically acceptable and include, but are not limited to, beta stearates such as magnesium stearate, talc, and the like, generally comprising from about 0.25 to about 1% of the composition. Lubricant particles are used to fill the final unit dose package, which provides medical particle light and moisture protection. An example of a suitable package is a metal foil (e.g., aluminum) bag or bag. The metal foil can be laminated with an outer polyester film for protection against children (piercing or tearing). The inner layer of linear low-density polyethylene sulphide is used as a heat seal component of the drug pack. Montelukast sodium is a leukotriene receptor antagonist and can therefore be used to treat and prevent leukotriene-regulated diseases and disorders. Baisanzhi anti-drug is used to treat asthma, allergic rhinitis (including seasonal and perennial), hereditary allergic dermatitis, chronic urticaria, sinusitis, intranasal polyps, chronic obstructive pulmonary disease, including spastic conjunctivitis Conjunctivitis 'migraine, cytoplasmic fibrosis, and its asthmatic virus (such as respiratory complications) fine suffocation-----6- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) ------ A7 B7 1326601 V. Description of the invention ( tube inflammation, etc. For asthma treatment, this combination can be placed directly in the mouth of the patient or by premixing with a sexual food such as applesauce The drug is administered to the patient. Iron Lucaster (mQntelukas_ determines the dose _ ordinary adult spoon 103⁄4 grams per day, and the child daily about 2 to about 5 mg. However, the dose is as much as the symptoms to be treated The nature and severity, age, weight and individual patient's foot response; physicians familiar with the art should be able to adjust the general dose up or down according to the individual characteristics and needs of the patient, and propose appropriate doses and medications. Timetable The treatment of allergic rhinitis (including seasonal and perennial) can be administered to a patient by directly placing it in the mouth of the patient or by premixing with food such as applesauce, etc. Allergic rhinitis The dose of sodium montelukast is about 1 mg per day for adults, and about 2 to about 5 grams per day for children. However, the dose is as much as the nature and severity of the symptoms to be treated, age, weight. And the response of individual patients; physicians familiar with the art should be able to adjust the general dose up or down according to the individual characteristics and needs of the patient's request for appropriate dosage and schedule of administration. For atopic The treatment of dermatitis can be administered to a patient by directly placing it in the mouth of the patient or by premixing with food such as applesauce, etc. Atherosic dermatitis for Montepulcated (montelukast) sodium dose is about 1 mg per day for adults and about 2 to about 5 mg per day for children. However, the dose varies with the nature and severity of the symptoms to be treated, age, weight, and individual patient response. Cooked Physicians of the art should be able to adjust the paper size up or down according to the individual characteristics and needs of the patient. The Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applicable.

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1326601

The appropriate dose, the appropriate dosage and schedule of administration. For the treatment of spastic ramie, the composition can be administered to a patient by placing it directly in the mouth of the patient or by premixing with food such as applesauce or the like. The sodium dose of montelukast used for chronic burial of measles is about 1 mg per day for adults and about 2 to 5 mg per litter for children. However, the amount of the dose varies with the nature and severity of the condition to be treated, age, weight, and the response of the individual patient; physicians skilled in the art should adjust to the individual characteristics and needs of the patient, up or down. The general dose, the appropriate dosage and schedule of administration. For the treatment of sinusitis, the composition can be administered to a patient by placing it directly in the mouth of the patient or by premixing with food such as applesauce or the like. For sinusitis, the steel of m〇ntelukast is about 1 gram per day for adults and about 2 to about 5 mg per day for children. However, the amount of the dose varies with the nature and severity of the condition to be treated, age, weight, and the response of the individual patient; physicians skilled in the art should be able to adjust up or down depending on the individual characteristics and needs of the patient. The general dose, the appropriate dosage and schedule of administration. For the treatment of intranasal polyps, the composition can be administered to a patient by placing it directly in the mouth of the patient or by premixing with food such as applesauce or the like. For intranasal polyps, m〇ntelukast is administered in an amount of about 1 mg per day for adults and from about 2 to about 5 mg per day for children. However, the amount of the dose varies with the nature and severity of the condition to be treated, age, weight, and the response of the individual patient; physicians skilled in the art should adjust to the individual characteristics and needs of the patient, up or down. The general dose, the appropriate dose and investment -____ -8- This paper wave scale Tongcai® s household material (CNS) A4 specification (210X297 mm) 1326601 A7 _____________B7_____ V. Invention description (6) - drug schedule. For the treatment of chronic obstructive pneumonia symptoms (C〇pD), the composition can be administered to a patient by placing it directly in the mouth of the patient or by premixing with food such as applesauce or the like. The chronic sodium obstructive pneumonia condition (c〇PD) uses a montelukast sodium dose of about 丨〇 mg per day for adults and about 2 to about 5 mg per litter for children. However, the amount of the dose varies with the nature and severity of the condition to be treated, age, weight, and the response of the individual patient; physicians skilled in the art should adjust to the individual characteristics and needs of the patient, up or down. The general dose, the appropriate dosage and schedule of administration. For the treatment of conjunctivitis (including nail conjunctivitis), the composition can be administered to a patient by directly placing it in the mouth of the patient or by premixing with food such as applesauce or the like. The sodium dosage of m〇ntelukast for conjunctivitis is about 10 mg per day for adults and about 2 to about 5 mg per day for children. However, the dose varies with the nature and severity of the condition to be treated, the age's weight, and the response of individual patients; physicians skilled in the art should be able to adjust up or down depending on the individual characteristics and needs of the patient. The general dose, the appropriate dosage and schedule of administration. The treatment for foliar fibrosis can be administered to a patient by placing it directly in the mouth of the patient or by premixing with food such as applesauce or the like. The sodium dose of m〇nte丨ukast for phyllodes fibrosis is about 10 mg per day for adults and about 2 to about 5 mg per litter for children. However, the amount of the dose varies with the nature and severity of the condition to be treated, age, weight, and the response of the individual patient; physicians skilled in the art should adjust to the individual characteristics and needs of the patient, up or down. The general dose, the appropriate dose is proposed _____ This paper scale applies China National Standard (CNS) Α 4 specifications (210 X 297 public) 1326601 V. Description of the invention (7 and the schedule of administration. For the milk% (four) disease Or the asthmatic secondary virus (such as the respiratory co-mother) of the '·' field branch tube inflammation "treatment, can be placed directly in the mouth of the patient or pre-mixed with food such as applesauce, etc." The composition is administered to the disease. These symptoms are used by ▲ iron Lucaster (then the heart is called steel fast! The amount of adult is about 1 每天 per day) and the child is about 2 to about 5 mg per day. However, the dose Depending on the nature and severity of the symptoms to be treated, the age, weight and the response of the individual's heart, the physician who is familiar with the skill should be able to adjust the general dose up or down depending on the individual characteristics and needs of the patient. Propose appropriate dose and cast The following description of the preparation of the present pharmaceutical composition is for illustrative purposes only and does not limit the scope of the invention in any way. For the preparation of pharmaceutical particles, the substrate is generally applied to a fluid bed granulation of a spray nozzle on a device. In the machine, the aqueous solution of the binder is smashed on the fluidized substrate at a specific rate to form granules. The granules are dried and granulated by spraying with a solution of sodium montelukast sodium. The granules were dried and the dried granules were sized < 850 microns, and then blended with the lubricant by rolling blending. The lubricated granules were refilled prior to filling the pack. Example 1 Montepulciano (montelukast) preparation of oral granules suitable for granulation of capitol: Pure water USP (102 kg) is placed in a suitably sized stainless steel container with a high shear agitator; hydroxyl is added at about 3 rpm with stirring Propylcellulose LF (HPC, 4.16 kg). Continue mixing at 300 rpm until the hydroxypropylcellulose is completely dissolved by visual inspection. The paper size is applicable to the Chinese National Standard (CNS> A4 specification (210 X 297 gong) before use. ) 10 1326601 A7 B7 Input Air Volume Input Air Temperature Input Air Dew Point Atomized Air Flow Spray Rate Input Air Volume Input Air Temperature Input Air Dew Point Atomized Air Flow V. Description of the Invention (To Complete Defoaming of Solution; The binder solution was used within 72 hours. 670 liters of granulated bowl of mannitol (Pearlitol SD 200, Roquette Freres, 194 kg) was transferred to a fluid bed granulator and the previously prepared HPC was processed using the following processing parameters. The solution (106 kg) was sprayed onto the mannitol in the column: about 25 00 scfm about 68 ° C about 12 〇 C about 46 scfm about 13 10 g / min After the solution was transferred, use the following processing parameters to dry Product in the column to the end point SO_5% LOD (drying loss): about 2500 scfm about 68 ° C about 12 〇 C about 30 scfm The dried product is discharged into a non-wired stainless steel drum. Preparation of the drug solution Pure water USP (49.0 kg, theoretical amount) was placed in a suitably sized stainless steel container equipped with a high shear stirrer; montelukast sodium (1.70 kg) was added with stirring at approximately 230 rpm. , theoretical quantity). Continue mixing at 230 rpm until visual inspection of the montelukast steel is completely dissolved. The solution was completely defoamed before use (the drug solution was used within 24 hours of manufacture). The preparation of the drug solution reflects the drying of the spray cloth by more than 2% of theory. If the coating efficiency of the process changes, it is adjustable-11 - This paper scale is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) Binding 1326661 A7 B7 V. Description of invention (9 required coating) The amount of cloth solution. Drug Coating/Drying 670 liters of granulated sphere-dried mannitol granules (198 kg, theoretical amount) were transferred to a fluid bed granulator. The following procedure parameters were used to Montelukas. Special (111〇1^61111^51) sodium solution (50.7 kg, theoretical amount) coated particles in the column: input air volume input air temperature input air dew point atomized air flow

Approximately 2500 scfm approx. 68〇C approx. 12〇C approx. 3 5 scfm spray rate approx. 13 10 g/min After the solution has been transferred, use the following processing parameters to dry the product in the column to the end point S 0.5% LOD:

The input air volume is about 2500 scfm. The input air temperature is about 6 8 °C. The input air dew point is about 12 °C. The atomizing air flows ' about 25 scfm. After drying, the dry particles (200 kg, theoretical amount) are passed through #20-mesh. Screened through a 850 micron screen. Store through a 20 mesh (approximately 850 micron) screen in an unwired stainless steel container until the particles are lubricated. The amount of the drug solution listed exceeds 2.14% of the theoretical amount of spray drying. If the coating efficiency of the process is changed, the amount of the coating solution required can be adjusted. In addition, the actual amount of the drug solution sprayed can be adjusted based on the gas produced by drying the mannitol granulation. The amount of the above drug solution is the maximum amount that can be sprayed (assuming 100% mannitol granulation yield). • 12- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1326601 A7 B7 V. INSTRUCTIONS (10) Lubricating sifted granules (200 kg, theoretical amount) and stearic acid Magnesium (which has been sieved through #30 mesh (approximately 600 micron screen), 0.500 kg) was added to a 600 liter vessel. The 600 liter container was blended at about 6 rpm for about 10 minutes. Drain the blended blend into an unwired stainless steel bucket. The blended particles were then blended into a 600 liter vessel and the 600 liter vessel was blended for 10 minutes at about 6 rpm. The re-blended particles are stored in a closed container until the drug pack is filled. The filling of the pack places the 600 liter container containing the re-blended particles on top of the pack filling line. The re-blended granules were filled in a metal foil pouch with a double screw filler. Average filling weight: target 0.500 g / drug pack ^ Sin.gulairTM Oral granule composition 4 mg as follows: Ingredient mg / drug source or supplier Monta Luccast Sodium 4.16* Merck & Co. mannose Alcohol (Pearlitol SD200) 484.9 Roquette Freres Hydroxypropyl Cellulose LFNF 10.4 Hercules Inc. Pure Water USP (374)** Merck & Co. Magnesium Stearate NF 1.25 Mallinckrodt Total 500.0 Bag Metal Foil Algroup Lawson Mardon * Equivalent 4.0 mg of Monteclamation sodium free acid** removed during processing-13- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm)

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