WO2017116031A1 - Pharmaceutical composition containing gefitinib, administrable to patients with lactose intolerance and having improved dosing convenience - Google Patents

Pharmaceutical composition containing gefitinib, administrable to patients with lactose intolerance and having improved dosing convenience Download PDF

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WO2017116031A1
WO2017116031A1 PCT/KR2016/014300 KR2016014300W WO2017116031A1 WO 2017116031 A1 WO2017116031 A1 WO 2017116031A1 KR 2016014300 W KR2016014300 W KR 2016014300W WO 2017116031 A1 WO2017116031 A1 WO 2017116031A1
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composition
gefitinib
comparative example
total weight
disintegrant
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French (fr)
Korean (ko)
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안병락
민미홍
정현준
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환인제약 주식회사
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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention relates to oral solid pharmaceutical compositions containing gefitinib as one of the active ingredients.
  • Gefitinibran is a kind of quinazoline derivative, and has a structure of the following [Formula 1], and the systemic name according to IUPAC is N- (3-chloro-4-fluoro-phenyl) -7-methoxy- 6- (3-morpholin-4-ylpropoxy) quinazolin-4-amine.
  • Gefitinib is a member of the tyrosine kinase region of the epithelial cell proliferation factor receptor (EGFR) which is known to cause overexpression of malignant tumors such as non-small cell lung cancer through in vitro results disclosed in International Publication No. 96/33980. Pharmacological mechanisms have been disclosed to inhibit the tyrosine kinase domain.
  • EGFR epithelial cell proliferation factor receptor
  • Gefitinib is then clinically used for primary treatment of locally advanced or metastatic non-small cell lung cancer with active mutations in epithelial cell proliferation factor (EGFR) and for non-small cell lung cancer (unoperable or relapsed) that fails conventional chemotherapy. It is known to be useful for treatment.
  • EGFR epithelial cell proliferation factor
  • the drug is orally administered and then moved along the gastrointestinal tract, such as the esophagus, stomach, duodenum, small intestine, and rectum, and the drug is exerted through the blood vessels or lymphatic vessels to the site of action.
  • the hydrogen ion concentration of is different.
  • the stomach has a pH of 1.0-3.0
  • the small intestine has a pH of 5.0-6.0 in the duodenum
  • the pH increases as it goes to the plant and ileum. 7.0-8.0. Because of this, drugs that are sensitive to solubility according to pH may exhibit undesirable pharmacokinetic properties by varying bioavailability by patient or dose.
  • Gefitinib is a basic compound having two basic groups with pKa of 5.3 and 7.2, which can be protonated or deprotonated depending on pH, which can significantly affect the solubility of the compound. That is, the solubility of gefitinib varies greatly with pH. For example, in the free base form of gefitinib, 10-30 ml of the solvent required to dissolve 1 g in an aqueous medium at pH 1 is soluble, while it is required to dissolve 1 g in an aqueous medium at pH 4-6. The solvent is poorly soluble at least 10,000 ml and substantially insoluble in aqueous media having a pH of 7 or higher.
  • Gefitinib has a high solubility in an acidic environment of the stomach, but moves to the small intestine with a high pH, or when the pH environment is locally changed depending on whether or not to eat and drink water, gefitinib has a low solubility and tends to precipitate from the solution. For this reason, the bioavailability of gefitinib is very variable. It is also known that the maximum intrinsic absorption site of gefitinib is not in the stomach but in the upper intestine, so it is necessary to improve the solubility sensitivity according to pH when designing gefitinib.
  • Korean Patent No. 1002374 discloses that uncoated tablets containing gefitinib are coated with an ester base of water-soluble cellulose ether or water-soluble cellulose ether such as hydroxypropylmethylcellulose, so that the drug will not precipitate even in an environment of pH 6.5. It has been disclosed that the technical idea that it can.
  • gefitinib contains active ingredients.
  • Irase is a tablet embodied by the technical idea disclosed in Korean Patent No. 1002374, which combines 250 mg of gefitinib with a specific additive and a water-soluble cellulose ether and a humectant to improve solubility sensitivity according to pH of gefitinib. It is known.
  • Iressa is a film-coated tablet with a total weight of about 512 mg with a major axis of about 11 mm and a thickness of about 5.3 mm.
  • Most cancer patients have difficulty swallowing large tablets, so even if you can't swallow all tablets, you need to disperse them in water. There is an advantage to improve the convenience.
  • There is also a contraindication to irrational administration in patients with genetic problems such as galactose intolerance, Lapp lactose deficiency or glucose-galactose absorption disorders.
  • the present invention is to reduce the weight of the tablet to increase the ease of taking the patients and to provide a composition that can be taken by patients with lactose intolerance.
  • the present invention has solved the above problems through the following means.
  • gefitinib contains at least 65% of the total weight of the formulation, at least one member selected from the group consisting of dexrate and isomalt, and at least one disintegrant of 6-14% relative to the total weight of one component A composition comprising a.
  • composition according to the above (1), wherein the disintegrant comprises 7-10% more preferably based on the total weight per one component.
  • composition according to (1), wherein the dexrate comprises 2-5% of the total weight of the composition.
  • composition according to the above (1) to (5) further comprising a pharmaceutically usable additive, stabilizer, lubricant and binder.
  • composition according to the above (6), wherein the stabilizer is Eudragit E-PO.
  • the present invention can prevent the precipitation of gefitinib due to the pH change, and can ensure drug equivalence with existing commercial preparations containing gefitinib. Further, according to one embodiment of the present invention, dissolution stability (stability of dissolution rate according to storage state) is excellent.
  • the weight and volume of the final formulation when formulated are smaller than those of conventional gefitinib-containing commercial preparations, thereby maximizing patient convenience.
  • the present invention can solve the above-mentioned problems even without lactose, and thus can be administered to patients with lactose intolerance.
  • the present invention can improve process formulation and provide formulation, which may occur if the proportion of active ingredient is high, even if it contains at least 65% gefitinib based on the total weight of the composition.
  • Figure 1 shows the precipitation test results of gefitinib according to the pH change of the formulation alone (API only), commercially available formulations (Erassa) and tablets prepared with the composition according to the present invention (Example 1).
  • Figure 2 shows the results of the dissolution test in the eluate of purified water (1000 mL, polysorbate 80, 5%) of the tablets prepared in the commercial preparation, Example 1 and Comparative Examples 20 to 23.
  • FIG. 3 shows the tablets prepared in Comparative Examples 13-19 and Examples 12-13 for 1, 2, and 4 weeks in a severe stability chamber, respectively, and then purified water (1000 ml, polysorbate 80, 5%). The results of elution stability in the eluate are shown.
  • FIG. 4 shows pH 1.2, 900 mL eluate, pH 4.0, 900 mL eluate and purified water (1000 mL, including 80%, 5%) of the tablets prepared by the commercially available formulation, Example 1, Comparative Example and Comparative Example 9.
  • FIG. 4 The results of the dissolution test in the eluate are shown.
  • Example 5 is a comparison of blood concentrations of gefitinib over time when a commercial preparation and a tablet of Example 1 were orally administered to a beagle dog.
  • gefitinib refers to a main ingredient that can exhibit the same pharmacological effect as gefitinib in the human body when taken with gefitinib and various pharmaceutically acceptable salts thereof or prodrugs thereof unless otherwise specified.
  • additives refer to additives in which the functions and ingredients are known pharmaceutically, for example see HANDBOOK OF PHARMACEUTICAL EXCIPIENTS. Interpret it as a concept that includes all of the enemy's choices.
  • the present inventors have recognized the disadvantage that the commercially available formulation containing gefitinib is large in weight and volume, and is inconvenient to take, and has made various experiments to improve it, and as a result, the present invention has been completed.
  • the present inventors tried to reduce the amount of microcrystalline cellulose and lactose as excipients in the uncoated tablet composition of Examples 1 and 2 of Patent No. 1002374 after minimizing other conditions in order to minimize the volume of the existing commercial formulation.
  • the dissolution rate of gefitinib was not satisfactory above all, and especially when the amount of lactose was reduced, the bulk density was relatively high, so that the flowability was not good when the tableting process was applied, making it unsuitable for mass production. did.
  • the present invention provides a solution of gefitinib, dexrate and / or isomalt, a ratio of 6-14% to the total weight per one component, more preferably 7-10% of at least one disintegrant Is a basic configuration, and may optionally contain stabilizers, pharmaceutically acceptable lubricants and binders for better expression of the desired effect.
  • the dexrate or isomalt is preferably 2-5% of the total weight of the formulation, respectively. If the amount is less than 2% by weight, sticking may occur and the process may be impaired. If the amount is more than 5% by weight, it is difficult to ensure the comparative dissolution equivalence of gefitinib with commercially available formulations. It was confirmed.
  • any component known as pharmaceutically acceptable additives may be selected and used.
  • the amount of disintegrant is one in proportion of 6-14%, more preferably 7-10%, based on the total weight of the composition per one component. If it is formulated at less than 6% by weight of one component, it is difficult to ensure the elution equivalence between commercially available formulations and gefitinib. Can be. It is well known that disintegrants can be incorporated into pharmaceutical compositions, but it is not known that disintegrants can be used to solve the solubility problem of pH sensitivity of gefitinib. Was a very surprising result.
  • the present invention can optionally be selected and blended with other well-known additives within a range that does not inhibit the expression of the desired effect of the present invention.
  • additives such as antioxidants, lubricants, and binders may be used in an amount selectable by those skilled in the art.
  • Eudragit E-PO may be selected as a material capable of maintaining the dissolution stability of gefitinib, and may include 1-5% of the total weight of the formulation. If it is outside the lower limit of this content can not be obtained as much as the purpose of the elution stability effect of gefitinib, if it is outside the upper limit may cause a process failure such as sticking.
  • lubricant commercially available magnesium stearate, sodium stearyl fumarate, castor oil, talc and the like can be used.
  • binder polyvinylpyrrolidone, corn starch, hydroxypropyl cellulose, gum and the like which can be used may be used.
  • Example 1 can be formulated into tablets or capsules or the like through known means.
  • Non-limiting examples can be prepared by mixing the active ingredient with excipients and the like to produce granules and then tableting and coating to obtain a tablet, or to fill the capsule to obtain a capsule.
  • One embodiment according to the present invention can be formulated into a tablet through the following process.
  • the binder is stirred in water to dissolve completely.
  • the formulation, dexrate (and / or isomalt), various additives and disintegrant are placed in a mixer and mixed.
  • the mixture of (2) is placed in an coalescing machine, the bonding liquid of (1) is added, coalesced and dried, and this is established.
  • the sieved material of (3) is put into a mixer, a disintegrant is added, and it mixes first. After the first mixing is completed, the lubricant is added and then the second mixture is prepared to prepare the final mixture, followed by tableting using a tableting machine.
  • the uncoated tablet of (4) is sprayed to form a film coating.
  • coatings When formulated as a film-coated tablets as described above, commercially available coatings can be selected, and non-limiting examples can be selected from HPMC or PVA based coatings.
  • the quantity of coating agent can be suitably selected by a person skilled in the art.
  • Povidone a binder in water, is completely dissolved in purified water or solvent.
  • the active ingredient, dexrate, isomalt, Eudragit E-PO and disintegrant are placed in a mixer and premixed.
  • the mixture of (2) is placed in an coalescing machine, the bonding liquid of (1) is added, the coalescing is carried out, and the mixture is put into a tray dryer to dry, and this is established.
  • the sieved material of (3) was put into a mixer, a lubricant was added thereto, followed by post-mixing to prepare a final mixture, and compression tableting to prepare a tablet.
  • the uncoated tablet of (4) is coated with a coating agent.
  • Example 1 As shown in Table 1, the tablet prepared in Example 1 is significantly smaller in weight and volume than the commercially available formulations, and the convenience of taking the drug is greatly improved.
  • the control example was prepared in the same manner as in the uncoated composition of Examples 1 and 2 of Patent No. 1002374, and then coated with the same amount as the commercially available formulation with HPMC.
  • Example 1 0.1 M hydrochloric acid solution750 ml 0 101.0 70.0 81.8 10 101.0 70.0 81.8 15 101.1 80.5 92.3 30 100.8 90.6 94.6 60 102.8 96.9 100.1 0.1 M hydrochloric acid solution 750 ml + 0.2 M sodium phosphate solution 250 ml 65 4.8 44.3 49.6 70 2.0 16.3 27.5 75 1.1 8.0 8.3 90 0.8 7.2 5.3
  • the comparative dissolution test was carried out in the commercial preparation and the tablet prepared in Example 1 in pH 1.2, pH 4.0 and purified water (including 1000 ml, polysorbate 80, 5%) as follows.
  • Tablets prepared according to the formulations of Comparative Examples 1 to 8 and Examples 2 to 5 were found to have a disability in the process or to compare the dissolution rate with a commercially available formulation, and the results were shown in Table 4 below.
  • Process failure in Table 4 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during continuous tableting over 100 tablets.
  • Tablets prepared according to the formulations of Comparative Examples 9 to 12 and Examples 6 to 11 were found to have a disability in the process, or dissolution rate was adequate when compared with a commercially available formulation, and the results were shown in Table 6 below.
  • Example 6 Example 7 Comparative Example 10 Comparative Example 11
  • Example 8 Example 9 Comparative Example 12
  • Example 10 Example 11 Process failure X X X O X X X O X X Dissolution Assessment incongruity fitness fitness fitness incongruity fitness fitness incongruity fitness fitness incongruity fitness fitness
  • Process failure in Table 6 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during the continuous tableting process over 100 tablets.
  • the elution dissolution evaluation in Table 6 refers to the results of analysis after performing the test according to the dissolution test method (Paddle method) of the Korean Pharmacopoeia in the eluate of purified water (1000ml, polysorbate 80, 5%). In this regard, compliance and nonconformity was determined based on the dissolution rate of 85% or more after 45 minutes after the start of the dissolution test.
  • the tablets prepared according to the formulations of Comparative Examples 13 to 19 and Examples 12 and 13 have their process disturbances or are first packaged with aluminum pouches in a stability chamber set to severe stability test conditions (60 ° C., 80% RH). When samples were left for initial, 2, and 4 weeks, each elution was assessed.
  • Comparative Example 19 shows that Eudragit E-PO is blended, but it indicates that process failure such as sticking may occur when it is out of the content range according to the present invention.
  • Process failure in Table 8 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during the continuous tableting process over 100 tablets.
  • the elution dissolution evaluation in Table 8 refers to the results of analysis after performing the test according to the dissolution test method (Paddle method) of the Korean Pharmacopoeia in the eluate of purified water (1000 ml, polysorbate 80, 5%). In this regard, compliance and nonconformity was determined based on the dissolution rate of 85% or more after 45 minutes after the start of the dissolution test.
  • Comparative Example 23 is the composition of Examples 1 and 2 of the Patent No. 1002374
  • the tablets were prepared by reducing the content of microcrystalline cellulose and lactose as excipients.
  • Example 1 Comparative Example 20 Comparative Example 21 Comparative Example 22 Comparative Example 23 mg / T mg / T mg / T mg / T chief ingredient Gefitinib 250.0 250.0 250.0 250.0 250.0 250.0 250.0 Excipient Isomalt 10.0 Excipient Dexrate 10.0 Excipient Lactose 20.0 55.0 Excipient Calcium hydrogen phosphate 20.0 Excipient Microcrystalline cellulose 20.0 23.0 Disintegrant Croscarmellose sodium 20.0 Disintegrant Crospovidone 35.0 35.0 35.0 35.0 Disintegrant Corn starch 32.5 32.5 32.5 32.5 Binder Povidone K-30 7.0 7.0 7.0 7.0 Solubilizer Sodium Lauryl Sulfate 1.5 Stabilizer Eudragit E-PO 12.0 12.0 12.0 12.0 slush Magnesium stearate 3.5 3.5 3.5 3.5 3.5 Najung 360.0 360.0 360.0 360.0 360.0 360.0 Coating base HPMC Base 12.25 Coating base Opadry II 10.0 10.0 10.0 10.0 10.0 10.0 10.0
  • Tablets prepared according to the formulation of Table 9 above and tablets prepared according to the formulation of Example 1 of Table 2 mentioned in Experimental Example 1 Physical property and elution dissolution evaluation (1000 ml of purified water, 80% polysorbate, 5%, paddle) 50 rpm, eluting at least 85% for 45 minutes) was performed, and the results were as shown in Table 10 and FIG. 2 below.
  • Carr's Index in Table 10 is an indicator for evaluating the fluidity and flowability of granules (powder) .
  • Process failure in Table 10 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during the continuous tableting process over 100 tablets.
  • Tablets and commercial preparations prepared in Example 1 of Table 2 were respectively dosed to beagle dogs, and blood was collected at each time to measure the concentrations of blood drugs.

Abstract

The present invention relates to a pharmaceutical composition containing gefitinib as a pharmaceutically active ingredient. When the present invention is prepared, the weight and the volume of the final formulation can be optimized in terms of dosing convenience for patients and can be administered to patients with lactose intolerance.

Description

유당불내성 환자에게 투여가 가능하며, 복용편의성이 향상된 게피티니브를 함유하는 약제학적 조성물Pharmaceutical composition containing gefitinib which can be administered to patients with lactose intolerance and has improved convenience of taking
본 발명은 게피티니브를 활성성분 중 하나로 함유하는 경구용 고형 약제학적 조성물에 관한 것이다.The present invention relates to oral solid pharmaceutical compositions containing gefitinib as one of the active ingredients.
[게피티니브][Gepitinib]
게피티니브란 퀴나졸린 유도체의 일종으로서, 하기 [화학식 1] 의 구조를 가지며, IUPAC 에 따른 명칭(systematic name)이 N-(3-클로로-4-플루오로-페닐)-7-메톡시-6-(3-모르폴린-4-일프로폭시)퀴나졸린-4-아민인 화합물을 말한다.Gefitinibran is a kind of quinazoline derivative, and has a structure of the following [Formula 1], and the systemic name according to IUPAC is N- (3-chloro-4-fluoro-phenyl) -7-methoxy- 6- (3-morpholin-4-ylpropoxy) quinazolin-4-amine.
[화학식 1][Formula 1]
Figure PCTKR2016014300-appb-I000001
Figure PCTKR2016014300-appb-I000001
게피티니브는 국제공개공보 제 96/33980호에 개시된 생체 외 실험(in vitro)결과를 통해 비소세포폐암 등 악성종양의 과잉 발현 원인으로 알려진 상피세포증식인자수용체(EGFR)의 티로신인산화효소 영역(tyrosine kinase domain)을 억제할 수 있다는 약리기전이 공개되었다.Gefitinib is a member of the tyrosine kinase region of the epithelial cell proliferation factor receptor (EGFR) which is known to cause overexpression of malignant tumors such as non-small cell lung cancer through in vitro results disclosed in International Publication No. 96/33980. Pharmacological mechanisms have been disclosed to inhibit the tyrosine kinase domain.
이후 게피티니브는 임상학적으로 상피세포증식인자(EGFR)의 활성 변이가 있는 국소 진행성 또는 전이성 비소세포폐암의 1 차 치료와 기존의 화학요법에 실패한 비소세포폐암(수술 불가능 또는 재발한 경우)의 치료에 유용한 것으로 알려졌다.Gefitinib is then clinically used for primary treatment of locally advanced or metastatic non-small cell lung cancer with active mutations in epithelial cell proliferation factor (EGFR) and for non-small cell lung cancer (unoperable or relapsed) that fails conventional chemotherapy. It is known to be useful for treatment.
[게피티니브의 제제설계]Formulation Design of Gefitinib
통상 약물은 경구 투여된 후 식도, 위, 십이지장, 소장 및 직장 등 위장관을 따라 이동하면서 흡수되어 혈액 또는 임파액 등의 맥관계를 거쳐 작용 부위에 운반됨으로써 약효가 발휘되는데, 위장관 등은 부위에 따라 생체액의 수소 이온농도가 상이하다. 예컨대, 수분에 의한 희석이나 음식물의 존재에 따라, 위는 pH 가 1.0-3.0 이고, 소장은 십이지장의 pH가 5.0-6.0 이며, 공장, 회장으로 감에 따라 pH 가 높아져 최종적으로 회장 하부의 pH는 7.0-8.0 이 된다. 때문에, pH 에 따라 용해도가 민감한 약물은 환자별 또는 용량별로 생체이용률이 가변화되어 바람직하지 않은 약동학적 성질을 나타낼 수 있다.Usually, the drug is orally administered and then moved along the gastrointestinal tract, such as the esophagus, stomach, duodenum, small intestine, and rectum, and the drug is exerted through the blood vessels or lymphatic vessels to the site of action. The hydrogen ion concentration of is different. For example, depending on dilution with water or the presence of food, the stomach has a pH of 1.0-3.0, the small intestine has a pH of 5.0-6.0 in the duodenum, and the pH increases as it goes to the plant and ileum. 7.0-8.0. Because of this, drugs that are sensitive to solubility according to pH may exhibit undesirable pharmacokinetic properties by varying bioavailability by patient or dose.
게피티니브는 pKa 가 5.3 과 7.2 인 2 개의 염기성기를 지닌 염기성 화합물인데, 이들 염기성 기는 pH 에 따라 양성자화 또는 탈양성자화되어 화합물의 용해도에 현저한 영향을 미칠 수 있다. 즉, 게피티니브는 pH 에 따라 그 용해도가 크게 다르다. 예를 들어, 게피티니브의 유리 염기 형태의 경우, pH 1 인 수성 매질에서는 1 g 을 용해시키는데 필요한 용매가 10-30 ㎖ 로 가용성이지만, pH 4-6 인 수성 매질에서는 1 g 을 용해시키는데 필요한 용매가 10,000 ㎖ 이상으로 난용성이며, pH 7 이상인 수성 매질에서는 실질적으로 불용성이다.Gefitinib is a basic compound having two basic groups with pKa of 5.3 and 7.2, which can be protonated or deprotonated depending on pH, which can significantly affect the solubility of the compound. That is, the solubility of gefitinib varies greatly with pH. For example, in the free base form of gefitinib, 10-30 ml of the solvent required to dissolve 1 g in an aqueous medium at pH 1 is soluble, while it is required to dissolve 1 g in an aqueous medium at pH 4-6. The solvent is poorly soluble at least 10,000 ml and substantially insoluble in aqueous media having a pH of 7 or higher.
게피티니브는 위의 산성 환경에서는 용해도가 높지만 pH 가 높은 소장으로 이동하거나, 식사 및 수분 섭취 여부 등에 따라 pH 환경이 국소적으로 변화할 경우, 용해도가 낮아져서 용액으로부터 침전되는 경향이 있다. 이러한 이유로 게피티니브의 생체이용률은 매우 가변적이다. 또한 게피티니브의 최대 고유 흡수 부위는 위가 아니라 장관 상부인 것으로 알려져 있기 때문에, 게피티니브의 제제설계시에는 pH 에 따른 용해도 민감성을 개선시킬 필요가 있다.Gefitinib has a high solubility in an acidic environment of the stomach, but moves to the small intestine with a high pH, or when the pH environment is locally changed depending on whether or not to eat and drink water, gefitinib has a low solubility and tends to precipitate from the solution. For this reason, the bioavailability of gefitinib is very variable. It is also known that the maximum intrinsic absorption site of gefitinib is not in the stomach but in the upper intestine, so it is necessary to improve the solubility sensitivity according to pH when designing gefitinib.
이와 관련하여, 대한민국 등록특허 제 1002374호에는 게피티니브를 포함하는 나정을 히드록시프로필메틸셀룰로스 등의 수용성 셀룰로스 에테르 또는 수용성 셀룰로스 에테르의 에스테르 기제로 코팅하면, pH 6.5 의 환경에서도 약물이 침전되지 않을 수 있다는 기술적 사상이 개시된 바 있다.In this regard, Korean Patent No. 1002374 discloses that uncoated tablets containing gefitinib are coated with an ester base of water-soluble cellulose ether or water-soluble cellulose ether such as hydroxypropylmethylcellulose, so that the drug will not precipitate even in an environment of pH 6.5. It has been disclosed that the technical idea that it can.
약리학적 활성을 나타내는 화합물을 제제설계할 때 성분의 특성을 살리고 유효성을 충분히 발휘시키기 위해 그 성분의 인체 내 투여 후의 흡수, 체내 이행, 약물대사 및 배설 등의 상태를 파악하고, 동시에 위 과정에 영향을 끼칠 수 있는 여러 가지 첨가물의 동태를 검토할 필요가 있다.When designing a compound that exhibits pharmacological activity, it is necessary to grasp the state of absorption, transmigration, drug metabolism and excretion after administration of the component in human body in order to utilize the properties of the component and to fully demonstrate its effectiveness. There is a need to review the kinetics of the various additives that may be present.
뿐만 아니라, 제제화 시 환자의 복용편의성 등도 고려하여 최종 제형의 중량과 부피 등에 대해서도 최적의 형태로 개발하는 것이 바람직하다.In addition, it is desirable to develop the optimal form for the weight and volume of the final formulation in consideration of the convenience of the patient when formulating.
현재 시판중인 의약품 중 게피티니브를 활성성분으로 하는 제품으로는 이레사정이 있다.Among the pharmaceutical products currently on the market, gefitinib contains active ingredients.
이레사정은 등록특허 제 1002374호에 개시된 기술적 사상에 의해 구현된 정제로서, 250 mg 의 게피티니브와 함께 특정의 첨가물 및 수용성 셀룰로스에테르와 습윤제를 배합하여 게피티니브의 pH 에 따른 용해도 민감성을 개선한 것으로 알려져 있다.Irase is a tablet embodied by the technical idea disclosed in Korean Patent No. 1002374, which combines 250 mg of gefitinib with a specific additive and a water-soluble cellulose ether and a humectant to improve solubility sensitivity according to pH of gefitinib. It is known.
그러나, 이레사정은 총 중량이 약 512 mg 인 필름코팅정으로서 장축이 약 11 mm 이며, 두께가 약 5.3 mm 이다. 대부분의 암환자의 경우 큰 정제를 삼키기에 어려움을 겪고 있기 때문에 이레사정의 복용방법에 있어서도 전체 정제를 삼킬 수 없는 경우에는 물에 분산시켜 복용하도록 되어 있어 정제의 크기를 줄일 경우 보다 암환자들의 복용편의성을 개선할 수 있는 장점이 있다. 또한 이레사정은 정제 중 유당을 함유하고 있어 갈락토오스 불내성, Lapp 유당분해효소 결핍증 또는 포도당-갈락토오스 흡수장애 등의 유전적인 문제가 있는 환자에게는 투여하지 못하도록 하는 금기사항이 있다. However, Iressa is a film-coated tablet with a total weight of about 512 mg with a major axis of about 11 mm and a thickness of about 5.3 mm. Most cancer patients have difficulty swallowing large tablets, so even if you can't swallow all tablets, you need to disperse them in water. There is an advantage to improve the convenience. There is also a contraindication to irrational administration in patients with genetic problems such as galactose intolerance, Lapp lactose deficiency or glucose-galactose absorption disorders.
이에 본 발명은 정제의 중량을 줄여 환자들의 복용편의성을 증가시키고 유당불내성 환자들도 복용가능한 조성물을 제공하고자 하였다.Accordingly, the present invention is to reduce the weight of the tablet to increase the ease of taking the patients and to provide a composition that can be taken by patients with lactose intolerance.
본 발명은 아래의 수단을 통해 전술한 과제를 해결했다.The present invention has solved the above problems through the following means.
(1) 게피티니브를 제형 총 중량의 65% 이상 함유하며, 덱스트레이트 및 이소말트로 이루어진 군으로부터 선택된 1 종 이상과, 하나의 성분당 총 중량 대비 6-14 % 의 1 종 이상의 붕해제를 포함하는 것을 특징으로 하는 조성물.(1) gefitinib contains at least 65% of the total weight of the formulation, at least one member selected from the group consisting of dexrate and isomalt, and at least one disintegrant of 6-14% relative to the total weight of one component A composition comprising a.
(2) 상기 (1) 에 있어서, 붕해제는 하나의 성분당 총 중량 대비 더 바람직하게 7-10% 를 포함하는 것을 특징으로 하는 조성물.(2) The composition according to the above (1), wherein the disintegrant comprises 7-10% more preferably based on the total weight per one component.
(3) 상기 (1) 에 있어서, 덱스트레이트는 조성물의 총 중량 대비 2-5% 를 포함하는 것을 특징으로 하는 조성물.(3) The composition according to (1), wherein the dexrate comprises 2-5% of the total weight of the composition.
(4) 상기 (1) 에 있어서, 이소말트는 조성물의 총 중량 대비 2-5% 를 포함하는 것을 특징으로 하는 조성물.(4) The composition according to the above (1), wherein the isomalt comprises 2-5% of the total weight of the composition.
(5) 상기 (1) 내지 (4) 에 있어서, 붕해제는 크로스포비돈 및 옥수수전분으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는 조성물.(5) The composition according to the above (1) to (4), wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch.
(6) 상기 (1) 내지 (5) 에 있어서, 약제학적으로 사용이 가능한 첨가제, 안정화제, 윤활제 및 결합제를 추가로 함유하는 것을 특징으로 하는 조성물.(6) The composition according to the above (1) to (5), further comprising a pharmaceutically usable additive, stabilizer, lubricant and binder.
(7) 상기 (6) 에 있어서, 안정화제는 유드라짓 E-PO 인 것을 특징으로 하는 조성물.(7) The composition according to the above (6), wherein the stabilizer is Eudragit E-PO.
(8) 상기 (7) 에 있어서, 유드라짓 E-PO 는 조성물의 총 중량 대비 1-5% 를 포함하는 것을 특징으로 하는 조성물.(8) The composition according to (7), wherein Eudragit E-PO comprises 1-5% of the total weight of the composition.
(9) 조성물의 총 중량 대비 65-75% 의 게피티니브; 2-5 % 의 덱스트레이트 및/또는 2-5% 의 이소말트; 안정화제; 및 하나의 성분당 6-14 % 의 1 종 이상의 붕해제를 포함하는 것을 특징으로 하는 조성물.(9) 65-75% gefitinib relative to the total weight of the composition; 2-5% dexrate and / or 2-5% isomalt; Stabilizer; And 6-14% of one or more disintegrants per component.
(10) 상기 (9) 에 있어서, 붕해제는 크로스포비돈 및 옥수수전분으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는 조성물.(10) The composition according to the above (9), wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch.
(11) 상기 (9) 에 있어서, 안정화제는 유드라짓 E-PO 인 것을 특징으로 하는 조성물.(11) The composition according to the above (9), wherein the stabilizer is Eudragit E-PO.
(12) 상기 (11) 에 있어서, 유드라짓 E-PO 는 조성물의 총 중량 대비 1-5% 를 포함하는 것을 특징으로 하는 조성물.(12) The composition according to the above (11), wherein Eudragit E-PO comprises 1-5% of the total weight of the composition.
본 발명은 pH 변화에 따른 게피티니브의 침전을 방지할 수 있고, 기존 게피티니브 함유 시판제제와의 의약품 동등성을 확보할 수 있다. 또한, 본 발명의 일 구현예에 의하면 용출안정성(저장 상태에 따른 용출률의 안정성)이 우수하다.The present invention can prevent the precipitation of gefitinib due to the pH change, and can ensure drug equivalence with existing commercial preparations containing gefitinib. Further, according to one embodiment of the present invention, dissolution stability (stability of dissolution rate according to storage state) is excellent.
본 발명은 제제화했을 때의 최종 제형의 중량 및 부피가 기존 게피티니브 함유 시판제제에 비해 작아 환자의 복용편의성을 보다 극대화할 수 있다. In the present invention, the weight and volume of the final formulation when formulated are smaller than those of conventional gefitinib-containing commercial preparations, thereby maximizing patient convenience.
본 발명은 기존 게피티니브 함유 시판제제와 달리 유당을 함유하지 않아도 전술한 과제를 해결할 수 있어, 유당불내성 환자에게 투여가 가능하다.Unlike the conventional gefitinib-containing commercially available formulations, the present invention can solve the above-mentioned problems even without lactose, and thus can be administered to patients with lactose intolerance.
본 발명은 조성물의 총 중량을 기준으로 65 % 이상의 게피티니브를 함유하더라도 통상 활성성분의 비율이 높은 경우에 발생할 수 있는 공정상의 장애를 개선하고 제제화를 제공할 수 있다.The present invention can improve process formulation and provide formulation, which may occur if the proportion of active ingredient is high, even if it contains at least 65% gefitinib based on the total weight of the composition.
도 1 은 제제단독(API 단독), 시판제제(이레사정) 및 본 발명에 따른 조성물(실시예1)로 제조한 정제의 pH 변화에 따른 게피티니브의 석출시험결과를 나타낸 것이다.Figure 1 shows the precipitation test results of gefitinib according to the pH change of the formulation alone (API only), commercially available formulations (Erassa) and tablets prepared with the composition according to the present invention (Example 1).
도 2는 시판제제, 실시예 1 및 비교예 20 내지 비교예 23 으로 제조한 정제의 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함) 의 용출액에서의 용출시험결과를 나타낸 것이다.Figure 2 shows the results of the dissolution test in the eluate of purified water (1000 mL, polysorbate 80, 5%) of the tablets prepared in the commercial preparation, Example 1 and Comparative Examples 20 to 23.
도 3 은 비교예 13 내지 19 및 실시예 12 내지 13 으로 제조한 정제를 가혹안정성 챔버에 각각 초기, 2주 및 4주간 보관한 후, 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함) 의 용출액에서의 용출안정성 결과를 나타낸 것이다.FIG. 3 shows the tablets prepared in Comparative Examples 13-19 and Examples 12-13 for 1, 2, and 4 weeks in a severe stability chamber, respectively, and then purified water (1000 ml, polysorbate 80, 5%). The results of elution stability in the eluate are shown.
도 4 는 시판제제, 실시예 1, 대조예 및 비교예 9 로 제조한 정제의 pH 1.2, 900 ㎖ 용출액, pH 4.0, 900 ㎖ 용출액 및 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)의 용출액에서의 용출시험결과를 나타낸 것이다.FIG. 4 shows pH 1.2, 900 mL eluate, pH 4.0, 900 mL eluate and purified water (1000 mL, including 80%, 5%) of the tablets prepared by the commercially available formulation, Example 1, Comparative Example and Comparative Example 9. FIG. The results of the dissolution test in the eluate are shown.
도 5 는 시판제제 및 실시예 1 의 정제를 비글견에 경구투여했을 때의 시간 경과에 따른 게피티니브의 혈중농도를 대비한 것이다.5 is a comparison of blood concentrations of gefitinib over time when a commercial preparation and a tablet of Example 1 were orally administered to a beagle dog.
본 명세서에서 “게피티니브” 는 특별한 언급이 없는 한 게피티니브 및, 이의 약제학적으로 허용 가능한 각종 염 또는 이의 프로드러그 등 복용 시 인체 내에서 게피티니브와 동일한 약리효과를 나타낼 수 있는 주성분을 모두 포함하는 개념으로 해석한다.In the present specification, "gefitinib" refers to a main ingredient that can exhibit the same pharmacological effect as gefitinib in the human body when taken with gefitinib and various pharmaceutically acceptable salts thereof or prodrugs thereof unless otherwise specified. Interpret all inclusive concepts.
본 명세서에서 언급하는 “붕해제”, “충전제”, “윤활제” 및 “기타 약제학적으로 허용 가능한 첨가제” 는 약제학적으로 그 기능 및 성분이 공지된 첨가물을 말하며, 예컨대 HANDBOOK OF PHARMACEUTICAL EXCIPIENTS 등을 참조하여 적의 선택할 수 있는 성분을 모두 포함하는 개념으로 해석한다.As used herein, “disintegrants”, “fillers”, “lubricants” and “other pharmaceutically acceptable additives” refer to additives in which the functions and ingredients are known pharmaceutically, for example see HANDBOOK OF PHARMACEUTICAL EXCIPIENTS. Interpret it as a concept that includes all of the enemy's choices.
본 발명자는 게피티니브를 함유하는 기존 시판 제제의 경우 그 중량 및 부피가 커, 복용이 불편하다는 단점을 인식하고, 이를 개선하고자 다양한 실험을 진행했으며, 그 결과 본 발명을 완성하기에 이르렀다.The present inventors have recognized the disadvantage that the commercially available formulation containing gefitinib is large in weight and volume, and is inconvenient to take, and has made various experiments to improve it, and as a result, the present invention has been completed.
먼저 본 발명자는 기존 시판 제제의 부피를 최소화하기 위해 다른 조건은 동일하게 한 후, 등록특허 제 1002374호의 실시예 1 및 2 의 나정 조성 중 부형제인 미결정셀룰로스와 유당의 분량만을 줄여보았다. 그 결과 무엇보다 게피티니브의 용출률이 만족스럽지 못하였으며, 특히 유당의 분량을 줄였을 때 부피 밀도(Bulk density)가 비교적 높아져 타정 공정 적용 시 흐름성이 좋지 않아, 대량생산에 적합하지 않게 됨을 확인했다.First, the present inventors tried to reduce the amount of microcrystalline cellulose and lactose as excipients in the uncoated tablet composition of Examples 1 and 2 of Patent No. 1002374 after minimizing other conditions in order to minimize the volume of the existing commercial formulation. As a result, the dissolution rate of gefitinib was not satisfactory above all, and especially when the amount of lactose was reduced, the bulk density was relatively high, so that the flowability was not good when the tableting process was applied, making it unsuitable for mass production. did.
그러나 계속된 실험 끝에 본 발명자는 우연하게도 부형제로서 덱스트레이트 및/또는 이소말트와, 하나의 성분 당, 총 중량 대비 6-14% 의 붕해제 조합, 더 바람직하게 7-10% 를 채택했을 때, 게피티니브의 용출률이 우수하고, 제제의 중량 및 부피의 소형화가 가능하며, 대량생산에도 적합함을 발견했다.However, after continuing experiments, the inventors accidentally adopted dexrate and / or isomalt as excipients and 6-14% of disintegrant combination, more preferably 7-10% by weight, per one component, It has been found that the dissolution rate of gefitinib is excellent, the weight and volume of the formulation can be reduced, and it is also suitable for mass production.
본 발명은 전술한 과제의 해결을 위해 게피티니브, 덱스트레이트 및/또는 이소말트, 하나의 성분 당 총 중량 대비 6-14% 의 비율, 더 바람직하게는 7-10% 의 1 종 이상의 붕해제를 기본 구성으로 하며, 목적하는 효과의 보다 우수한 발현을 위해 선택적으로 안정화제, 약제학적으로 허용 가능한 윤활제 및 결합제를 포함할 수 있다.The present invention provides a solution of gefitinib, dexrate and / or isomalt, a ratio of 6-14% to the total weight per one component, more preferably 7-10% of at least one disintegrant Is a basic configuration, and may optionally contain stabilizers, pharmaceutically acceptable lubricants and binders for better expression of the desired effect.
덱스트레이트 또는 이소말트는 각각 제형 총 중량 대비 2-5 % 인 것이 바람직하다. 본 분량의 2% 중량비 미만으로 배합할 경우에는 스티킹이 발생해 공정상에 장애가 나타날 수 있고, 5% 중량비를 초과하여 배합할 경우에는 시판 제제와의 게피티니브의 비교용출 동등성을 확보하는데 어렵다는 것을 확인하였다.The dexrate or isomalt is preferably 2-5% of the total weight of the formulation, respectively. If the amount is less than 2% by weight, sticking may occur and the process may be impaired. If the amount is more than 5% by weight, it is difficult to ensure the comparative dissolution equivalence of gefitinib with commercially available formulations. It was confirmed.
붕해제로는 약제학적으로 배합 가능한 첨가제로서 알려진 임의의 성분을 1 종 이상 선택하여 사용할 수 있다. 다만, 붕해제로는 크로스포비돈 및 옥수수전분으로 이루어진 군으로부터 선택된 하나 이상을 선택했을 때, pH 의 변화에 따라 용해도가 민감한 게피티니브의 특성을 보다 효과적으로 개선할 수 있다. 붕해제의 분량은 하나의 성분당 조성물의 총 중량을 기준으로 하나의 성분 당 6-14% 의 비율, 더 바람직하게는 7-10 % 인 것이다. 하나의 성분 당 6% 중량비 미만으로 배합한 경우에는 시판 제제와 게피티니브의 용출 동등성을 확보하는데 어렵고, 상한선을 벗어날 경우에는 흡습 현상이 발생해 공정상 타정장애 및 의약품의 안정성 확보에 문제가 발생할 수 있다. 약제학적 조성물에 붕해제를 배합할 수 있음은 잘 알려져 있는 사실이나 게피티니브의 pH 민감성에 따른 용해도 문제를 해결하기 위해 붕해제를 사용할 수 있음은 전혀 알려진 바 없었기에 위 붕해제 배합에 따른 효과는 매우 놀라운 결과였다.As the disintegrant, any component known as pharmaceutically acceptable additives may be selected and used. However, when one or more selected from the group consisting of crospovidone and corn starch as the disintegrant, it is possible to more effectively improve the characteristics of gefitinib solubility sensitive to changes in pH. The amount of disintegrant is one in proportion of 6-14%, more preferably 7-10%, based on the total weight of the composition per one component. If it is formulated at less than 6% by weight of one component, it is difficult to ensure the elution equivalence between commercially available formulations and gefitinib. Can be. It is well known that disintegrants can be incorporated into pharmaceutical compositions, but it is not known that disintegrants can be used to solve the solubility problem of pH sensitivity of gefitinib. Was a very surprising result.
본 발명은 본 발명이 목적하는 효과의 발현을 저해하지 않는 범위 내에서 잘 알려진 기타 첨가제를 경우에 따라 선택하여 배합할 수 있다. 이때 기타 첨가제로는 안정화제, 윤활제 및 결합제를 통상의 기술자가 선택할 수 있는 분량으로 사용할 수 있다.The present invention can optionally be selected and blended with other well-known additives within a range that does not inhibit the expression of the desired effect of the present invention. In this case, as other additives, stabilizers, lubricants, and binders may be used in an amount selectable by those skilled in the art.
안정화제로는 게피티니브의 용출 안정성을 유지시켜줄 수 있는 물질로서 유드라짓 E-PO 를 선택할 수 있으며, 제형 총 중량 대비 1-5% 를 포함할 수 있다. 본 함량의 하한선을 벗어날 경우 게피티니브의 용출 안정성 효과를 목적하는 만큼 얻을 수 없고, 상한선을 벗어날 경우 스티킹 등의 공정장애가 발생할 수 있다.As a stabilizer, Eudragit E-PO may be selected as a material capable of maintaining the dissolution stability of gefitinib, and may include 1-5% of the total weight of the formulation. If it is outside the lower limit of this content can not be obtained as much as the purpose of the elution stability effect of gefitinib, if it is outside the upper limit may cause a process failure such as sticking.
윤활제로는 통상적으로 사용 가능한 마그네슘스테아레이트, 소디움스테아릴푸마레이트, 캐스터오일, 탈크 등을 사용할 수 있다.As the lubricant, commercially available magnesium stearate, sodium stearyl fumarate, castor oil, talc and the like can be used.
결합제로는 통상적으로 사용 가능한 폴리비닐피롤리돈, 옥수수전분, 히드록시프로필셀룰로오스, 검류 등을 사용할 수 있다.As the binder, polyvinylpyrrolidone, corn starch, hydroxypropyl cellulose, gum and the like which can be used may be used.
[제제화][Shoemaking]
실시예 1 은 공지의 수단을 통해 정제 또는 캡슐제 등으로 제제화할 수 있다. 비제한적인 예로는 활성성분을 부형제 등과 혼합해 과립을 제조하고 이를 타정한 후 코팅하여 정제를 수득하거나, 캡슐에 충진하여 캡슐제를 수득할 수 있다. Example 1 can be formulated into tablets or capsules or the like through known means. Non-limiting examples can be prepared by mixing the active ingredient with excipients and the like to produce granules and then tableting and coating to obtain a tablet, or to fill the capsule to obtain a capsule.
본 발명에 따른 일 구현예는 아래와 같은 공정을 통해 정제로 제제화할 수 있다.One embodiment according to the present invention can be formulated into a tablet through the following process.
(1) 결합액의 조제(1) Preparation of binding liquid
물에 결합제를 교반하여 완전히 용해시킨다.The binder is stirred in water to dissolve completely.
(2) 혼합(2) mixed
제제, 덱스트레이트(및/또는 이소말트), 각종 첨가제 및 붕해제를 혼합기에 넣어 혼합한다.The formulation, dexrate (and / or isomalt), various additives and disintegrant are placed in a mixer and mixed.
(3) 연합, 건조 및 정립(3) Union, drying and formulation
(2) 의 혼합물을 연합기에 넣고, (1) 의 결합액을 넣어 연합한 뒤 건조하고, 이를 정립한다.The mixture of (2) is placed in an coalescing machine, the bonding liquid of (1) is added, coalesced and dried, and this is established.
(4) 후혼합 및 타정(4) post-mixing and tableting
(3) 의 정립물을 혼합기에 넣고 붕해제를 투입하여 1 차 혼합한다. 1 차 혼합이 완료되면 윤활제를 투입한 후 2 차 혼합하여 최종 혼합물을 조제한 후, 타정기를 이용하여 타정한다.The sieved material of (3) is put into a mixer, a disintegrant is added, and it mixes first. After the first mixing is completed, the lubricant is added and then the second mixture is prepared to prepare the final mixture, followed by tableting using a tableting machine.
(5) 코팅(5) coating
(4) 의 나정에 코팅제를 분무하여 필름피막을 형성한다.The uncoated tablet of (4) is sprayed to form a film coating.
위와 같이 필름코팅정제로 제제화할 때에는 시중에서 구입할 수 있는 코팅제를 선택할 수 있으며, 비제한적인 예로서 HPMC 또는 PVA 기제의 코팅제를 선택할 수 있다. 코팅제의 분량은 통상의 기술자가 적의 선택할 수 있다.When formulated as a film-coated tablets as described above, commercially available coatings can be selected, and non-limiting examples can be selected from HPMC or PVA based coatings. The quantity of coating agent can be suitably selected by a person skilled in the art.
이하에서는 본 발명을 특정 실시예를 통해 더욱 상세하게 설명하고자 한다. 다만, 이하의 실시예는 본 발명을 예시한 것에 불과할 뿐, 본 발명의 범위가 이것으로 한정되는 것은 아님에 유의할 필요가 있다.Hereinafter, the present invention will be described in more detail with reference to specific examples. It should be noted, however, that the following examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.
[실험 예 1] 비교용출실험 등Experimental Example 1 Comparative Dissolution Experiment
아래의 표 1 의 분량으로 정제를 제조했다.Tablets were prepared in the amounts shown in Table 1 below.
(1) 결합액의 조제(1) Preparation of binding liquid
물에 결합제인 포비돈을 정제수 또는 용매에 완전히 용해시킨다.Povidone, a binder in water, is completely dissolved in purified water or solvent.
(2) 혼합(2) mixed
활성성분, 덱스트레이트, 이소말트, 유드라짓 E-PO 및 붕해제를 혼합기에 넣어 전혼합한다.The active ingredient, dexrate, isomalt, Eudragit E-PO and disintegrant are placed in a mixer and premixed.
(3) 연합, 건조 및 정립(3) Union, drying and formulation
(2) 의 혼합물을 연합기에 넣고, (1) 의 결합액을 넣어 연합을 진행한 뒤, 트레이 건조기에 넣어 건조하고, 이를 정립한다.The mixture of (2) is placed in an coalescing machine, the bonding liquid of (1) is added, the coalescing is carried out, and the mixture is put into a tray dryer to dry, and this is established.
(4) 후혼합 및 타정(4) post-mixing and tableting
(3) 의 정립물을 혼합기에 넣고 윤활제를 투입하여 후혼합을 진행하여 최종 혼합물을 조제한 후, 압축타정하여 정제를 제조한다.The sieved material of (3) was put into a mixer, a lubricant was added thereto, followed by post-mixing to prepare a final mixture, and compression tableting to prepare a tablet.
(5) 코팅(5) coating
(4) 의 나정을 코팅제로 코팅한다.The uncoated tablet of (4) is coated with a coating agent.
배합목적Purpose of Mixing 성분명Ingredient Name 시판제제Commercially available 대조예Control 실시예1Example 1
mg/Tmg / T 중량 %weight % mg/Tmg / T 중량 %weight % mg/Tmg / T 중량 %weight %
주성분chief ingredient 게피티니브Gefitinib 250.0250.0 48.848.8 250.0250.0 48.848.8 250.0250.0 67.667.6
부형제Excipient 첨가제additive 250.0250.0 48.848.8
부형제Excipient 유당Lactose 163.5163.5 31.931.9
부형제Excipient 미결정셀룰로스Microcrystalline cellulose 50.050.0 9.89.8
부형제Excipient 덱스트레이트Dexrate 10.010.0 2.72.7
부형제Excipient 이소말트Isomalt 10.010.0 2.72.7
부형제Excipient 유드라짓 E-POEudragit E-PO 12.012.0 3.23.2
붕해제Disintegrant 크로스포비돈Crospovidone 35.035.0 9.59.5
붕해제Disintegrant 옥수수전분Corn starch 32.532.5 8.88.8
붕해제Disintegrant 크로스카멜로스소디움Croscarmellose Sodium 20.020.0 3.93.9
결합제Binder 포비돈Povidone 10.010.0 2.02.0 7.07.0 1.91.9
윤활제slush 라우릴황산나트륨Sodium Lauryl Sulfate 1.51.5 0.30.3
윤활제slush 스테아르산 마그네슘Magnesium stearate 5.05.0 1.01.0 3.53.5 0.90.9
나정Najung 500.0 500.0 97.6 97.6 500.0 500.0 97.6 97.6 360.0 360.0 97.3 97.3
코팅기제Coating base HPMC기제HPMC mechanism 12.2512.25 2.4 2.4 12.2512.25 2.4 2.4
코팅기제Coating base Opadry IIOpadry II 　 　 10.010.0 2.72.7
코팅정Coated tablet 512.3 512.3 100.0 100.0 512.3 512.3 100.0 100.0 370.0 370.0 100.0 100.0
정제 사이즈Tablet size 장축: 11 mm, 두께: 5.3 mmLong axis: 11 mm, thickness: 5.3 mm 장축: 11 mm, 두께: 5.3 mmLong axis: 11 mm, thickness: 5.3 mm 장축: 9.5 mm, 두께: 4.7 mmLong axis: 9.5 mm, thickness: 4.7 mm
정제 경도Tablet hardness 22 kp22 kp 22 kp22 kp 20 kp20 kp
위 표 1 에 나타난 바와 같이, 실시예 1로 제조한 정제는 그 중량 및 부피가 시판제제에 비해 상당히 작아 복용편의성이 월등히 향상되었다. 대조예는 등록특허 제 1002374 호의 실시예 1 및 2의 나정 조성과 동일하게 제조한 후, HPMC 기제로 시판제제와 동일한 분량을 코팅한 것이다.As shown in Table 1, the tablet prepared in Example 1 is significantly smaller in weight and volume than the commercially available formulations, and the convenience of taking the drug is greatly improved. The control example was prepared in the same manner as in the uncoated composition of Examples 1 and 2 of Patent No. 1002374, and then coated with the same amount as the commercially available formulation with HPMC.
시판제제와 실시예 1로 제조한 정제에 대해 아래와 같이 pH 전환시험을 실시했다.The pH conversion test was done for the tablet manufactured by the commercial preparation and Example 1 as follows.
pH 전환 용출시험은 대한민국약전의 용출시험법(패들법)에 따르고, 패들회전속도는 50rpm로 설정하였다. 이 방법으로 산성용액인 0.1M 염산용액 750㎖ (pH약 1.2 부근) 내에서 60분간의 용출률을 측정하고, 60분 이후에는 0.2M 소디움포스페이트 용액 250㎖ 을 신속히 추가하여 pH 6.5 이상으로 전환시킨 뒤, 용출률을 평가하였다.pH conversion dissolution test according to the dissolution test (paddle method) of the Korean Pharmacopoeia, the paddle rotation speed was set to 50rpm. In this way, the dissolution rate was measured for 60 minutes in 750 ml of 0.1 M hydrochloric acid solution (near pH 1.2), and after 60 minutes, 250 ml of 0.2 M sodium phosphate solution was rapidly added to pH 6.5 or more. , Dissolution rate was evaluated.
그 결과 아래의 표 2 및 대표도면 1 과 같이 pH 6.5 에서 제제단독(API 단독) 및 시판제제(이레사정)보다 실시예 1 로 제조한 정제의 pH 전환에 따른 석출방지효과가 우수했다.As a result, as shown in Table 2 and Representative Drawing 1 below, the precipitation prevention effect according to the pH conversion of the tablets prepared in Example 1 was superior to the formulation alone (API alone) and the commercially available formulations (Erassa) at pH 6.5.
용출액 조건Eluent Condition 시간(분)Minutes 제제 단독Formulation alone 시판제제Commercially available 실시예1Example 1
0.1 M 염산용액750 ㎖0.1 M hydrochloric acid solution750 ml 00 101.0101.0 70.070.0 81.881.8
1010 101.0101.0 70.070.0 81.881.8
1515 101.1101.1 80.580.5 92.392.3
3030 100.8100.8 90.690.6 94.694.6
6060 102.8102.8 96.996.9 100.1100.1
0.1 M 염산용액750 ㎖+0.2M소디움포스페이트 용액 250㎖0.1 M hydrochloric acid solution 750 ml + 0.2 M sodium phosphate solution 250 ml 6565 4.84.8 44.344.3 49.649.6
7070 2.02.0 16.316.3 27.527.5
7575 1.11.1 8.08.0 8.38.3
9090 0.80.8 7.27.2 5.35.3
시판제제와 실시예 1 로 제조한 정제에 대해 아래와 같이 pH 1.2, pH 4.0 및 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)에서의 비교용출시험을 실시했다.The comparative dissolution test was carried out in the commercial preparation and the tablet prepared in Example 1 in pH 1.2, pH 4.0 and purified water (including 1000 ml, polysorbate 80, 5%) as follows.
그 결과 도 4 와 같이 모든 용출액에서 실시예 1 로 제조한 정제의 초기용출이 신속했다.As a result, as shown in FIG. 4, the initial elution of the tablet prepared in Example 1 was rapid in all the eluents.
[실험 예2] 덱스트레이트 및 이소말트 분량에 따른 효과의 비교실험[Experimental Example 2] Comparative experiment of the effect of the amount of dexrate and isomalt
아래의 표 3 의 분량으로 정제를 제조했다.Tablets were prepared in the amounts shown in Table 3 below.
성분명Ingredient Name 비교예 1Comparative Example 1 비교예 2Comparative Example 2 비교예 3Comparative Example 3 비교예 4Comparative Example 4 비교예 5Comparative Example 5 실시예 2Example 2 실시예 3Example 3 비교예 6Comparative Example 6 비교예7Comparative Example 7 실시예4Example 4 실시예5Example 5 비교예8Comparative Example 8
게피티니브Gefitinib 71.5%71.5% 71.5%71.5% 71.5%71.5% 71.5%71.5% 73.4%73.4% 71.5%71.5% 69.4%69.4% 67.4%67.4% 73.4%73.4% 71.5%71.5% 69.4%69.4% 67.4%67.4%
유당Lactose 2.9%2.9%
미결정셀룰로스Microcrystalline cellulose 2.9%2.9%
인산수소칼슘Calcium hydrogen phosphate 2.9%2.9%
경질무수규산Light anhydrous silicic acid 2.9%2.9%
이소말트Isomalt 1.0%1.0% 2.9%2.9% 5.0%5.0% 7.0%7.0%
덱스트레이트Dexrate 1.0%1.0% 2.9%2.9% 5.0%5.0% 7.0%7.0%
크로스포비돈Crospovidone 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0% 10.0%10.0%
옥수수전분Corn starch 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5% 9.5%9.5%
포비돈 K-30Povidone K-30 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9%
스테아르산마그네슘Magnesium stearate 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0%
오파드라이IIOpadry II 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2%
*위 표 3 의 % 는 중량 % 를 나타낸다.*% In Table 3 represents weight%.
비교예 1 내지 8 과 실시예 2 내지 5 의 처방으로 제조한 정제에 그 공정상 장애가 있는지, 또는 시판제제와 비교했을 때 용출률은 적합한지를 알아보았으며, 그 결과는 아래의 표 4와 같았다.Tablets prepared according to the formulations of Comparative Examples 1 to 8 and Examples 2 to 5 were found to have a disability in the process or to compare the dissolution rate with a commercially available formulation, and the results were shown in Table 4 below.
평가항목Evaluation item 비교예 1Comparative Example 1 비교예 2Comparative Example 2 비교예 3Comparative Example 3 비교예 4Comparative Example 4 비교예 5Comparative Example 5 실시예 1Example 1 실시예 2Example 2 비교예 6Comparative Example 6 비교예7Comparative Example 7 실시예4Example 4 실시예5Example 5 비교예8Comparative Example 8
공정장애Process failure XX XX OO OO OO XX XX XX OO XX XX XX
용출적부평가Dissolution Assessment 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 적합fitness 적합fitness 부적합incongruity 부적합incongruity 적합fitness 적합fitness 부적합incongruity
*위 표 4 의 공정장애란 타정 시 발생할 수 있는 정제의 스티킹, 라미네이팅, 캡핑 등을 말하며, O 와 X 는 100 정 분량 이상의 연속적인 타정공정 중 장애발생의 여부를 기준으로 판단한 것이다.* Process failure in Table 4 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during continuous tableting over 100 tablets.
*위 표 4 의 용출적부평가란 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)의 조건의 용출액에서, 대한민국약전의 용출시험법(패들법)에 따라 시험을 실시한 후 분석한 결과를 말하며, 적합과 부적합은 용출시험 시작 후 45분 후에 85% 이상의 용출률을 기준으로 판단한 것이다.* The elution devaluation in Table 4 above is the result of analysis after conducting the test according to the dissolution test method (Paddle method) of the Korean Pharmacopoeia in the eluate of purified water (1000ml, polysorbate 80, 5%). In this regard, compliance and nonconformity was determined based on the dissolution rate of 85% or more 45 minutes after the start of the dissolution test.
[실험 예3] 붕해제 분량에 따른 효과의 비교실험[Experimental Example 3] Comparative experiment of the effect according to the amount of disintegrant
아래의 표 5 의 분량으로 정제를 제조했다.Tablets were prepared in the amounts shown in Table 5 below.
성분명Ingredient Name 비교예9Comparative Example 9 실시예6Example 6 실시예7Example 7 비교예10Comparative Example 10 비교예11Comparative Example 11 실시예8Example 8 실시예9Example 9 비교예12Comparative Example 12 실시예10Example 10 실시예11Example 11
게피티니브Gefitinib 84.3%84.3% 82.3%82.3% 79.3%79.3% 74.3%74.3% 84.3%84.3% 82.3%82.3% 79.3%79.3% 74.3%74.3% 75.3%75.3% 69.3%69.3%
이소말트Isomalt 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3%
덱스트레이트Dexrate 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3%
크로스포비돈Crospovidone 5.0%5.0% 7.0%7.0% 10.0%10.0% 15.0%15.0% 7.0%7.0% 10.0%10.0%
옥수수전분Corn starch 5.0%5.0% 7.0%7.0% 10.0%10.0% 15.0%15.0% 7.0%7.0% 10.0%10.0%
PVP K-30PVP K-30 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9%
스테아르산마그네슘Magnesium stearate 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0%
오파드라이IIOpadry II 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2%
*위 표 5 의 % 는 중량 % 를 나타낸다.*% In Table 5 represents weight%.
비교예 9 내지 12 와 실시예 6 내지 11 의 처방으로 제조한 정제에 그 공정상 장애가 있는지, 또는 시판제제와 비교했을 때 용출률은 적합한지를 알아보았으며, 그 결과는 아래의 표 6 과 같았다.Tablets prepared according to the formulations of Comparative Examples 9 to 12 and Examples 6 to 11 were found to have a disability in the process, or dissolution rate was adequate when compared with a commercially available formulation, and the results were shown in Table 6 below.
평가항목Evaluation item 비교예9Comparative Example 9 실시예6Example 6 실시예7Example 7 비교예10Comparative Example 10 비교예11Comparative Example 11 실시예8Example 8 실시예9Example 9 비교예12Comparative Example 12 실시예10Example 10 실시예11Example 11
공정장애Process failure XX XX XX OO XX XX XX OO XX XX
용출적부평가Dissolution Assessment 부적합incongruity 적합fitness 적합fitness 적합fitness 부적합incongruity 적합fitness 적합fitness 부적합incongruity 적합fitness 적합fitness
*위 표 6 의 공정장애란 타정 시 발생할 수 있는 정제의 스티킹, 라미네이팅, 캡핑 등을 말하며, O 와 X 는 100 정 분량 이상 연속적인 타정공정 중 장애발생의 여부를 기준으로 판단한 것이다.* Process failure in Table 6 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during the continuous tableting process over 100 tablets.
*위 표 6 의 용출적부평가란 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)의 조건의 용출액에서, 대한민국약전의 용출시험법(패들법)에 따라 시험을 실시한 후 분석한 결과를 말하며, 적합과 부적합은 용출시험 시작 후 45분 후에 85% 이상의 용출률을 기준으로 판단한 것이다.* The elution dissolution evaluation in Table 6 refers to the results of analysis after performing the test according to the dissolution test method (Paddle method) of the Korean Pharmacopoeia in the eluate of purified water (1000ml, polysorbate 80, 5%). In this regard, compliance and nonconformity was determined based on the dissolution rate of 85% or more after 45 minutes after the start of the dissolution test.
특히, 비교예 9 의, 시판제제 및 대조예와의 비교용출 시험결과가 도 4 와 같았는데, pH 1.2 와 pH 4.0 에서의 용출시험결과에서는 붕해제의 투입비율이 큰 영향을 끼치지 않았으나, 게피티니브의 용해도가 낮은 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)에서는 붕해제의 투입비율이 큰 영향을 끼쳐 용출기준에 부적합했다. 실험 결과 붕해제는 하나의 성분 당 조성물의 총 중량을 기준으로 최소 6 % 이상, 더 바람직하게는 7 % 이상 투입해야 약물의 방출이 원활했다.In particular, the comparative dissolution test results of the commercial preparation and the comparative example of Comparative Example 9 were as shown in Figure 4, the dissolution rate of the disintegrant in pH 1.2 and pH 4.0 did not significantly affect, but Gepitti In neat solubility of purified water (including 1000 ml, polysorbate 80, 5%), the disintegrant ratio was greatly affected and therefore unsuitable to the elution criteria. Experimental results show that disintegrants should be injected at least 6%, more preferably at least 7%, based on the total weight of the composition per one component, to facilitate drug release.
[실험 예4] 안정화제 종류 및 분량에 따른 효과의 비교실험[Experimental Example 4] Comparative experiment of the effect according to the type and amount of stabilizer
아래의 표 7의 분량으로 정제를 제조했다.Tablets were prepared in the amounts shown in Table 7 below.
성분명Ingredient Name 비교예13Comparative Example 13 비교예14Comparative Example 14 비교예15Comparative Example 15 비교예16Comparative Example 16 비교예17Comparative Example 17 비교예18Comparative Example 18 실시예12Example 12 실시예13Example 13 비교예19Comparative Example 19
게피티니브Gefitinib 74.2%74.2% 71.3%71.3% 73.3%73.3% 64.3%64.3% 73.3%73.3% 69.3%69.3% 68.3%68.3% 64.3%64.3% 59.3%59.3%
이소말트Isomalt 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3%
덱스트레이트Dexrate 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3% 2.3%2.3%
크로스포비돈Crospovidone 15.0%15.0% 15.0%15.0% 15.0%15.0% 15.0%15.0% 15.0%15.0% 15.0%15.0% 10.0%10.0% 10.0%10.0% 10.0%10.0%
옥수수전분Corn starch 10.0%10.0% 10.0%10.0% 10.0%10.0%
PVP K-30PVP K-30 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9% 1.9%1.9%
라우릴황산나트륨Sodium Lauryl Sulfate 0.1%0.1% 3.0%3.0%
시클로덱스트린Cyclodextrin 1.0%1.0% 10.0%10.0%
폴리에틸렌글리콜Polyethylene glycol 1.0%1.0% 5.0%5.0%
유드라짓E-POEudragit E-PO 1.0%1.0% 5.0%5.0% 10.0%10.0%
스테아르산마그네슘Magnesium stearate 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0% 1.0%1.0%
오파드라이 IIOpadry II 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2% 3.2%3.2%
*위 표 7 의 % 는 중량 % 를 나타낸다.*% In Table 7 above represents weight%.
비교예 13 내지 19 와 실시예 12 및 13 의 처방으로 제조한 정제에 그 공정상 장애가 있는지, 또는 가혹안정성 시험조건(60℃, 80%RH)으로 설정된 안정성 챔버에 알루미늄파우치로 1차 포장한 상태의 검체를 초기, 2주 및 4주간 방치하였을 때, 각각의 용출적부평가를 실시하였다.The tablets prepared according to the formulations of Comparative Examples 13 to 19 and Examples 12 and 13 have their process disturbances or are first packaged with aluminum pouches in a stability chamber set to severe stability test conditions (60 ° C., 80% RH). When samples were left for initial, 2, and 4 weeks, each elution was assessed.
그 결과 아래의 표 8 및 도 3 과 같이 유드라짓 E-PO 를 안정화제로 사용하였을 때, 초기 및 4주간의 용출안정성이 적합했다.As a result, when Eudragit E-PO was used as a stabilizer as shown in Table 8 and FIG. 3 below, dissolution stability of the initial and four weeks was suitable.
참고로 비교예 19 는 유드라짓 E-PO 를 배합하고 있으나, 본 발명에 따른 함량 범위를 벗어날 경우 스티킹 등의 공정장애가 발생할 수 있음을 나타낸 것이다.For reference, Comparative Example 19 shows that Eudragit E-PO is blended, but it indicates that process failure such as sticking may occur when it is out of the content range according to the present invention.
평가항목Evaluation item 비교예13Comparative Example 13 비교예14Comparative Example 14 비교예15Comparative Example 15 비교예16Comparative Example 16 비교예17Comparative Example 17 비교예18Comparative Example 18 실시예12Example 12 실시예13Example 13 비교예19Comparative Example 19
공정장애Process failure OO OO OO OO OO OO XX XX OO
용출적부평가(초기)Dissolution Assessment (Initial) 적합fitness 적합fitness 적합fitness 적합fitness 적합fitness 적합fitness 적합fitness 적합fitness 적합fitness
용출적부평가(2주)Dissolution Assessment (2 weeks) 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 적합fitness 적합fitness 적합fitness
용출적부평가(4주)Dissolution Assessment (4 weeks) 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity 적합fitness 적합fitness 적합fitness
*위 표 8 의 공정장애란 타정 시 발생할 수 있는 정제의 스티킹, 라미네이팅, 캡핑 등을 말하며, O 와 X 는 100 정 분량 이상 연속적인 타정공정 중 장애발생의 여부를 기준으로 판단한 것이다.* Process failure in Table 8 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during the continuous tableting process over 100 tablets.
*위 표 8 의 용출적부평가란 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)의 조건의 용출액에서, 대한민국약전의 용출시험법(패들법)에 따라 시험을 실시한 후 분석한 결과를 말하며, 적합과 부적합은 용출시험 시작 후 45분 후에 85% 이상의 용출률을 기준으로 판단한 것이다* The elution dissolution evaluation in Table 8 refers to the results of analysis after performing the test according to the dissolution test method (Paddle method) of the Korean Pharmacopoeia in the eluate of purified water (1000 ml, polysorbate 80, 5%). In this regard, compliance and nonconformity was determined based on the dissolution rate of 85% or more after 45 minutes after the start of the dissolution test.
[실험 예5] 부형제의 종류에 따른 효과의 비교실험Experimental Example 5 Comparative Experiment of Effects According to Excipients
표 9 와 같이, 표 2 의 실시예 1 로 제조한 정제와 완제 중량이 유사하게 비교예 20 내지 23 의 분량으로 정제를 제조하였으며, 비교예 23 은 등록특허 제 1002374호의 실시예 1 및 2 의 조성 중, 부형제인 미결정셀룰로스와 유당의 함량을 감소하여 정제를 제조하였다.As shown in Table 9, the tablet prepared in Example 1 of Table 2 and the finished weight was similarly prepared in the amount of Comparative Examples 20 to 23, Comparative Example 23 is the composition of Examples 1 and 2 of the Patent No. 1002374 The tablets were prepared by reducing the content of microcrystalline cellulose and lactose as excipients.
배합목적Purpose of Mixing 성분명Ingredient Name 실시예 1Example 1 비교예20Comparative Example 20 비교예21Comparative Example 21 비교예 22Comparative Example 22 비교예 23Comparative Example 23
mg/Tmg / T mg/Tmg / T mg/Tmg / T mg/Tmg / T mg/Tmg / T
주성분chief ingredient 게피티니브Gefitinib 250.0250.0 250.0250.0 250.0250.0 250.0250.0 250.0250.0
부형제Excipient 이소말트Isomalt 10.010.0
부형제Excipient 덱스트레이트Dexrate 10.010.0
부형제Excipient 유당Lactose 20.020.0 55.055.0
부형제Excipient 인산수소칼슘Calcium hydrogen phosphate 20.020.0
부형제Excipient 미결정셀룰로스Microcrystalline cellulose 20.020.0 23.023.0
붕해제Disintegrant 크로스카멜로스소듐Croscarmellose sodium 20.020.0
붕해제Disintegrant 크로스포비돈Crospovidone 35.035.0 35.035.0 35.035.0 35.035.0
붕해제Disintegrant 옥수수전분Corn starch 32.532.5 32.532.5 32.532.5 32.532.5
결합제Binder 포비돈 K-30Povidone K-30 7.07.0 7.07.0 7.07.0 7.07.0 7.07.0
가용화제Solubilizer 라우릴황산나트륨Sodium Lauryl Sulfate 1.51.5
안정화제Stabilizer 유드라짓E-POEudragit E-PO 12.012.0 12.012.0 12.012.0 12.012.0
윤활제slush 스테아르산마그네슘Magnesium stearate 3.53.5 3.53.5 3.53.5 3.53.5 3.53.5
나정Najung 360.0360.0 360.0360.0 360.0360.0 360.0360.0 360.0360.0
코팅기제Coating base HPMC 기제HPMC Base 12.2512.25
코팅기제Coating base 오파드라이 IIOpadry II 10.010.0 10.010.0 10.010.0 10.010.0
코팅정Coated tablet 370.0370.0 370.0370.0 370.0370.0 370.0370.0 372.25372.25
위 표 9 의 처방에 따라 제조한 정제와 실험 예 1 에서 언급한 표 2 의 실시예 1 처방에 따라 제조한 정제의 물성과 용출적부평가(정제수 1000㎖, 폴리소르베이트 80, 5 % 포함, 패들속도 50rpm, 45분 85% 이상 용출)를 진행하였으며, 그 결과는 아래의 표 10 및 도 2 와 같았다.Tablets prepared according to the formulation of Table 9 above and tablets prepared according to the formulation of Example 1 of Table 2 mentioned in Experimental Example 1 Physical property and elution dissolution evaluation (1000 ml of purified water, 80% polysorbate, 5%, paddle) 50 rpm, eluting at least 85% for 45 minutes) was performed, and the results were as shown in Table 10 and FIG. 2 below.
평가항목Evaluation item 실시예 1Example 1 비교예20Comparative Example 20 비교예21Comparative Example 21 비교예 22Comparative Example 22 비교예 23Comparative Example 23
Carr's IndexCarr's Index 1717 2424 2323 3030 2525
공정장애Process failure XX XX XX XX XX
용출적부평가Dissolution Assessment 적합fitness 부적합incongruity 부적합incongruity 부적합incongruity 부적합incongruity
*위 표 10 의 Carr's Index 는 과립물(분체)의 유동성 및 흐름성을 평가하는 지표로서, 과립의 유동성 및 흐름성이 높을수록 정량충전성, 혼합균일성이 증가하고, 이에 따라 타정공정의 적용에 매우 중요한 기준이 된다. Carr's Index 값이 낮을 수록 흐름성이 좋은 것으로 평가되며 통상적으로 수치가 30 이상일 경우 개선이 반드시 필요한 불량 기준으로 판정한다. * Carr's Index in Table 10 is an indicator for evaluating the fluidity and flowability of granules (powder) .The higher the fluidity and flowability of granules, the higher the quantitative filling and mixing uniformity. This is a very important criterion. The lower the Carr's Index value, the better the flowability. In general, when the value is 30 or more, it is determined as a defective criterion that must be improved.
*위 표 10 의 공정장애란 타정 시 발생할 수 있는 정제의 스티킹, 라미네이팅, 캡핑 등을 말하며, O 와 X 는 100 정 분량 이상 연속적인 타정공정 중 장애발생의 여부를 기준으로 판단한 것이다.* Process failure in Table 10 refers to the sticking, laminating, and capping of tablets that may occur during tableting, and O and X are determined based on the occurrence of failure during the continuous tableting process over 100 tablets.
*위 표 10 의 용출적부평가란 정제수(1000㎖, 폴리소르베이트 80, 5 % 포함)의 조건의 용출액에서, 대한민국약전의 용출시험법(패들법)에 따라 시험을 실시한 후 분석한 결과를 말하며, 적합과 부적합은 용출시험 시작 후 45분 후에 85% 이상의 용출률을 기준으로 판단한 것이다.* Elution Defective Evaluation in Table 10 refers to the results of analysis after performing the test according to the dissolution test method (Paddle method) of the Korean Pharmacopoeia in the eluate of purified water (1000ml, polysorbate 80, 5%). In this regard, compliance and nonconformity was determined based on the dissolution rate of 85% or more after 45 minutes after the start of the dissolution test.
표 10 에 나타나 있듯이, 이소말트와 덱스트레이트를 인산수소칼슘, 유당 또는 미결정셀룰로스로 전환한 경우(비교예 20 내지 22), 용출적부평가 결과가 부적합하였으며, 정제 크기 감소를 위해 등록특허 제 1002374호의 실시예 1 및 2 의 부형제인 미결정셀룰로스와 유당의 함량을 단순히 감소시킨 것만으로도 용출적부평가 결과가 부적합하였다(비교예 23).As shown in Table 10, when isomalt and dexrate were converted to calcium hydrogen phosphate, lactose, or microcrystalline cellulose (Comparative Examples 20 to 22), the results of the elution inadequate evaluation were inadequate, and in order to reduce the tablet size, The results of elution disparity were inadequate simply by reducing the contents of microcrystalline cellulose and lactose, the excipients of Examples 1 and 2 (Comparative Example 23).
[실험예 6] 실시예 1 및 시판제제의 약물동등성시험Experimental Example 6 Drug Equivalence Test of Example 1 and Commercially Available Preparations
표 2 의 실시예 1 로 제조한 정제와 시판제제를 각각 비글견에 동시에 투약 후, 각 시간 별로 혈액을 채취하여 혈중약물의 농도를 측정하였다.Tablets and commercial preparations prepared in Example 1 of Table 2 were respectively dosed to beagle dogs, and blood was collected at each time to measure the concentrations of blood drugs.
그 결과, 도 5 와 같이 동일시간에 동등한 혈중농도를 나타내어, 시판제제와 실시예 1 의 약물동등성이 증명되었다.As a result, as shown in Fig. 5, the same blood concentrations were shown at the same time, and the pharmacokinetics of the commercial preparations and Example 1 were demonstrated.

Claims (12)

  1. 게피티니브를 총 중량의 65% 이상 함유하며, 덱스트레이트 및 이소말트로 이루어진 군으로부터 선택된 1 종 이상과, 하나의 성분 당 총 중량 대비 6-14% 의 1 종 이상의 붕해제를 포함하는 것을 특징으로 하는 조성물.It contains at least 65% of the total weight of gefitinib, and comprises at least one member selected from the group consisting of dexrate and isomalt, and at least one disintegrant of 6-14% of the total weight per one component. Composition.
  2. 제 1 항에 있어서, 붕해제는 바람직하게, 하나의 성분 당 총 중량 대비 7-10% 를 포함하는 것을 특징으로 하는 조성물.The composition of claim 1 wherein the disintegrant comprises preferably 7-10% of the total weight per one component.
  3. 제 1 항에 있어서, 덱스트레이트는 조성물의 총 중량 대비 2-5% 를 포함하는 것을 특징으로 하는 조성물.The composition of claim 1, wherein the dexrate comprises 2-5% of the total weight of the composition.
  4. 제 1 항에 있어서, 이소말트는 조성물의 총 중량 대비 2-5% 를 포함하는 것을 특징으로 하는 조성물.The composition of claim 1 wherein the isomalt comprises 2-5% of the total weight of the composition.
  5. 제 1 항에 있어서, 붕해제는 크로스포비돈 및 옥수수전분으로 이루어진 군으로부터 선택된 하나 이상을 포함하는 것을 특징으로 하는 조성물.The composition of claim 1 wherein the disintegrant comprises one or more selected from the group consisting of crospovidone and corn starch.
  6. 제 1 항 내지 제 5 항에 있어서, 약제학적으로 사용이 가능한 첨가제, 안정화제, 윤활제 및 결합제를 추가로 함유하는 것을 특징으로 하는 조성물.The composition according to claim 1, further comprising pharmaceutically usable additives, stabilizers, lubricants and binders.
  7. 제 6 항에 있어서, 안정화제는 유드라짓 E-PO 인 것을 특징으로 하는 조성물.7. The composition of claim 6, wherein the stabilizer is Eudragit E-PO.
  8. 제 7 항에 있어서, 유드라짓 E-PO 는 조성물의 총 중량 대비 1-5% 를 포함하는 것을 특징으로 하는 조성물.8. The composition of claim 7, wherein Eudragit E-PO comprises 1-5% of the total weight of the composition.
  9. 조성물의 총 중량 대비 65-75% 의 게피티니브; 2-5 % 의 덱스트레이트 및/또는 2-5% 의 이소말트; 안정화제 및 하나의 성분 당 6-14 % 의 1 종 이상의 붕해제를 포함하는 것을 특징으로 하는 조성물.Gefitinib of 65-75% relative to the total weight of the composition; 2-5% dexrate and / or 2-5% isomalt; A composition comprising a stabilizer and 6-14% of one or more disintegrants per component.
  10. 제 9 항에 있어서, 붕해제는 크로스포비돈 및 옥수수전분으로 이루어진 군으로부터 선택된 하나 이상인 것을 특징으로 하는 조성물.10. The composition of claim 9, wherein the disintegrant is at least one selected from the group consisting of crospovidone and corn starch.
  11. 제 9 항에 있어서, 안정화제는 유드라짓 E-PO 인 것을 특징으로 하는 조성물.10. The composition of claim 9, wherein the stabilizer is Eudragit E-PO.
  12. 제 11 항에 있어서, 유드라짓 E-PO 는 조성물의 총 중량 대비 1-5% 를 포함하는 것을 특징으로 하는 조성물.12. The composition of claim 11, wherein the Eudragit E-PO comprises 1-5% of the total weight of the composition.
PCT/KR2016/014300 2015-12-31 2016-12-07 Pharmaceutical composition containing gefitinib, administrable to patients with lactose intolerance and having improved dosing convenience WO2017116031A1 (en)

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