WO2019199136A1 - Lenalidomide oral tablet composition enabling enhanced disintegration - Google Patents

Lenalidomide oral tablet composition enabling enhanced disintegration Download PDF

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Publication number
WO2019199136A1
WO2019199136A1 PCT/KR2019/004476 KR2019004476W WO2019199136A1 WO 2019199136 A1 WO2019199136 A1 WO 2019199136A1 KR 2019004476 W KR2019004476 W KR 2019004476W WO 2019199136 A1 WO2019199136 A1 WO 2019199136A1
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WO
WIPO (PCT)
Prior art keywords
lenalidomide
granules
tablet
weight
tablets
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PCT/KR2019/004476
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French (fr)
Korean (ko)
Inventor
박상엽
임혜정
이사원
서민효
Original Assignee
주식회사 삼양바이오팜
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Priority claimed from KR1020190043378A external-priority patent/KR102259798B1/en
Application filed by 주식회사 삼양바이오팜 filed Critical 주식회사 삼양바이오팜
Publication of WO2019199136A1 publication Critical patent/WO2019199136A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention relates to oral tablet compositions of lenalidomide with improved disintegration.
  • oral disintegrating tablets that can be taken without water.
  • Lenalidomide (Chemical Formula: 3- (4'-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione) As a compound disclosed in heading 534498, it is used as a therapeutic agent for multiple myeloma.
  • Lenalidomide is an IMiDs (Immnunomodulatory imide drugs) compound belonging to a new group of immunomodulators. The structure is similar to thalidomide, but its biological activity is stronger and the effect is better. In addition, it is said to have lower side effects than thalidomide.
  • Celgene's levimid capsules which are hard capsules and are licensed in doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.
  • Hard capsules are prepared by filling granules and the like into capsules.
  • the levimide capsule is a formulation prepared by filling a hard mixture of a solid mixture of a drug and an excipient.
  • Revelim capsules are filled in No. 0 capsules for 10 mg, 15 mg, 20 mg, and 25 mg doses of the formulation, which are quite long and bulky with a long axis of about 2.17 cm. Because of the disadvantages of taking the elderly patients are disadvantageous. In addition, capsules are also a problem when the capsule is taken with water, the capsule is stuck to the throat or esophagus during swallowing.
  • oral disintegrating tablets do not require the use of capsules of a certain size, such as No. 0, which can further reduce the volume. Above all, it is a dosage form that disintegrates quickly in the mouth without water. Does not tend to stick.
  • the present inventors attempted to develop orally disintegrating tablets of lenalidomide that can be rapidly disintegrated in the oral cavity without water, in order to improve the convenience of the medication for lenalidomide, which is mainly prescribed to elderly patients.
  • the present invention is to provide a lenalidomide-containing oral disintegrating tablets with improved ease of taking.
  • the present invention relates to oral disintegrating tablet containing lenalidomide as an active ingredient.
  • the orally disintegrating tablet of the present invention preferably contains mannitol as a diluent.
  • the orally disintegrating tablet of the present invention preferably has a hardness of 1.2 to 25 Kp.
  • Oral disintegrating tablet of the present invention may be within oral disintegration time of 60 seconds.
  • Oral disintegrating tablet of the present invention is 1-1) after mixing a composition comprising lenalidomide and a diluent and granulate it, and then mixing the granules with a composition comprising a disintegrant and a lubricant,
  • mannitol as a diluent.
  • the oral disintegration time is within 60 seconds, so that disintegrating tablets can be rapidly disintegrated, thereby maximizing the convenience of taking lenalidomide formulations mainly prescribed to elderly patients.
  • the present invention since the present invention is implemented as an oral disintegrating tablet, it overcomes the disadvantage that the hard capsules have a large volume and a tendency to stick to the throat or esophagus when taken with water.
  • the present invention has bioequivalence as compared to conventionally available hard capsules.
  • the present invention is equivalent to the reference drug levimide capsule and the dissolution results, so that in the bioequivalence test the level of AUC and Cmax is within 80 to 125% compared to the conventional capsule, preferably 90 to 110 It is within% and most preferably satisfies 95 to 105%.
  • lenalidomide means a main ingredient raw material in which the active ingredient is lenalidomide, and lenalidomide free base (base drug without a separate salt), or a pharmaceutically acceptable salt thereof, or Isomers, or mixtures thereof. It may also be in each case forming various hydrates and in each case various crystalline forms. For example, it may be various hydrates or various solvates, such as lenalidomide anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or mixtures thereof.
  • Excipients in the present specification means known pharmaceutically addable inert ingredients such as pharmaceutical excipients.
  • diluents, disintegrants, glidants all of which are known to be usable ingredients, and unless otherwise indicated herein, those skilled in the art will understand any one of the ingredients that can be adopted.
  • drying weight loss is a value expressed as a percentage (%) of the weight before drying, in which the moisture, solvent, volatiles, etc. contained in the sample are dried under heating conditions and blown off.
  • An exemplary measuring method is as follows. Take a sample of approximately 2 g or more, spread it evenly on an aluminum plate, and use Sartorius' MA100 LOD meter for several to several minutes at 105 ° C until no further value change (this is referred to as "dry weight"). Measure The drying weight is subtracted from the weight before drying, and then multiplied by 100 divided by the weight before drying to obtain a drying loss (%).
  • the drying loss is 2.50%.
  • the temperature of the sample input part is cooled to 35 ° C or lower, and then the next measurement is started. The average value obtained by measuring three times is determined as the loss on drying.
  • the term " dry granules " refers to granules produced by a wet granule manufacturing method and then dried to obtain a dry granule of the same value even after further drying.
  • the same value of drying loss means that the value of drying loss is within ⁇ 0.3%, preferably within ⁇ 0.2% in consideration of the measurement error.
  • the loss on drying of such dry granules may, for example, typically exhibit values within 3%, within 2%, within 1%, or within 0.5%.
  • low wet granules refers to a loss of dry granules obtained by a wet granule manufacturing method, from 1.05 times to 5 times, preferably from 1.1 times to 3 times, Most preferably, it refers to granules having a loss of drying of 1.2 times or more and 2.5 times or less.
  • the low-wet granules have characteristics that are not at all problematic in preparing tablets in a general tablet production process by using the amount of the lubricant commonly used for tableting.
  • General tablet production process refers to a process using a general tableting machine or a molding machine used in pharmaceuticals, and adopting a temperature and humidity condition in a general tableting room.
  • General tableting machine or molding machine may be a single or multiple-shot tableting machine, and it is possible to make special modifications such as using a special film to prevent sticking of a part to a punch when tableting, or spraying a lubricant into a mold. Refers to a tableting machine or a molding machine that is not used.
  • temperature and humidity inside a general tableting room means that the conditions of the internal air in the space where the tableting machine or molding machine is located are within a range of temperature and humidity that are normally controlled. Refers to the humidity conditions.
  • the present invention provides oral disintegrating tablets that can replace conventional commercially available hard capsules.
  • the present inventors began the development of oral disintegrating tablets to eliminate stomach discomfort.
  • Oral disintegrating tablet is a preparation that disintegrates rapidly in the oral cavity even when taken without a small amount of water or water, and is easy to take even elderly people whose swallowing ability is degraded because they disintegrate rapidly in the oral cavity even when taken without water.
  • oral disintegrating tablets have low hardness, when exposed to humidification conditions, the hardness of the tablets may be lowered and the tablets may be broken, resulting in the loss of the drug and the stability of the drugs.
  • the disintegration time may be delayed if the hardness of the tablet is lowered. Therefore, when developing lenalidomide as an oral disintegrating tablet, it was necessary to consider that the hardness of tablets was reduced and disintegration could be maintained even if stored under humid conditions.
  • oral disintegrating tablets can produce impurities by reacting with other excipient components when sugar alcohols such as mannitol are used as diluents.
  • sugar alcohols such as mannitol
  • International Publication No. 2005/123040 discloses oral disintegrating tablets comprising a main component, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and no disintegrating agent.
  • Korean Unexamined Patent Publication No. 2010-0096179 also employs microcrystalline cellulose and calcium hydrogen phosphate as diluents.
  • the inventors have surprisingly found that by adopting a component containing mannitol as a diluent, it is possible to obtain oral disintegrating tablets having satisfactory disintegration rate, excellent tablet hardness, and excellent storage stability. Lenalidomide was confirmed to have very good stability even in the compatibility test with mannitol.
  • One embodiment may include mannitol as a diluent.
  • One embodiment employs spray dried mannitol, permburst, F-Melt, or a combination thereof as a diluent.
  • Pharmaburst or F-Melt is the product name of the diluent containing mannitol.
  • F-Melt is a product containing D-Mannitol, Xylitol, MCC, Crospovidone and inorganic ingredients.
  • Pharmaburst is a product containing mannitol, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal anhydrous silica and colloidal hydrated silica.
  • the granules are mixed with disintegrants, glidants, and other pharmaceutically acceptable excipients.
  • it can manufacture by tableting.
  • Oral disintegrating tablet according to the production method granules containing lenalidomide and diluent; And it may have a form containing a disintegrant and a lubricant on the outside of the granules.
  • the stability of the orally disintegrating tablets with fast disintegrating tablets can be improved in the external environment, and high content uniformity of the drug can be achieved in the oral disintegrating tablets in which special excipients such as porous materials may be added.
  • the granules may have a drying loss of 3% or less.
  • the drying loss may be 2% or less, 1.5% or less, or 1.2% or less.
  • the loss of drying of the granules forming the oral disintegrating tablets can greatly change the disintegration or dissolution rate of the oral disintegrating tablets.
  • wet granulation is performed using high-density white sugar solution to control the loss of drying to form low-wet granules, the hardness increases over time even after tableting at low tablet pressure, resulting in high hardness and good wear A tablet showing rapid disintegration can be obtained.
  • the granules included in the orally disintegrating tablet may be low wet granules.
  • Low wet granules may comprise spray dried mannitol and a white sugar binder.
  • the low-wetting granules are a variety of additional additives for the purpose of efficiency of the preparation of lenalidomide, and / or granules, stability, appearance, color, protection, retention, bonding, performance improvement, improvement of manufacturing process, etc. of lenalidomide. It may further contain ingredients.
  • Mannitol is well soluble in water (1 part per 5.5 parts of water at 20 ° C), chemically stable, non-hygroscopic, does not undergo Maillard reaction with amino groups, and has a good taste when disintegrating in the oral cavity. .
  • Spray-dried mannitol in addition to the properties of mannitol described above, is porous and rapidly dissolved in water, and may be preferable as a diluent because it has good fluidity and good compressibility.
  • spray-dried mannitol include, but are not limited to, commercially available MannogemTM EZ (SPI Pharma), Pearlitol®SD (Roquette), and the like. Spray dried mannitol may be particularly preferred in the manner of direct tableting.
  • the present invention unlike the conventional application method by using the spray-dried mannitol in the manufacture of wet granules, so as to contain more fine pores than wet granulation of mannitol (mannitol powder) in the form of powder, better compressibility and It has a flowability to show faster disintegration when produced in tablets, and has a better hardness and wear and tear.
  • the spray-dried mannitol is preferably from 20 to 98% by weight, more preferably from 30 to 95% by weight, even more preferably from 50 to 90% by weight relative to 100% by weight of the granules. Include. If the content of the spray-dried mannitol is less than 20% by weight or more than 98% by weight with respect to 100% by weight of the low-wetting granules, there may be a problem of low hardness or delayed disintegration time.
  • the sucrose binder may be preferably dissolved in water, a non-aqueous solvent or a mixed solvent thereof, and more preferably dissolved in water or a mixed solvent of water and ethanol.
  • the concentration of white sugar in such a solvent may be 1 to 60% (weight / weight) (w / w), and preferably may be prepared at a concentration of 5 to 50%.
  • the low-wetting granules of the present invention preferably contain 1 to 50 parts by weight, more preferably 2 to 30 parts by weight, and even more preferably, the amount of the dried sugars to 100 parts by weight of the spray dried mannitol. 3 to 15 parts by weight. If the content of the dried sugar-based binder is less than 1 part by weight with respect to 100 parts by weight of the spray-dried mannitol, there may be a problem that the hardness of the tablet is lowered, and if it exceeds 50 parts by weight, the disintegration time may be a problem.
  • the low wet granules of the present invention may or may not include lenalidomide. If the low-wetting granules contain lenalidomide, they may be included in a solid state, such as spray-dried mannitol, before the binder is added to prepare wet granules, whereby the properties of lenalidomide are in powder form. It may be in a crystalline state, a granular state, or a fine powder state. Alternatively, it may be included to dissolve or disperse together in the preparation of the sugar mixture.
  • a solid state such as spray-dried mannitol
  • the granules of the present invention may further comprise additional ingredients for producing the granules.
  • Additional ingredients for producing granules include dry binders, colorants, flavors, sweeteners, stabilizers, antioxidants, and the like, which may be added in solid form with spray dried mannitol.
  • the dry binder is preferably 50 parts by weight or less (for example, 0.1 to 50 parts by weight), more preferably 30 parts by weight or less, based on 100 parts by weight of the spray-dried mannitol.
  • it may be included in the low wet granules of the present invention in an amount of 15 parts by weight or less.
  • sugars, sugar alcohols, starch, polysaccharides, cellulose derivatives, or mixtures thereof may be used.
  • specific examples include fructose (fructose), lactitol, lactose (lactose), maltitol, maltose, mannitol, sorbitol, sucrose, erythritol, xylitol, maltodextrin, isomalt, dextrin, dextrose, dextrate, Starch, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, STARLAC® (spray dried solids containing 15% corn starch and 85% alpha-lactose monohydrate, manufactured by Roquette American, Inc.) Consisting of MICROCELAC® (spray dried solids containing 75% alpha-lactose monohydrate and 25% microcrystalline cellulose, manufactured by Meggle excipients & technology) and CELLACT
  • the remaining components except the dry binder ie, colorants, flavors, sweeteners, stabilizers, antioxidants, etc. may be dissolved or dispersed together in the preparation of the sugar mixture.
  • the low-wet granules of the present invention as described above preferably form a granule comprising spray dried mannitol and a white sugar binder, and wherein the granules are not less than 1.05 times or less than 5 times the dry weight loss of the dry granules. It may be prepared by a method comprising the step of drying to a low wet granule having a loss on drying value.
  • the sucrose binder is used in the form of dissolved in water, a non-aqueous solvent or a mixed solvent thereof in preparing a mixture for granulation formation comprising spray dried mannitol and sucrose binder.
  • the granules comprising the spray dried mannitol and the sucrose binder may further comprise additional ingredients for the preparation of lenalidomide and / or granules, and the manner of introducing them into the mixture has been described above.
  • Low wet granules manufacturing method of the present invention it can be carried out utilizing the manufacturing method of wet granules commonly used in the pharmaceutical field.
  • spray dried mannitol and sucrose binders, and optionally lenalido using methods such as granulators, mixers, U-type mixers, high speed mixers, fluidized bed granulators, manual work, and the like
  • Mixtures comprising additional components for the production of amides and / or granules may be prepared in the form of agglomerated particles.
  • the prepared agglomerated particle mass may enter the drying step as it is, or may enter the drying step after sieving.
  • the aggregated particles can be granulated through a sieve of 30 mesh.
  • Drying for the production of low-wet granules can be carried out utilizing methods for drying the common granules.
  • the drying operation may be performed in a convection oven, vacuum oven, fluidized bed dryer, dryer, natural drying at room temperature, or the like.
  • Sokbung tablet of the present invention is characterized in that it comprises the low-wetting granules of the present invention.
  • the amount of the low-wetting granules included in the fast borosilicate tablet of the present invention is preferably 50 to 99% by weight, more preferably 60 to 98% by weight, even more preferably 70 to 97% by weight based on 100% by weight of the tablet. If the content of the low-wetting granules is less than 50% by weight based on 100% by weight of the tablet, there may be a problem in that it does not exhibit the characteristics of high hardness and rapid disintegration of fast disintegrating tablets. There can be.
  • Sokbung tablets of the present invention may further comprise additional ingredients for the preparation of lenalidomide and / or tablets, in addition to the spray dried mannitol and the sucrose binder contained in the low wet granules. Additional ingredients for preparing these lenalidomides and / or tablets may be incorporated into the low-wet granules, or alternatively may be introduced upon formation of the postmixture for tableting.
  • Lenalidomide introduced in the post-mixture forming step may be in a powder state, crystal state, granule state, fine powder state, taste shielding or particulate state with a controlled release release control.
  • Additional ingredients for the manufacture of tablets may be introduced for additional purposes such as efficiency of tableting, promotion of disintegration, stability of lenalidomide, appearance, color, protection, retention, binding, improved performance, improved manufacturing process, and the like.
  • additional ingredients for the manufacture of tablets include, but are not limited to, disintegrants, lubricants, surfactants, dry binders, colorants, flavors, sweeteners, stabilizers, antioxidants, sour agents, and the like.
  • the disintegrant may be at least one selected from the group consisting of sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl cellulose sodium, starch and the like.
  • the disintegrant may be contained within 100% by weight of the tablet, preferably within 7% by weight, preferably within 5% by weight, more preferably within 3% by weight.
  • the glidants include stearic acid, glyceryl behenate, glyceryl monostearate, magnesium stearate, calcium stearate, silicon dioxide, talc, sugar ester, stearyl fumarate sodium and magnesium silicate, sodium stearate, Poly (ethylene glycol), polyoxypropylene-polyoxyethylene block copolymer, colloidal silicon dioxide, sucrose fatty acid ester, and the like.
  • the glidant may be contained within 100% by weight of the tablet, preferably within 3% by weight, preferably within 2% by weight, more preferably within 1.5% by weight.
  • Sokbung tablet of the present invention as described above, comprising the steps of forming a tableting post-mixture containing the low-wetting granules, compressing the tableting post-mixture to obtain a tablet, and drying the tablet It can be produced by the method.
  • the method for preparing fast borosilicate tablet of the present invention may be performed using a tableting machine or a molding machine generally used in the pharmaceutical field. Tableting may also be carried out in a low pressure compression mode, and the drying of the tablets may be under mild conditions.
  • the compression pressure used to compress the tableting postmixture comprising low wet granules into tablets is generally about 150 MPa or less (e.g., 1 Pa to 150 MPa), preferably about 35 MPa or less, more preferably Low pressure of about 10 MPa or less.
  • the tablet In order for the tablet to disintegrate quickly in the mouth, the tablet must quickly absorb water into its inner core and the components must dissolve quickly. Therefore, it is important for compressed tablets to maintain high porosity. In order to maintain high porosity after compression, low pressure tableting is usually required. However, when tablets are manufactured at low pressure, their hardness and wear and tear are inevitably deteriorated. However, by using the low-wetting granules according to the present invention, it is possible to produce tablets with low pressure tableting without such a tableting disorder, and to obtain tablets having fast disintegration properties with good physical properties of high hardness and low wear through the drying step. have,
  • Mild conditions of drying the tablets may be conditions of room temperature that are not severely wet, such as temperatures of 20 to 30 ° C. and humidity conditions of 40% RH or less.
  • a low temperature convection oven at 20 to 50 ° C. may be used, and a method of supplying dry air, a method using a dehumidifier, a method using a dehumidifying agent, and the like may also be used.
  • an embodiment of the present invention may be prepared by mixing lenalidomide, mannitol, disintegrant, glidants, and other pharmaceutically acceptable excipients and then tableting them.
  • mannitol is contained in 20 to 98% by weight, preferably 50 to 95% by weight relative to the total weight of the tablet.
  • acidifying agents can be further blended in the ingredients that do not lower the hardness of the tablet without delaying the disintegration time in order to neutralize bitter taste in the mouth.
  • One embodiment of the invention is characterized in that the hardness is 1.2-25 Kp, preferably 1.5-12 Kp, preferably 2-10 Kp. More preferably 3-10 Kp, still more preferably 4-10 Kp. If it is higher than the above hardness, there may be a delay in the release of the drug due to the disintegration delay, and if it is low, the tablet may be weak and may break during coating, transportation, storage, packaging, and taking. However, the hardness may vary depending on the size and weight of the tablet. Small tablets have good physical properties such as high hardness and wear and tear even at lower hardness. In one embodiment 5 to 10 Kp is preferred when having a dose of 25 mg of lenalidomide.
  • One embodiment of the present invention is characterized in that the degree of wear and tear is 2% or less. It may be more preferably 1% or less, even more preferably 0.6% or less. If gastric abrasion is higher than that, powder may occur during coating, transportation, storage, packaging and taking.
  • One embodiment of the present invention is characterized in that the oral disintegration time is within 60 seconds. More preferably within 50 seconds, even more preferably within 40 seconds, most preferably within 30 seconds. If it is longer than the above time, the time to hold the drug in the oral cavity may be long, which may cause inconvenience to the patient.
  • 1-1) after mixing a composition comprising lenalidomide and a diluent and granulate it, and then mixing the granules with a composition comprising a disintegrant and a lubricant,
  • the manufacturing method may further comprise the step of controlling the drying loss by drying the granules.
  • the loss on drying may be 3% or less.
  • the hardness of the tablets was measured using a hardness tester 8M (Hardness tester 8M, Dr. Schleuniger, Switzerland), and at least six samples were measured to describe the average value.
  • the disintegration test of the fast disintegrating tablets in the oral cavity was performed to the volunteers. Volunteers (healthy adult males) were randomly selected to flush their mouths with water, and then tablets were placed on the volunteers' tongues and immediately operated with a stopwatch to measure disintegration time. Volunteers were allowed to move fast disintegrating tablets to the ceiling of their mouths using their tongues and to smoothly roll or roll the tablets without biting. As soon as the tablet collapsed and became swallowable with the saliva, the stopwatch was stopped and the time was recorded.
  • the hardness was 6.7 Kp
  • the friability was 0.16%
  • the disintegration time in water was 20.5 seconds
  • the disintegration time in the oral cavity was 18 seconds
  • the weight loss of the tablet was 0.25%.

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Abstract

An orally disintegrating lenalidomide tablet is disclosed.

Description

붕해가 개선된 레날리도마이드의 경구용 정제 조성물Oral Tablet Composition of Lenalidomide with Improved Disintegration
본 발명은 붕해가 개선된 레날리도마이드의 경구용 정제 조성물에 관한 것이다. 특별히 물 없이 복용할 수 있는 구강붕해정에 관한 것이다.The present invention relates to oral tablet compositions of lenalidomide with improved disintegration. In particular it relates to oral disintegrating tablets that can be taken without water.
레날리도마이드(화학식:3-(4'-아미노-1-옥소-1,3-디히드로-2H-이소인돌-2-일)피페리딘-2,6-디온)는 대한민국 등록특허공보 제 534498호에 개시된 화합물로서, 다발성골수종의 치료제로 사용되고 있다. 레날리도마이드는 새로운 면역조절제 그룹에 속하는 IMiDs (Immnunomodulatory imide drugs) 화합물로서, 구조는 탈리도마이드와 유사하지만 생물학적 활성도가 더 강력해 효과가 보다 우수하다. 게다가 탈리도마이드보다 부작용도 더 낮췄다는 평가를 받는다.Lenalidomide (Chemical Formula: 3- (4'-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione) As a compound disclosed in heading 534498, it is used as a therapeutic agent for multiple myeloma. Lenalidomide is an IMiDs (Immnunomodulatory imide drugs) compound belonging to a new group of immunomodulators. The structure is similar to thalidomide, but its biological activity is stronger and the effect is better. In addition, it is said to have lower side effects than thalidomide.
종래의 레날리도마이드는 캡슐제로 등장했다. 상용화된 제품으로는 Celgene사의 레블리미드캡슐로서, 경질캡슐제이며, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg 의 용량으로 허가 받았다. Conventional lenalidomide has appeared in capsules. Commercially available products are Celgene's levimid capsules, which are hard capsules and are licensed in doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.
경질캡슐제는 과립 등을 캡슐 안에 충진하여 제조한다. 특히 레블리미드캡슐은 약물과 부형제가 혼합된 고형의 혼합물을 경질캡슐제에 충진하여 구현된 제제이다.Hard capsules are prepared by filling granules and the like into capsules. In particular, the levimide capsule is a formulation prepared by filling a hard mixture of a solid mixture of a drug and an excipient.
레블리미드 캡슐은 10 mg, 15 mg, 20 mg, 25 mg 용량의 제제의 경우 모두 0 호 캡슐에 충진하는데, 이는 장축이 약 2.17 cm 에 달할 정도로 길이가 상당히 길고, 부피가 크다. 때문에 고령의 환자들의 경우 복용하는데 불편하다는 단점이 있다. 또한 캡슐은 물과 함께 복용할 때 삼키는 과정에서 목이나 식도에 캡슐이 달라붙어서 걸리는 문제도 있다.Revelim capsules are filled in No. 0 capsules for 10 mg, 15 mg, 20 mg, and 25 mg doses of the formulation, which are quite long and bulky with a long axis of about 2.17 cm. Because of the disadvantages of taking the elderly patients are disadvantageous. In addition, capsules are also a problem when the capsule is taken with water, the capsule is stuck to the throat or esophagus during swallowing.
하지만 구강붕해정은 0호 등 정해진 크기의 캡슐을 사용할 필요가 없어서 부피를 더 줄일 수 있으며, 무엇보다 물 없이도 입안에서 신속히 붕해되는 투여 제형이기 때문에 캡슐처럼 물과 함께 복용할 때 목이나 식도에 제제가 달라붙는 경향이 없다. However, oral disintegrating tablets do not require the use of capsules of a certain size, such as No. 0, which can further reduce the volume. Above all, it is a dosage form that disintegrates quickly in the mouth without water. Does not tend to stick.
본 발명자는 주로 고령의 환자들에게 처방되는 레날리도마이드의 복약편의성을 개선하고자, 물이 없이 구강 내에서 속붕해가 가능한 레날리도마이드의 구강붕해정을 개발하고자 하였다.The present inventors attempted to develop orally disintegrating tablets of lenalidomide that can be rapidly disintegrated in the oral cavity without water, in order to improve the convenience of the medication for lenalidomide, which is mainly prescribed to elderly patients.
본 발명은 복용편의성을 증진시킨 레날리도마이드 함유 구강붕해정을 제공하기 위한 것이다.The present invention is to provide a lenalidomide-containing oral disintegrating tablets with improved ease of taking.
본 발명은 유효성분으로서 레날리도마이드를 포함하는 구강붕해정에 관한 것이다.The present invention relates to oral disintegrating tablet containing lenalidomide as an active ingredient.
본 발명의 구강 붕해정은 희석제로서 만니톨을 포함하는 것이 바람직하다.The orally disintegrating tablet of the present invention preferably contains mannitol as a diluent.
본 발명의 구강 붕해정은 경도가 1.2 내지 25 Kp 인 것이 바람직하다.The orally disintegrating tablet of the present invention preferably has a hardness of 1.2 to 25 Kp.
본 발명의 구강 붕해정은 구강내 붕해시간이 60초 이내일 수 있다.Oral disintegrating tablet of the present invention may be within oral disintegration time of 60 seconds.
본 발명의 구강 붕해정은 1-1) 레날리도마이드와 희석제를 포함하는 조성물을 혼합한 후 이를 과립화한 다음, 당해 과립물을 붕해제 및 활택제를 포함하는 조성물과 혼합하거나,Oral disintegrating tablet of the present invention is 1-1) after mixing a composition comprising lenalidomide and a diluent and granulate it, and then mixing the granules with a composition comprising a disintegrant and a lubricant,
1-2) 레날리도마이드를 희석제, 붕해제 및 활택제를 포함하는 조성물과 혼합하는 단계; 및 1-2) mixing lenalidomide with a composition comprising a diluent, a disintegrant and a lubricant; And
2) 단계 1-1) 또는 1-2)에서 얻어진 혼합물을 타정하는 단계:2) tableting the mixture obtained in step 1-1) or 1-2):
를 포함한다.It includes.
본 발명에 따른 상기 제조방법에서, 희석제로서 만니톨을 포함하는 것이 바람직하다.In the above production method according to the present invention, it is preferable to include mannitol as a diluent.
본 발명은 구강내 붕해시간이 60초 이내로서 속붕해가 가능한 구강붕해정이므로, 주로 고령의 환자들에게 처방되는 레날리도마이드 제제의 복용편리성을 극대화한 것이다.In the present invention, the oral disintegration time is within 60 seconds, so that disintegrating tablets can be rapidly disintegrated, thereby maximizing the convenience of taking lenalidomide formulations mainly prescribed to elderly patients.
또한 본 발명은 구강붕해정으로 구현했기 때문에, 경질캡슐제가 갖는 단점인 부피가 크다는 점과, 물과 함께 복용시 목이나 식도에 달라붙는 경향이 있다는 점을 극복했다.In addition, since the present invention is implemented as an oral disintegrating tablet, it overcomes the disadvantage that the hard capsules have a large volume and a tendency to stick to the throat or esophagus when taken with water.
또한, 본 발명은 종래 시판 중인 경질캡슐제와 대비했을 때 생물학적 동등성을 갖는다. 구체적으로 본 발명은 대조약인 레블리미드 캡슐과 용출결과가 동등하며, 이로 인해 생물학적 동등성 시험에서 AUC 와 Cmax 의 수치가 종래의 캡슐제에 비해서 80 내지 125 % 이내이고, 바람직하게는 90 내지 110 % 이내이며, 가장 바람직하게는 95 내지 105 % 를 만족한다.In addition, the present invention has bioequivalence as compared to conventionally available hard capsules. Specifically, the present invention is equivalent to the reference drug levimide capsule and the dissolution results, so that in the bioequivalence test the level of AUC and Cmax is within 80 to 125% compared to the conventional capsule, preferably 90 to 110 It is within% and most preferably satisfies 95 to 105%.
먼저, 명시적인 다른 기재가 없는 한, 본 명세서 전체에서 사용되는 몇 가지 용어 내지 표현들은 다음과 같이 정의될 수 있다.First, unless otherwise stated, some terms or expressions used throughout this specification may be defined as follows.
본 명세서에서 레날리도마이드라 함은 활성성분이 레날리도마이드인 주성분 원료를 의미하고, 레날리도마이드 유리 염기 (별도의 염이 없는 베이스 약물), 또는 그의 약학적으로 허용 가능한 염 또는 그의 이성질체, 또는 이들의 혼합물일 수 있다. 또한 각각의 경우에 다양한 수화물, 또 각각의 경우에 다양한 결정형을 형성하는 것일 수 있다. 예를 들어, 레날리도마이드 무수물, 반수화물, 일수화물, 이수화물, 삼수화물 등 다양한 수화물 또는 다양한 용매화물, 또는 이들의 혼합물일 수 있다.In the present specification, lenalidomide means a main ingredient raw material in which the active ingredient is lenalidomide, and lenalidomide free base (base drug without a separate salt), or a pharmaceutically acceptable salt thereof, or Isomers, or mixtures thereof. It may also be in each case forming various hydrates and in each case various crystalline forms. For example, it may be various hydrates or various solvates, such as lenalidomide anhydride, hemihydrate, monohydrate, dihydrate, trihydrate, or mixtures thereof.
본 명세서에서 부형제라 함은 pharmaceutical excipients 와 같이 공지의 약제학적으로 첨가 가능한 비활성 성분을 뜻한다. 희석제, 붕해제, 활택제의 경우도 마찬가지며, 이들은 모두 사용 가능한 성분이 공지되어 있으며, 본 명세서에서 별도의 설명이 없으면 통상의 기술자가 적의 채택 가능한 성분 중 어느 하나로 이해한다.Excipients in the present specification means known pharmaceutically addable inert ingredients such as pharmaceutical excipients. The same is true for diluents, disintegrants, glidants, all of which are known to be usable ingredients, and unless otherwise indicated herein, those skilled in the art will understand any one of the ingredients that can be adopted.
본 명세서에서 언급된 “건조 감량”이란 시료에 포함된 수분, 용매, 휘발성 물질 등이 가온 조건에서 건조되어 날아간 양을 건조전 중량 대비 백분율(%)로 나타낸 값이다. 그 예시적 측정 방법은 다음과 같다. 약 2g 이상의 시료를 취해서 알루미늄 접시에 골고루 펴서 넣고 Sartorius사의 MA100 LOD meter를 이용하여 105℃에서 수 내지 수십분 동안, 더 이상 수치의 변화가 없을 때까지 시료의 중량(이를 “건조후 중량”이라 한다)을 측정한다. 건조전 중량에서 건조후 중량을 뺀 후, 이를 건조전 중량으로 나눈 값에 100을 곱하면 건조 감량(%)이 얻어진다. 예를 들어, 2.0000 g의 시료를 측정하여 용매 혹은 수분이 건조되어 날아가고 1.9500g이 남았을 때의 건조감량은 2.50%가 된다. 이때 정확성을 기하기 위하여 1회 측정 후에 시료 투입부의 온도가 35℃ 이하로 냉각된 후에 다음 측정을 시작하며, 3회 측정하여 얻어진 평균값을 건조 감량으로 정한다.As used herein, the term "drying weight loss" is a value expressed as a percentage (%) of the weight before drying, in which the moisture, solvent, volatiles, etc. contained in the sample are dried under heating conditions and blown off. An exemplary measuring method is as follows. Take a sample of approximately 2 g or more, spread it evenly on an aluminum plate, and use Sartorius' MA100 LOD meter for several to several minutes at 105 ° C until no further value change (this is referred to as "dry weight"). Measure The drying weight is subtracted from the weight before drying, and then multiplied by 100 divided by the weight before drying to obtain a drying loss (%). For example, if a sample of 2.0000 g is measured and the solvent or moisture is dried off and 1.9500 g is left, the drying loss is 2.50%. At this time, in order to ensure accuracy, after the measurement, the temperature of the sample input part is cooled to 35 ° C or lower, and then the next measurement is started. The average value obtained by measuring three times is determined as the loss on drying.
본 명세서에서 언급된 “건조 과립”이란, 습식과립 제조방식으로 제조된 후 건조하여 얻어진 과립으로서 추가적인 건조를 하여도 동일한 수치의 건조 감량을 나타내는 상태에 있는 과립을 말한다. 이때 “동일한 수치의 건조감량”이라 함은 측정 오차를 고려하여 건조감량의 수치가 ±0.3% 이내, 바람직하게는 ±0.2% 이내의 차이를 갖는 것을 말한다. 이러한 건조 과립의 건조 감량은 예컨대 통상적으로는 3% 이내, 2% 이내, 1% 이내, 또는 0.5% 이내의 값을 나타낼 수 있다.As used herein, the term " dry granules " refers to granules produced by a wet granule manufacturing method and then dried to obtain a dry granule of the same value even after further drying. In this case, "the same value of drying loss" means that the value of drying loss is within ± 0.3%, preferably within ± 0.2% in consideration of the measurement error. The loss on drying of such dry granules may, for example, typically exhibit values within 3%, within 2%, within 1%, or within 0.5%.
본 명세서에서 언급된 “저습윤 과립”이란, 습식 과립 제조방식으로 얻어진 과립의 건조감량을 측정하였을 때 “건조 과립”의 1.05 배 이상에서 5배 이하, 바람직하게는 1.1 배 이상에서 3배 이하, 가장 바람직하게는 1.2 배 이상에서 2.5배 이하의 건조 감량을 갖는 과립을 말한다.As used herein, the term "low wet granules" refers to a loss of dry granules obtained by a wet granule manufacturing method, from 1.05 times to 5 times, preferably from 1.1 times to 3 times, Most preferably, it refers to granules having a loss of drying of 1.2 times or more and 2.5 times or less.
상기 저습윤 과립은 정제의 타정에 통상적으로 활용되는 활택제를 통상적으로 사용하는 분량으로 사용하여, 일반적인 정제 생산 공정으로 정제를 제조하는 데에 전혀 문제가 없는 특성을 갖는다.The low-wet granules have characteristics that are not at all problematic in preparing tablets in a general tablet production process by using the amount of the lubricant commonly used for tableting.
“일반적인 정제 생산 공정”이란, 제약에서 활용하는 일반적인 타정기 혹은 성형기를 활용하고, 일반적인 타정실 내부의 온습도 조건을 채택한 공정을 말한다."General tablet production process" refers to a process using a general tableting machine or a molding machine used in pharmaceuticals, and adopting a temperature and humidity condition in a general tableting room.
“일반적인 타정기 혹은 성형기”란, 단발 혹은 다연발 타정기일 수 있으며, 특수한 필름을 이용하여 정제의 타정시 펀치에 일부분이 달라붙는 현상을 막거나, 활택제를 몰드 내로 분무하거나 하는 등의 특수한 개조를 하지 않은 타정기 혹은 성형기를 말한다.“General tableting machine or molding machine” may be a single or multiple-shot tableting machine, and it is possible to make special modifications such as using a special film to prevent sticking of a part to a punch when tableting, or spraying a lubricant into a mold. Refers to a tableting machine or a molding machine that is not used.
“일반적인 타정실 내부의 온습도”란, 타정기나 성형기가 위치한 공간의 내부 공기의 조건이 통상적으로 관리되는 온도와 습도의 범위 내에 있는 것으로, 예를 들면, 20~30℃의 온도 및 40%RH 이하의 습도 조건을 말한다.The term “temperature and humidity inside a general tableting room” means that the conditions of the internal air in the space where the tableting machine or molding machine is located are within a range of temperature and humidity that are normally controlled. Refers to the humidity conditions.
“정제를 제조하는 데에 전혀 문제가 없다”는 것은, 펀치나 몰드에 정제의 일부분 혹은 전체가 달라 붙거나 타정이나 성형시 정제의 일부분 혹은 전체가 부서지거나, 생산되어 나오는 정제를 용기에 받거나 다른 용기에 옮겨 담는 중에 일부분 혹은 전체가 부서지거나 하는 등의 타정 장애가 없는 것을 말하며, 또한 생산되는 정제 간의 중량편차가 발생하지 않도록 타정을 위한 혼합물의 흐름성에 아무런 문제가 없다는 것을 말한다.“There is no problem in the manufacture of tablets” means that some or all of the tablets stick to the punch or mold, or some or all of the tablets are broken during tableting or molding, It means that there are no tableting obstacles such as breakage of part or the whole during transfer into the container, and there is no problem in the flowability of the mixture for tableting so that no weight deviation occurs between the tablets produced.
본 발명은 종래 시판 중인 경질캡슐제를 대체할 수 있는 구강붕해정을 제공한다.The present invention provides oral disintegrating tablets that can replace conventional commercially available hard capsules.
시판 중인 레날리도마이드 경질캡슐제는 정해진 규격의 캡슐을 사용해야 하는데, 그 크기가 복약편의성을 저해할 정도로 큰 것들이 있다. 또한 경질캡슐제는 물과 함께 복용할 때 젤라틴의 캡슐 표면에 접착력이 생겨, 목이나 식도에 제제가 달라붙는 불편함이 동반되는데, 고령의 환자들이 주된 대상임을 고려할 때 상당한 복용불편이 있을 수 있다.Commercial lenalidomide hard capsules require the use of capsules of a specified size, which are large enough to impede the convenience of medication. In addition, the hard capsules are adhered to the gelatin capsule surface when taken with water, which is accompanied by discomfort in the preparation of the preparation to the neck or esophagus, which may be a significant discomfort considering the elderly patients as the main target .
본 발명자는 위 불편함을 제거하기 위해 구강붕해정의 개발에 착수했다.The present inventors began the development of oral disintegrating tablets to eliminate stomach discomfort.
구강붕해정은 소량의 물 또는 물 없이 복용해도 구강 내에서 신속하게 붕해되는 제제로서, 물 없이 복용해도 구강에서 신속하게 붕해되기 때문에 연하능력이 저하된 고령자도 복용하기 쉬운 제제다.Oral disintegrating tablet is a preparation that disintegrates rapidly in the oral cavity even when taken without a small amount of water or water, and is easy to take even elderly people whose swallowing ability is degraded because they disintegrate rapidly in the oral cavity even when taken without water.
그러나, 취급의 어려움 등을 이유로 항암제에 대해서는 아직까지 구강붕해정으로 만들려는 시도가 거의 존재하지 않았다. 레날리도마이드는 심각한 최기형성의 부작용 때문에 오남용이 금기시되는 약물이다. 따라서 이러한 약물의 경우에는 경질캡슐로 보호되어 있어야 안전하다는 인식이 있어서 일반적으로 정제로 제형 변경을 하려 하지 않을 뿐 아니라, 더군다나 구강붕해정으로 제공하려는 의도를 가지기는 상당히 쉽지 않다. 왜냐하면 통상적인 구강붕해정은 경도가 낮으며 쉽게 부서지기 때문에 약물이 환자 외에도 보호자, 동료, 가족, 의료인, 복약을 돕는 자 등에게 노출될 확률이 크기 때문이다. However, there have been few attempts to make oral disintegrating tablets for anticancer drugs due to difficulties in handling. Lenalidomide is a drug that is contraindicated for abuse because of the side effects of severe teratogenicity. Therefore, in the case of these drugs, there is a recognition that it is safe to be protected with hard capsules, and therefore, it is generally not intended to change the dosage form into tablets, and moreover, it is not easy to have an intention to provide oral disintegrating tablets. Because oral disintegrating tablets have low hardness and are easily broken, the drug is more likely to be exposed to caregivers, colleagues, family members, medical personnel, and medication supporters.
아울러 통상적인 구강붕해정은 정제의 경도가 낮기 때문에 가습 조건하에 노출되면 정제의 경도가 저하되어 정제가 파손됨으로써 약물이 유실될 가능성이 있으며, 약물의 안정성도 저하될 우려가 있다. 또한 구강붕해정은 가습 조건하에서 노출되어 정제의 경도가 저하되면 붕해시간도 지연될 가능성이 있다. 때문에 레날리도마이드를 구강붕해정으로 개발할 때는 가습 조건하에서 보관해도 정제의 경도 저하가 작고 붕해성이 유지될 수 있는 것을 고려해야 했다.In addition, since oral disintegrating tablets have low hardness, when exposed to humidification conditions, the hardness of the tablets may be lowered and the tablets may be broken, resulting in the loss of the drug and the stability of the drugs. In addition, when oral disintegrating tablets are exposed under humid conditions, the disintegration time may be delayed if the hardness of the tablet is lowered. Therefore, when developing lenalidomide as an oral disintegrating tablet, it was necessary to consider that the hardness of tablets was reduced and disintegration could be maintained even if stored under humid conditions.
한편 구강붕해정은 만니톨과 같은 당 알코올을 희석제로 사용하면 다른 부형제 성분과 반응하여 불순물을 생성시킬 수 있어, 구강붕해정을 구현할 때는 당 알코올 보다는 미결정 셀룰로오스나 무수 인산 수소 칼슘 등을 희석제로 사용하는 것이 보편적이다. 예컨대 국제공개공보 제 2005/123040호에는 주성분, 미결정 셀룰로스, 무수인산수소칼슘을 포함하고, 붕해제를 포함하지 않는 것을 특징으로 하는 구강붕해정이 개시되어 있다. 대한민국 공개특허공보 제 2010-0096179호 또한 미결정 셀룰로스, 인산수소칼슘을 희석제로서 채택한다.On the other hand, oral disintegrating tablets can produce impurities by reacting with other excipient components when sugar alcohols such as mannitol are used as diluents. Is universal. For example, International Publication No. 2005/123040 discloses oral disintegrating tablets comprising a main component, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and no disintegrating agent. Korean Unexamined Patent Publication No. 2010-0096179 also employs microcrystalline cellulose and calcium hydrogen phosphate as diluents.
그러나 본 발명자는 놀랍게도 희석제로서 만니톨을 포함하는 성분을 채택함으로써 붕해속도도 만족스럽고, 정제의 경도도 우수할 뿐 아니라, 뛰어난 보관 안정성을 가지는 구강붕해정을 얻을 수 있음을 발견했다. 레날리도마이드는 만니톨과의 배합적합성 시험에서도 매우 우수한 안정성을 갖는 것을 확인할 수 있었다. However, the inventors have surprisingly found that by adopting a component containing mannitol as a diluent, it is possible to obtain oral disintegrating tablets having satisfactory disintegration rate, excellent tablet hardness, and excellent storage stability. Lenalidomide was confirmed to have very good stability even in the compatibility test with mannitol.
일 구현예는 희석제로서 만니톨을 포함할 수 있다. 일 구현예는 분무건조 만니톨, 파마버스트, F-Melt 또는 이들의 조합을 희석제로서 채택한다. 파마버스트나 F-Melt 는 만니톨을 포함하는 희석제의 제품명이다. F-Melt 는 D-Mannitol, Xylitol, MCC, Crospovidone 및 무기 성분을 포함하는 제품이다. 파마버스트는 mannitol, pregelatinised starch, crospovidone, croscarmellose sodium, colloidal anhydrous silica 및 colloidal hydrated silica을 포함하는 제품이다.One embodiment may include mannitol as a diluent. One embodiment employs spray dried mannitol, permburst, F-Melt, or a combination thereof as a diluent. Pharmaburst or F-Melt is the product name of the diluent containing mannitol. F-Melt is a product containing D-Mannitol, Xylitol, MCC, Crospovidone and inorganic ingredients. Pharmaburst is a product containing mannitol, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal anhydrous silica and colloidal hydrated silica.
본 발명의 일 구현예는 레날리도마이드, 만니톨, 기타 약제학적으로 허용되는 부형제를 혼합한 후 이를 과립화한 다음, 당해 과립물을 붕해제, 활택제, 기타 약제학적으로 허용되는 부형제를 혼합하여, 이를 타정함으로써 제조할 수 있다. 상기 제조 방법에 따른 구강붕해정은 레날리도마이드 및 희석제를 포함하는 과립; 및 상기 과립의 외부에 붕해제 및 활택제를 포함하는 형태를 가질 수 있다. 이 경우, 속붕정을 갖는 구강붕해정의 외부 환경에 대한 안정성을 높일 수 있고, 다공성 물질과 같은 특수 부형제가 첨가될 가능성이 있는 구강붕해정에서 약물의 높은 함량 균일성을 달성할 수 있도록 한다.In one embodiment of the present invention, after mixing lenalidomide, mannitol, and other pharmaceutically acceptable excipients and granulating them, the granules are mixed with disintegrants, glidants, and other pharmaceutically acceptable excipients. In addition, it can manufacture by tableting. Oral disintegrating tablet according to the production method granules containing lenalidomide and diluent; And it may have a form containing a disintegrant and a lubricant on the outside of the granules. In this case, the stability of the orally disintegrating tablets with fast disintegrating tablets can be improved in the external environment, and high content uniformity of the drug can be achieved in the oral disintegrating tablets in which special excipients such as porous materials may be added.
상기 과립은 건조감량이 3% 이하일 수 있다. 바람직하게는 상기 건조감량은 2% 이하, 1.5% 이하, 또는 1.2% 이하일 수 있다. 구강붕해정을 이루는 과립의 건조감량은 구강붕해정의 붕해 또는 용출속도가 크게 변할 수 있으므로, 상기 범위를 벗어나는 경우 부작용 또는 약효 감소의 우려가 있다. 또한 고농도의 백당 용액을 사용하여 습식 과립화 한 후에 건조감량을 조절하여 저습윤 과립을 형성하면 낮은 타정압에서 타정하여도 시간이 지남에 따라 경도가 올라가게 되어 높은 경도와 좋은 마손도를 가지면서도 빠른 붕해를 보이는 정제를 얻을 수 있다. The granules may have a drying loss of 3% or less. Preferably the drying loss may be 2% or less, 1.5% or less, or 1.2% or less. The loss of drying of the granules forming the oral disintegrating tablets can greatly change the disintegration or dissolution rate of the oral disintegrating tablets. In addition, if wet granulation is performed using high-density white sugar solution to control the loss of drying to form low-wet granules, the hardness increases over time even after tableting at low tablet pressure, resulting in high hardness and good wear A tablet showing rapid disintegration can be obtained.
이하, 보다 구체적으로 설명한다.Hereinafter, it demonstrates more concretely.
저습윤Low wetting 과립 Granules
일 구체예에서, 구강붕해정에 포함되는 과립은 저습윤 과립일 수 있다.In one embodiment, the granules included in the orally disintegrating tablet may be low wet granules.
저습윤 과립은 분무 건조 만니톨 및 백당 결합제를 포함할 수 있다. 상기 저습윤 과립은 레날리도마이드, 및/또는 과립의 제조의 효율성, 레날리도마이드의 안정성, 외관, 색상, 보호, 유지, 결합, 성능 개선, 제조 공정 개선 등의 목적을 위하여 다양한 부가적인 성분들을 추가로 함유할 수 있다.Low wet granules may comprise spray dried mannitol and a white sugar binder. The low-wetting granules are a variety of additional additives for the purpose of efficiency of the preparation of lenalidomide, and / or granules, stability, appearance, color, protection, retention, bonding, performance improvement, improvement of manufacturing process, etc. of lenalidomide. It may further contain ingredients.
만니톨은 물에 잘 용해되며(20℃에서 물 5.5부당 1부), 화학적으로 안정하고, 비흡습성이며, 아미노 그룹과 메일라드 반응(Maillard reaction)을 하지 않으며, 구강내에서 붕해시 좋은 맛을 낸다.Mannitol is well soluble in water (1 part per 5.5 parts of water at 20 ° C), chemically stable, non-hygroscopic, does not undergo Maillard reaction with amino groups, and has a good taste when disintegrating in the oral cavity. .
분무 건조 만니톨은, 상기한 만니톨의 특성에 더하여, 다공성이어서 물에 신속하게 용해되며, 유동성이 좋고, 압축성이 좋으므로 희석제로서 바람직할 수 있다. 이러한 분무 건조 만니톨의 예로는 시판품인 MannogemTM EZ(SPI Pharma), Pearlitol®SD(Roquette) 등을 들 수 있으나, 이에 제한되는 것은 아니다. 분무 건조 만니톨은 직접 타정하는 방식에서 특히 바람직할 수 있다. 본 발명에서는 이러한 종래의 활용방식과 달리 습식과립의 제조시에 분무 건조 만니톨을 활용함으로써, 가루 형태의 만니톨(만니톨 파우더)을 습식제립하는 것보다 더 많은 미세 공극을 함유하도록 하며, 더 좋은 압축성 및 흐름성을 가지도록 하여 정제로 제조될 때 보다 빠른 붕해를 보이며, 보다 좋은 경도와 마손도를 갖도록 한다.Spray-dried mannitol, in addition to the properties of mannitol described above, is porous and rapidly dissolved in water, and may be preferable as a diluent because it has good fluidity and good compressibility. Examples of such spray-dried mannitol include, but are not limited to, commercially available MannogemTM EZ (SPI Pharma), Pearlitol®SD (Roquette), and the like. Spray dried mannitol may be particularly preferred in the manner of direct tableting. In the present invention, unlike the conventional application method by using the spray-dried mannitol in the manufacture of wet granules, so as to contain more fine pores than wet granulation of mannitol (mannitol powder) in the form of powder, better compressibility and It has a flowability to show faster disintegration when produced in tablets, and has a better hardness and wear and tear.
본 발명의 저습윤 과립은, 상기 분무건조 만니톨을 상기 과립 100중량%에 대하여 바람직하게는 20~98중량%, 보다 바람직하게는 30~95중량%, 보다 더 바람직하게는 50~90중량%로 포함한다. 분무건조 만니톨의 함량이 저습윤 과립 100중량%에 대하여 20중량% 미만이거나 98중량%를 초과하면 경도가 낮거나 붕해시간이 지연되는 문제가 있을 수 있다.Low-wetting granules of the present invention, the spray-dried mannitol is preferably from 20 to 98% by weight, more preferably from 30 to 95% by weight, even more preferably from 50 to 90% by weight relative to 100% by weight of the granules. Include. If the content of the spray-dried mannitol is less than 20% by weight or more than 98% by weight with respect to 100% by weight of the low-wetting granules, there may be a problem of low hardness or delayed disintegration time.
백당 결합제는 바람직하게는 물, 비수성 용매 또는 이들의 혼합용매에 용해시켜 사용할 수 있으며, 보다 바람직하게는 물 또는 물과 에탄올의 혼합 용매에 녹여 사용할 수 있다. 이러한 용매에 대한 백당의 농도는 1 내지 60%(무게/무게)(w/w)일 수 있으며, 바람직하게는 5 내지 50%의 농도로 제조하여 사용할 수 있다.The sucrose binder may be preferably dissolved in water, a non-aqueous solvent or a mixed solvent thereof, and more preferably dissolved in water or a mixed solvent of water and ethanol. The concentration of white sugar in such a solvent may be 1 to 60% (weight / weight) (w / w), and preferably may be prepared at a concentration of 5 to 50%.
본 발명의 저습윤 과립은 백당 결합제를, 상기 분무 건조 만니톨 100중량부에 대한 건조된 백당의 양으로 바람직하게는 1 내지 50중량부, 보다 바람직하게는 2 내지 30중량부, 보다 더 바람직하게는 3 내지 15중량부로 포함한다. 건조된 백당 결합제의 함량이 분무 건조 만니톨 100중량부에 대하여 1중량부 미만이면 정제의 경도가 낮아지는 문제점이 있을 수 있고, 50중량부를 초과하면 붕해시간이 늦어지는 문제가 있을 수 있다.The low-wetting granules of the present invention preferably contain 1 to 50 parts by weight, more preferably 2 to 30 parts by weight, and even more preferably, the amount of the dried sugars to 100 parts by weight of the spray dried mannitol. 3 to 15 parts by weight. If the content of the dried sugar-based binder is less than 1 part by weight with respect to 100 parts by weight of the spray-dried mannitol, there may be a problem that the hardness of the tablet is lowered, and if it exceeds 50 parts by weight, the disintegration time may be a problem.
본 발명의 저습윤 과립은 레날리도마이드를 포함할 수도 있고, 포함하지 않을 수도 있다. 저습윤 과립이 레날리도마이드를 포함하는 경우에는 습식과립의 제조를 위해 결합액을 가하기 전에 분무 건조 만니톨과 같이 고체 상태에서 혼합하여 포함되도록 할 수 있으며, 이때 레날리도마이드의 성상은 분말상태, 결정상태, 과립상태, 미세분말상태일 수 있다. 다르게는, 백당 결합액의 제조시에 함께 용해 혹은 분산시켜 포함되도록 할 수도 있다.The low wet granules of the present invention may or may not include lenalidomide. If the low-wetting granules contain lenalidomide, they may be included in a solid state, such as spray-dried mannitol, before the binder is added to prepare wet granules, whereby the properties of lenalidomide are in powder form. It may be in a crystalline state, a granular state, or a fine powder state. Alternatively, it may be included to dissolve or disperse together in the preparation of the sugar mixture.
본 발명의 과립에는 상기 과립 제조를 위한 부가적인 성분이 추가로 포함될 수 있다. 과립 제조를 위한 부가적인 성분으로는 건조 결합제, 착색제, 착향제, 감미제, 안정화제, 산화방지제 등을 들 수 있으며, 이들은 분무 건조 만니톨과 함께 고체 상태로 부가될 수 있다.The granules of the present invention may further comprise additional ingredients for producing the granules. Additional ingredients for producing granules include dry binders, colorants, flavors, sweeteners, stabilizers, antioxidants, and the like, which may be added in solid form with spray dried mannitol.
상기 과립 제조를 위한 부가적인 성분 중 건조 결합제는, 상기 분무 건조 만니톨 100중량부에 대하여 바람직하게는 50중량부 이하(예컨대 0.1 내지 50중량부)로, 보다 바람직하게는 30중량부 이하, 보다 더 바람직하게는 15중량부 이하의 양으로 본 발명의 저습윤 과립에 포함될 수 있다.Among the additional components for the preparation of the granules, the dry binder is preferably 50 parts by weight or less (for example, 0.1 to 50 parts by weight), more preferably 30 parts by weight or less, based on 100 parts by weight of the spray-dried mannitol. Preferably it may be included in the low wet granules of the present invention in an amount of 15 parts by weight or less.
상기 건조 결합제로는 당류, 당알코올류, 녹말, 다당류, 셀룰로오스 유도체, 또는 이들의 혼합물을 사용할 수 있다. 구체적인 예로는 프럭토오스(과당), 락티톨, 락토오스(유당), 말티톨, 말토오스, 만니톨, 소르비톨, 수크로오스, 에리트리톨, 크실리톨, 말토덱스트린, 이소말트, 덱스트린, 덱스트로오스, 덱스트레이트, 녹말, 미세결정성 셀룰로오스, 규화된 미세결정성 셀룰로오스, 분말상 셀룰로오스, 셀룰로오스 아세테이트, STARLAC®(15% 옥수수 녹말 및 85% 알파-락토오스 일수염을 함유하는 분무 건조된 고형분, Roquette American, Inc. 제조), MICROCELAC®(75% 알파-락토오스 일수염 및 25% 미세결정성 셀룰로오스를 함유하는 분무 건조된 고형분, Meggle excipients & technology 제조) 및 CELLACTOSE®(75% 알파-락토오스 일수염 및 25% 셀룰로오스 분말로 구성된 분무 건조된 화합물, Meggle excipients & technology 제조) 등에서 선택되는 1종 이상을 들 수 있으나, 이들에 한정되는 것은 아니다.As the dry binder, sugars, sugar alcohols, starch, polysaccharides, cellulose derivatives, or mixtures thereof may be used. Specific examples include fructose (fructose), lactitol, lactose (lactose), maltitol, maltose, mannitol, sorbitol, sucrose, erythritol, xylitol, maltodextrin, isomalt, dextrin, dextrose, dextrate, Starch, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, STARLAC® (spray dried solids containing 15% corn starch and 85% alpha-lactose monohydrate, manufactured by Roquette American, Inc.) Consisting of MICROCELAC® (spray dried solids containing 75% alpha-lactose monohydrate and 25% microcrystalline cellulose, manufactured by Meggle excipients & technology) and CELLACTOSE® (75% alpha-lactose monohydrate and 25% cellulose powder) Spray-dried compounds, Meggle excipients & technology production) and the like, but may be selected from one or more.
과립 제조를 위한 부가적인 성분 중에서 상기 건조 결합제를 제외한 나머지 성분들, 즉 착색제, 착향제, 감미제, 안정화제, 산화방지제 등은 백당 결합액의 제조시에 함께 용해 혹은 분산시켜 사용할 수 있다.Among the additional components for the preparation of granules, the remaining components except the dry binder, ie, colorants, flavors, sweeteners, stabilizers, antioxidants, etc. may be dissolved or dispersed together in the preparation of the sugar mixture.
저습윤Low wetting 과립의 제조 방법 Method of Preparation of Granules
상기한 바와 같은 본 발명의 저습윤 과립은, 바람직하게는, 분무 건조 만니톨 및 백당 결합제를 포함하는 과립을 형성하는 단계, 및 상기 과립을, 건조 과립의 건조감량의 1.05배 이상에서 5배 이하의 건조감량 값을 갖는 저습윤 과립이 되도록 건조하는 단계를 포함하는 방법에 의해 제조될 수 있다.The low-wet granules of the present invention as described above preferably form a granule comprising spray dried mannitol and a white sugar binder, and wherein the granules are not less than 1.05 times or less than 5 times the dry weight loss of the dry granules. It may be prepared by a method comprising the step of drying to a low wet granule having a loss on drying value.
바람직하게는, 분무 건조 만니톨 및 백당 결합제를 포함하는 과립 형성을 위한 혼합물 제조시에 백당 결합제가 물, 비수성 용매 또는 이들의 혼합용매에 용해된 형태로 사용된다.Preferably, the sucrose binder is used in the form of dissolved in water, a non-aqueous solvent or a mixed solvent thereof in preparing a mixture for granulation formation comprising spray dried mannitol and sucrose binder.
상기 분무 건조 만니톨 및 백당 결합제를 포함하는 과립에는 레날리도마이드 및/또는 과립 제조를 위한 부가적인 성분이 추가로 포함될 수 있으며, 이들을 상기 혼합물에 도입하는 방식에 대해서는 앞서 설명한 바 있다.The granules comprising the spray dried mannitol and the sucrose binder may further comprise additional ingredients for the preparation of lenalidomide and / or granules, and the manner of introducing them into the mixture has been described above.
본 발명의 저습윤 과립 제조방법은, 통상적으로 제약 분야에서 사용하는 습식 과립의 제조 방식을 활용하여 수행될 수 있다. 본 발명의 일 구체예에 따르면, 과립기, 믹서, U형 혼합기, 고속 믹서(high speed mixer), 유동층 과립기, 수작업 등의 방식을 사용하여, 분무 건조 만니톨 및 백당 결합제, 및 임의로 레날리도마이드 및/또는 과립 제조를 위한 부가적인 성분을 포함하는 혼합물을 응집 입자 덩어리 형태로 제조할 수 있다. 제조된 응집 입자 덩어리는 그대로 건조 단계에 들어갈 수도 있으며, 체질(sieving)을 거친 후에 건조 단계에 들어갈 수도 있다.Low wet granules manufacturing method of the present invention, it can be carried out utilizing the manufacturing method of wet granules commonly used in the pharmaceutical field. According to one embodiment of the invention, spray dried mannitol and sucrose binders, and optionally lenalido, using methods such as granulators, mixers, U-type mixers, high speed mixers, fluidized bed granulators, manual work, and the like Mixtures comprising additional components for the production of amides and / or granules may be prepared in the form of agglomerated particles. The prepared agglomerated particle mass may enter the drying step as it is, or may enter the drying step after sieving.
본 발명의 일 구체예에 따르면, 응집 입자 덩어리는 30 mesh의 체를 통과하여 제립시킬 수 있다.According to one embodiment of the invention, the aggregated particles can be granulated through a sieve of 30 mesh.
저습윤 과립의 제조를 위한 건조는 일반적인 과립의 건조를 위한 방식을 활용하여 수행될 수 있다. 예컨대, 대류 오븐, 진공 오븐, 유동층 건조기, 건조기, 상온에서의 자연 건조 등의 방식으로 건조작업이 수행될 수 있다.Drying for the production of low-wet granules can be carried out utilizing methods for drying the common granules. For example, the drying operation may be performed in a convection oven, vacuum oven, fluidized bed dryer, dryer, natural drying at room temperature, or the like.
건조 중 혹은 건조가 완료된 상태에서 다시 한번 체질을 통하여 원하는 크기의 저습윤 과립을 수득할 수도 있다.It is also possible to obtain low wet granules of a desired size through sieving once again during drying or in a complete drying state.
속붕정Sokbungjeong
본 발명의 속붕정은 상기 본 발명의 저습윤 과립을 포함하는 것을 특징으로 한다.Sokbung tablet of the present invention is characterized in that it comprises the low-wetting granules of the present invention.
본 발명의 속붕정에 포함되는 저습윤 과립의 양은 정제 100중량%에 대해 바람직하게는 50 내지 99중량%, 더 바람직하게는 60 내지 98중량%, 더욱 더 바람직하게는 70 내지 97중량%이다. 저습윤 과립의 함량이 정제 100중량%에 대하여 50중량% 미만이면 높은 경도와 빠른 붕해의 속붕정의 특성을 나타내지 못하는 문제점이 있을 수 있고, 99중량%를 초과하면 타정 장애 혹은 수붕해 지연의 문제가 있을 수 있다.The amount of the low-wetting granules included in the fast borosilicate tablet of the present invention is preferably 50 to 99% by weight, more preferably 60 to 98% by weight, even more preferably 70 to 97% by weight based on 100% by weight of the tablet. If the content of the low-wetting granules is less than 50% by weight based on 100% by weight of the tablet, there may be a problem in that it does not exhibit the characteristics of high hardness and rapid disintegration of fast disintegrating tablets. There can be.
본 발명의 속붕정은 저습윤 과립에 포함된 분무 건조 만니톨 및 백당 결합제 이외에, 레날리도마이드 및/또는 정제 제조를 위한 부가적인 성분을 추가로 포함할 수 있다. 이들 레날리도마이드 및/또는 정제 제조를 위한 부가적인 성분은, 저습윤 과립에 도입될 수도 있으며, 다르게는 타정을 위한 후혼합물 형성 시에 도입될 수도 있다. 후혼합물 형성 단계에서 도입되는 레날리도마이드는 분말상태, 결정상태, 과립상태, 미세분말상태, 미각차폐 혹은 서방성 방출제어용 코팅이 된 미립자 상태 등일 수 있다. 정제 제조를 위한 부가적인 성분은 타정의 효율성, 붕해의 촉진, 레날리도마이드의 안정성, 외관, 색상, 보호, 유지, 결합, 성능 개선, 제조 공정 개선 등의 부가적인 목적을 위하여 도입될 수 있다. 정제 제조를 위한 부가적인 성분의 예로는 붕해제, 활택제, 계면활성제, 건조 결합제, 착색제, 착향제, 감미제, 안정화제, 산화방지제, 신맛제 등을 들 수 있으나, 이에 한정되는 것은 아니다.Sokbung tablets of the present invention may further comprise additional ingredients for the preparation of lenalidomide and / or tablets, in addition to the spray dried mannitol and the sucrose binder contained in the low wet granules. Additional ingredients for preparing these lenalidomides and / or tablets may be incorporated into the low-wet granules, or alternatively may be introduced upon formation of the postmixture for tableting. Lenalidomide introduced in the post-mixture forming step may be in a powder state, crystal state, granule state, fine powder state, taste shielding or particulate state with a controlled release release control. Additional ingredients for the manufacture of tablets may be introduced for additional purposes such as efficiency of tableting, promotion of disintegration, stability of lenalidomide, appearance, color, protection, retention, binding, improved performance, improved manufacturing process, and the like. . Examples of additional ingredients for the manufacture of tablets include, but are not limited to, disintegrants, lubricants, surfactants, dry binders, colorants, flavors, sweeteners, stabilizers, antioxidants, sour agents, and the like.
상기 부가적인 성분의 구체적 종류, 사용법 그리고 이러한 물질들을 본 발명의 정제에 도입시키는 방법 등은 본 발명이 속하는 기술분야에 잘 알려져 있으며, 또한 다양한 범주에서 변형될 수 있다.The specific kinds of the additional ingredients, the use and methods of introducing such materials into the tablets of the present invention are well known in the art and may be modified in various categories.
구체적으로, 상기 붕해제는 전분글리콜산 나트륨, 크로스포비돈, 저치환도 히드록시프로필셀룰로오스, 가교화된 카르복시메틸셀룰로오스 나트륨, 녹말 등으로 이루어진 군에서 선택되는 1종 이상일 수 있다. 상기 붕해제는 정제 100중량% 내에 적절하게는 7중량% 이내, 바람직하게는 5중량% 이내, 더욱 바람직하게는 3중량% 이내로 함유될 수 있다.Specifically, the disintegrant may be at least one selected from the group consisting of sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl cellulose sodium, starch and the like. The disintegrant may be contained within 100% by weight of the tablet, preferably within 7% by weight, preferably within 5% by weight, more preferably within 3% by weight.
구체적으로, 상기 활택제는 스테아르산, 글리세릴 베헤네이트, 글리세릴 모노스테아레이트, 마그네슘 스테아레이트, 칼슘 스테아레이트, 이산화규소, 탈크, 슈가에스터, 스테아릴 퓨마레이트 나트륨 및 마그네슘 실리케이트, 스테아르산나트륨, 폴리(에틸렌 글리콜), 폴리옥시프로필렌-폴리옥시에틸렌 블록 공중합체, 콜로이드성 이산화실리콘, 자당 지방산 에스테르 등으로 이루어진 군에서 선택되는 1종 이상일 수 있다. 상기 활택제는 정제 100중량% 내에 적절하게는 3중량% 이내, 바람직하게는 2중량% 이내, 더욱 바람직하게는 1.5중량% 이내로 함유될 수 있다.Specifically, the glidants include stearic acid, glyceryl behenate, glyceryl monostearate, magnesium stearate, calcium stearate, silicon dioxide, talc, sugar ester, stearyl fumarate sodium and magnesium silicate, sodium stearate, Poly (ethylene glycol), polyoxypropylene-polyoxyethylene block copolymer, colloidal silicon dioxide, sucrose fatty acid ester, and the like. The glidant may be contained within 100% by weight of the tablet, preferably within 3% by weight, preferably within 2% by weight, more preferably within 1.5% by weight.
속붕정의Fast-paced 제조방법 Manufacturing method
상기한 바와 같은 본 발명의 속붕정은, 상기 저습윤 과립을 포함하는 타정용 후혼합물을 형성하는 단계, 상기 타정용 후혼합물을 압축하여 정제를 얻는 단계, 및 상기 정제를 건조하는 단계를 포함하는 방법에 의해 제조될 수 있다.Sokbung tablet of the present invention as described above, comprising the steps of forming a tableting post-mixture containing the low-wetting granules, compressing the tableting post-mixture to obtain a tablet, and drying the tablet It can be produced by the method.
본 발명의 속붕정 제조방법은 제약분야에서 일반적으로 활용하는 타정기 혹은 성형기를 사용하여 수행될 수 있다. 또한 타정은 저압 압축 방식으로 수행될 수 있으며, 정제의 건조는 온화한 조건 하에서 이루어질 수 있다.The method for preparing fast borosilicate tablet of the present invention may be performed using a tableting machine or a molding machine generally used in the pharmaceutical field. Tableting may also be carried out in a low pressure compression mode, and the drying of the tablets may be under mild conditions.
저습윤 과립을 포함하는 타정용 후혼합물을 압축하여 정제로 만들기 위해 이용되는 압축 압력은 일반적으로 약 150 MPa 이하(예컨대, 1 Pa~150 MPa), 바람직하게는 약 35 MPa 이하, 보다 바람직하게는 약 10 MPa 이하의 저압이다.The compression pressure used to compress the tableting postmixture comprising low wet granules into tablets is generally about 150 MPa or less (e.g., 1 Pa to 150 MPa), preferably about 35 MPa or less, more preferably Low pressure of about 10 MPa or less.
정제가 입 속에서 신속하게 붕해되기 위하여 정제는 물을 그 내부 코어로 신속하게 흡수해야 하며, 성분들이 신속하게 용해되어야 한다. 따라서, 압축된 정제가 고-다공성을 유지하는 것이 중요하다. 압축 후에 고-다공성을 유지하기 위해서는 통상 저압 타정이 필요하나, 정제가 저압에서 제조되면 이들의 경도와 마손도 등은 불량해질 수밖에 없었다. 그러나 본 발명에 따른 저습윤 과립을 이용하면 이러한 타정 장애 없이 저압타정으로도 정제의 생산이 가능하며, 건조 단계를 거쳐 높은 경도와 낮은 마손도의 좋은 물성과 아울러 빠른 붕해성을 갖는 정제를 얻을 수 있다,In order for the tablet to disintegrate quickly in the mouth, the tablet must quickly absorb water into its inner core and the components must dissolve quickly. Therefore, it is important for compressed tablets to maintain high porosity. In order to maintain high porosity after compression, low pressure tableting is usually required. However, when tablets are manufactured at low pressure, their hardness and wear and tear are inevitably deteriorated. However, by using the low-wetting granules according to the present invention, it is possible to produce tablets with low pressure tableting without such a tableting disorder, and to obtain tablets having fast disintegration properties with good physical properties of high hardness and low wear through the drying step. have,
정제를 건조하는 온화한 조건은, 심하게 습하지 않은 상온의 조건일 수 있으며, 예컨대 20 내지 30℃의 온도 및 40%RH 이하의 습도 조건일 수 있다. 보다 빠르고 확실한 건조를 위해서는 20 내지 50℃의 저온의 대류 오븐을 활용할 수 있으며, 건조한 공기를 공급하는 방식이나, 제습기를 이용하는 방법, 제습제를 이용하는 방법 등을 사용할 수도 있다.Mild conditions of drying the tablets may be conditions of room temperature that are not severely wet, such as temperatures of 20 to 30 ° C. and humidity conditions of 40% RH or less. For faster and more reliable drying, a low temperature convection oven at 20 to 50 ° C. may be used, and a method of supplying dry air, a method using a dehumidifier, a method using a dehumidifying agent, and the like may also be used.
또는 본 발명의 일 구현예는 레날리도마이드, 만니톨, 붕해제, 활택제, 기타 약제학적으로 허용되는 부형제를 혼합한 후, 이를 타정함으로써 제조할 수 있다. 여기에서 상기 만니톨은 정제의 총 중량에 대하여 20~98중량%, 바람직하게는 50~95중량%로 포함한다.Alternatively, an embodiment of the present invention may be prepared by mixing lenalidomide, mannitol, disintegrant, glidants, and other pharmaceutically acceptable excipients and then tableting them. Here, mannitol is contained in 20 to 98% by weight, preferably 50 to 95% by weight relative to the total weight of the tablet.
기타 약제학적으로 허용 가능한 부형제로서 입안에서 고미를 중화시키기 위해 산성화제나 감미제 등을 붕해시간을 지연시키지 않고, 정제의 경도를 저하시키지 않는 성분 중에서 추가로 배합할 수 있다.As other pharmaceutically acceptable excipients, acidifying agents, sweeteners, and the like can be further blended in the ingredients that do not lower the hardness of the tablet without delaying the disintegration time in order to neutralize bitter taste in the mouth.
본 발명의 일 구현예는 경도가 1.2-25 Kp, 바람직하게는 1.5-12 Kp, 바람직하게는 2-10 Kp 인 것을 특징으로 한다. 보다 바람직하게는 3-10Kp 일 수 있으며, 보다 더 바람직하게는 4내지 10 Kp 일 수 있다. 위 경도보다 높으면 붕해 지연으로 인해 약물의 방출 지연이 있을 수 있으며, 낮으면 정제가 약하여 코팅, 운반, 보관, 포장, 복용시 부서지는 경우가 있을 수 있다. 그러나 경도는 정제의 크기와 무게 등에 따라 달라질 수 있다. 작은 정제의 경우에는 보다 낮은 경도에서도 높은 경도 및 마손도 등 좋은 물리적 물성을 갖는다. 일 구현예에서 레날리도마이드의 25mg의 용량을 갖는 경우에는 5 내지 10 Kp가 바람직하다. One embodiment of the invention is characterized in that the hardness is 1.2-25 Kp, preferably 1.5-12 Kp, preferably 2-10 Kp. More preferably 3-10 Kp, still more preferably 4-10 Kp. If it is higher than the above hardness, there may be a delay in the release of the drug due to the disintegration delay, and if it is low, the tablet may be weak and may break during coating, transportation, storage, packaging, and taking. However, the hardness may vary depending on the size and weight of the tablet. Small tablets have good physical properties such as high hardness and wear and tear even at lower hardness. In one embodiment 5 to 10 Kp is preferred when having a dose of 25 mg of lenalidomide.
본 발명의 일 구현예는 마손도가 2% 이하인 것을 특징으로 한다. 보다 바람직하게는 1% 이하 일 수 있으며, 보다 더 바람직하게는 0.6% 이하일 수 있다. 위 마손도보다 높으면 코팅, 운반, 보관, 포장, 복용시 가루가 발생하는 경우가 있을 수 있다.One embodiment of the present invention is characterized in that the degree of wear and tear is 2% or less. It may be more preferably 1% or less, even more preferably 0.6% or less. If gastric abrasion is higher than that, powder may occur during coating, transportation, storage, packaging and taking.
본 발명의 일 구현예는 구강내 붕해시간이 60초 이내인 것을 특징으로 한다. 보다 바람직하게는 50초 이내, 보다 더 바람직하게는 40초 이내, 가장 바람직하게는 30초 이내에 붕해되는 것을 특징으로 한다. 위 시간 보다 길면 구강 내에 약물을 머금고 있는 시간이 길어지게 되어 환자에게 불편을 초래할 수 있다.One embodiment of the present invention is characterized in that the oral disintegration time is within 60 seconds. More preferably within 50 seconds, even more preferably within 40 seconds, most preferably within 30 seconds. If it is longer than the above time, the time to hold the drug in the oral cavity may be long, which may cause inconvenience to the patient.
일 양상은, 1-1) 레날리도마이드와 희석제를 포함하는 조성물을 혼합한 후 이를 과립화한 다음, 상기 과립물을 붕해제 및, 활택제를 포함하는 조성물과 혼합하거나, In one aspect, 1-1) after mixing a composition comprising lenalidomide and a diluent and granulate it, and then mixing the granules with a composition comprising a disintegrant and a lubricant,
1-2) 레날리도마이드를 희석제, 붕해제 및 활택제를 포함하는 조성물과 혼합하는 단계; 및,1-2) mixing lenalidomide with a composition comprising a diluent, a disintegrant and a lubricant; And,
2) 단계 1-1) 또는 1-2)에서 얻어진 혼합물을 타정하는 단계:2) tableting the mixture obtained in step 1-1) or 1-2):
를 포함하는, 구강붕해정의 제조방법을 제공한다.It includes, provides a method for producing oral disintegrating tablets.
일 구체예에서, 상기 제조방법은 과립을 건조시켜 건조감량을 조절하는 단계를 더 포함할 수 있다. 상기 건조감량은 3% 이하일 수 있다.In one embodiment, the manufacturing method may further comprise the step of controlling the drying loss by drying the granules. The loss on drying may be 3% or less.
이하 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 보호범위가 이에 의해 한정되는 것은 아님에 유의한다.Hereinafter, preferred examples are provided to help understanding of the present invention. However, the following examples are only for illustrating the present invention, it is noted that the protection scope of the present invention is not limited thereto.
먼저, 하기 실시예 및 비교예에서 수행한 특성 분석 방법은 다음과 같다.First, the characteristic analysis method performed in the following Examples and Comparative Examples is as follows.
경도 측정Hardness measurement
정제의 경도는 경도계 8 M(Hardness tester 8M, Dr. Schleuniger, 스위스)을 사용하여 측정하였고, 적어도 6개의 검체를 측정하여 평균치를 기재하였다.The hardness of the tablets was measured using a hardness tester 8M (Hardness tester 8M, Dr. Schleuniger, Switzerland), and at least six samples were measured to describe the average value.
마손도Masson 측정 Measure
USP(US Pharmacopoeia) 25의 일반적 시험과 분석에 대한 Tablet Friability of the General chapters에 기재된 정제 마손도 측정 방법에 따라 시험하였다.Tablet friability was measured according to the Tablet Friability of the General chapters for general testing and analysis of US Pharmacopoeia (USP) 25.
구강내Intraoral 붕해Disintegration 시험 exam
속붕해성 정제인 경우, 구강 내에서 속붕해성 정제의 붕해 시험을 지원자에게 실시하였다. 지원자(건강한 성인 남성)들을 무작위로 선정하여 물로 입을 세정하도록 한 후, 정제를 지원자들의 혀에 놓고 즉시 스톱워치를 작동시켜 붕해시간을 측정하였다. 지원자들은 자신의 혀를 이용해서 속붕해성 정제를 입 천정으로 이동시키는 것과 정제를 깨물지 않고 부드럽게 굴리는 작용이나 좌우로 굴리는 것이 허용되었다. 정제가 붕괴되어 침과 함께 삼킬 수 있는 상태가 된 즉시 스톱워치를 중지시키고 시간을 기록하였다. In the case of fast disintegrating tablets, the disintegration test of the fast disintegrating tablets in the oral cavity was performed to the volunteers. Volunteers (healthy adult males) were randomly selected to flush their mouths with water, and then tablets were placed on the volunteers' tongues and immediately operated with a stopwatch to measure disintegration time. Volunteers were allowed to move fast disintegrating tablets to the ceiling of their mouths using their tongues and to smoothly roll or roll the tablets without biting. As soon as the tablet collapsed and became swallowable with the saliva, the stopwatch was stopped and the time was recorded.
건조 감량Dry weight loss
분말이나 과립 등의 건조감량의 경우 약 2g의 시료를 취해서 알루미늄 접시에 골고루 펴서 넣고, Sartorius사의 MA100 LOD meter를 이용하여 105℃에서 수 내지 십수분 동안 측정하였으며, 수치의 변화가 없을 때 자동 설정으로 시험이 종료되도록 하였다. 정제의 건조감량의 경우에는 약 2g에 해당하는 시료를 취해서 알루미늄 접시에 넣고 분말이나 과립의 건조감량 측정과 동일한 방식으로 측정하였다. 분쇄된 정제의 건조감량의 경우에는 약 2g에 해당하는 정제를 취하여 막자 사발에서 갈아서 분쇄된 상태로 만든 후, 분말이나 과립의 건조 감량 측정과 동일한 방식으로 측정하였다.In case of loss of dryness such as powder or granules, about 2g of sample was taken and spread evenly on an aluminum plate, measured by Sartorius MA100 LOD meter for several to ten minutes at 105 ℃. The test was allowed to end. In the case of weight loss of tablets, a sample corresponding to about 2 g was taken and placed in an aluminum dish and measured in the same manner as in the measurement of weight loss of powder or granules. In the case of loss of crushed tablets, about 2 g of tablets were taken, ground in a mortar and pestle, and then pulverized, and then measured in the same manner as in the measurement of dry loss of powder or granules.
실시예EXAMPLE 1 One
레날리도마이드 12.5g 및 하기의 표 1의 함량비로 분무 건조 만니톨(MannogemTM EZ, SPI)과 유당(Pharmatose 200M), 아세설팜 칼륨을 3L 용량의 고속 믹서에 넣고, 임펠러 150rpm, 쵸퍼 1700rpm의 조건으로 회전시켜 혼합하면서, 백당(sucrose, Samyang) 50%(w:w) 용액(에탄올:물=4:6(w:w)) 7.8g을 투입하여 반죽하고, 꺼낸 후 30 mesh (체눈 크기: 600㎛) 체를 통과시켜 제립하고, 50℃ 오븐에서 1시간 가량 건조하되, 최종 저습윤 과립의 건조감량이 대략 1.0%가 되도록 하기 위하여 건조 시간을 적절히 조절하였다. 건조된 저습윤 과립의 최종 건조감량은 1.08%이었다. Spray dry mannitol (Mannogem TM EZ, SPI), lactose (Pharmatose 200M) and acesulfame potassium were added to a 3 L high-speed mixer at a ratio of 12.5 g of lenalidomide and Table 1 below, and the impeller 150 rpm, chopper 1700 rpm While rotating under conditions, 7.8 g of 50% (w: w) solution of sugar (sucrose, Samyang) (ethanol: water = 4: 6 (w: w)) was added, kneaded, and taken out, followed by 30 mesh (eye size). : 600 μm) The granules were passed through a sieve and dried in an oven at 50 ° C. for about 1 hour, but the drying time was appropriately adjusted so that the drying loss of the final low wet granule was approximately 1.0%. The final loss on dried low wet granules was 1.08%.
상기 제조된 저습윤 과립과 저치환도 히드록시프로필 셀룰로오스(L-HPC), 칼슘스테아레이트, 스테아르산을 혼합한 후, 직경 11mm, 무게 500 mg의 속붕정이 되도록 단발타정기(EK-0, Korsch)로 타정하였다. 타정 직후 정제의 경도는 약 1.8Kp이었으며, 타정이 종료된 후 상온(대략 25℃, 10~30% RH)에서 2일간 방치한 후 포장하였다. 포장이 완료된 정제의 물성을 평가한 결과 경도는 6.7Kp이었고, 마손도는 0.16%, 수중 붕해시간은 20.5초, 구강내 붕해시간은 18초, 정제의 건조감량은 0.25%이었다.After mixing the prepared low-wetting granules and low-substituted hydroxypropyl cellulose (L-HPC), calcium stearate, stearic acid, a single shot tableting machine (EK-0, Korsch) to be a fast bovine tablet of diameter 11mm, weight 500 mg ) Was compressed. Immediately after tableting, the tablet had a hardness of about 1.8 Kp. After tableting, the tablet was left at room temperature (approximately 25 ° C., 10-30% RH) for 2 days and then packaged. As a result of evaluating the physical properties of the packaged tablets, the hardness was 6.7 Kp, the friability was 0.16%, the disintegration time in water was 20.5 seconds, the disintegration time in the oral cavity was 18 seconds, and the weight loss of the tablet was 0.25%.
성분명Ingredient Name 1정당 분량 (mg)Servings Per Tablet (mg) 함량 (content ( %% ))
레날리도마이드Lenalidomide 2525 55
분무건조 만니톨Spray drying mannitol 422.95422.95 84.5984.59
유당수화물Lactose Carb 2121 4.24.2
정제백당Purified sugar 7.87.8 1.561.56
저지환도히드록시프로필셀룰로오스Low ring degree hydroxypropyl cellulose 1515 33
스테아르산Stearic acid 2.52.5 0.50.5
스테아르산칼슘Calcium stearate 55 1One
아세설팜칼륨Acesulfame Potassium 0.750.75 0.150.15
TotalTotal 500500 100100
실시예EXAMPLE 2 2
레날리도마이드 12.5g 및 하기의 표 2의 함량비로 파마버스트 (Pharmaburst 500, SPI), 칼슘스테아레이트, 스테아르산을 혼합한 후, 직경 11mm, 무게 500 mg의 속붕정이 되도록 단발타정기(EK-0, Korsch)로 타정하였다. 정제의 경도는 7.3Kp이었으며, 마손도는 0.08%, 구강내 붕해시간은 26초이었다.12.5 g of lenalidomide and Pharmaburst 500 (SPI), calcium stearate, and stearic acid were mixed in the content ratio of Table 2 below, and a single shot tableting machine (EK-) was made to have a diameter of 11 mm and a fast 500 mg weight. 0, Korsch). The hardness of the tablet was 7.3Kp, the friability was 0.08%, and the oral disintegration time was 26 seconds.
품명Product Name 1정당 분량 (mg)Servings Per Tablet (mg) 함량 (content ( %% ))
레날리도마이드Lenalidomide 2525 55
파마버스트Pharma Burst 467.5467.5 93.593.5
스테아르산Stearic acid 2.52.5 0.50.5
스테아르산칼슘Calcium stearate 55 1One
TotalTotal 500500 100100
실시예EXAMPLE 3 3
레날리도마이드 12.5g 및 하기의 표 3의 함량비로 F-melt (C type, Fuji Chemical), 저치환도 히드록시프로필 셀룰로오스 (L-HPC), 칼슘스테아레이트, 스테아르산을 혼합한 후, 직경 11mm, 무게 500 mg의 속붕정이 되도록 단발타정기(EK-0, Korsch)로 타정하였다. 정제의 경도는 6.6Kp이었으며, 마손도는 0.53%, 구강내 붕해시간은 17초이었다.After mixing 12.5 g of lenalidomide and F-melt (C type, Fuji Chemical), low-substituted hydroxypropyl cellulose (L-HPC), calcium stearate, stearic acid, It was compressed with a single-shot tablet machine (EK-0, Korsch) so that the fast bovine tablet of 11 mm, weight 500 mg. The hardness of the tablet was 6.6 Kp, the friability was 0.53%, and the disintegration time in the oral cavity was 17 seconds.
품명Product Name 1정당 분량 (mg)Servings Per Tablet (mg) 함량 (content ( %% ))
레날리도마이드Lenalidomide 2525 55
F-MeltF-Melt 452.5452.5 90.590.5
저지환도히드록시프로필셀룰로오스Low ring degree hydroxypropyl cellulose 1515 33
스테아르산Stearic acid 2.52.5 0.50.5
스테아르산칼슘Calcium stearate 55 1One
TotalTotal 500500 100100

Claims (10)

  1. 유효성분으로서 레날리도마이드를 포함하는 구강붕해정.Oral disintegrating tablet containing lenalidomide as an active ingredient.
  2. 제1항에 있어서, 희석제로서 만니톨을 포함하는 것을 특징으로 하는 구강붕해정.The orally disintegrating tablet according to claim 1, comprising mannitol as a diluent.
  3. 제1항에 있어서, 상기 구강붕해정은 레날리도마이드와 희석제를 포함하는 과립을 포함하고, 그 외부에 붕해제 및 활택제를 포함하는 것인 구강붕해정.The orally disintegrating tablet according to claim 1, wherein the orally disintegrating tablet includes granules including lenalidomide and a diluent, and includes a disintegrating agent and a lubricant on the outside thereof.
  4. 제3항에 있어서, 상기 과립은 건조감량이 3% 이하인 것을 특징으로 하는 제조방법.The method of claim 3, wherein the granules have a drying loss of 3% or less.
  5. 제 1 항에 있어서, 경도가 1.2-25 Kp 인 것을 특징으로 하는 구강붕해정.The orally disintegrating tablet according to claim 1, wherein the hardness is 1.2-25 Kp.
  6. 제 1 항에 있어서, 경도가 1.5-12 Kp 인 것을 특징으로 하는 구강붕해정.The orally disintegrating tablet according to claim 1, wherein the hardness is 1.5-12 Kp.
  7. 제 1 항에 있어서, 구강내 붕해시간이 60초 이내인 것을 특징으로 하는 구강붕해정.The oral disintegrating tablet according to claim 1, wherein the oral disintegration time is within 60 seconds.
  8. 1-1) 레날리도마이드와 희석제를 포함하는 조성물을 혼합한 후 이를 과립화한 다음, 상기 과립물을 붕해제 및, 활택제를 포함하는 조성물과 혼합하거나,1-1) after mixing a composition comprising lenalidomide and a diluent and granulating it, and then mixing the granules with a composition containing a disintegrant and a lubricant,
    1-2) 레날리도마이드를 희석제, 붕해제 및 활택제를 포함하는 조성물과 혼합하는 단계; 및, 1-2) mixing lenalidomide with a composition comprising a diluent, a disintegrant and a lubricant; And,
    2) 단계 1-1) 또는 1-2)에서 얻어진 혼합물을 타정하는 단계:2) tableting the mixture obtained in step 1-1) or 1-2):
    를 포함하는, 구강붕해정의 제조방법Including, oral disintegrating tablet manufacturing method
  9. 제8항에 있어서, 희석제로서 만니톨을 포함하는 것을 특징으로 하는, 제조방법.The manufacturing method of Claim 8 containing mannitol as a diluent.
  10. 제8항에 있어서, 상기 과립물은 건조감량이 3 % 이하인 제조방법.The method of claim 8, wherein the granules have a loss of drying of 3% or less.
PCT/KR2019/004476 2018-04-13 2019-04-13 Lenalidomide oral tablet composition enabling enhanced disintegration WO2019199136A1 (en)

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KR1020190043378A KR102259798B1 (en) 2018-04-13 2019-04-12 Oral tablet formulation of lenalidomide with improved disintegration
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Citations (6)

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WO2011069608A1 (en) * 2009-12-09 2011-06-16 Ratiopharm Gmbh S-lenalidomide, polymorphic forms thereof and blend comprising s- und r-lenalidomide
US20120046315A1 (en) * 2008-11-14 2012-02-23 Katrin Rimkus Intermediate and oral administrative formats containing lenalidomide
CN105534981A (en) * 2016-03-04 2016-05-04 四川美大康华康药业有限公司 Lenalidomide composition tablets and preparation method thereof
CN106309403A (en) * 2016-09-30 2017-01-11 江苏豪森药业集团有限公司 Pharmaceutical composition containing lenalidomide, and preparation method and medical application thereof
WO2017109041A1 (en) * 2015-12-22 2017-06-29 Synthon B.V. Pharmaceutical composition comprising amorphous lenalidomide and an antioxidant
KR20180042115A (en) * 2016-10-14 2018-04-25 주식회사 삼양바이오팜 Oral tablet formulation of lenalidomide

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Publication number Priority date Publication date Assignee Title
US20120046315A1 (en) * 2008-11-14 2012-02-23 Katrin Rimkus Intermediate and oral administrative formats containing lenalidomide
WO2011069608A1 (en) * 2009-12-09 2011-06-16 Ratiopharm Gmbh S-lenalidomide, polymorphic forms thereof and blend comprising s- und r-lenalidomide
WO2017109041A1 (en) * 2015-12-22 2017-06-29 Synthon B.V. Pharmaceutical composition comprising amorphous lenalidomide and an antioxidant
CN105534981A (en) * 2016-03-04 2016-05-04 四川美大康华康药业有限公司 Lenalidomide composition tablets and preparation method thereof
CN106309403A (en) * 2016-09-30 2017-01-11 江苏豪森药业集团有限公司 Pharmaceutical composition containing lenalidomide, and preparation method and medical application thereof
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