WO2017116031A1 - Composition pharmaceutique contenant du géfitinib, pouvant être administrée à des patients présentant une intolérance au lactose, et présentant une commodité de dosage améliorée - Google Patents

Composition pharmaceutique contenant du géfitinib, pouvant être administrée à des patients présentant une intolérance au lactose, et présentant une commodité de dosage améliorée 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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PCT/KR2016/014300
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English (en)
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.

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Abstract

La présente invention concerne une composition pharmaceutique contenant du géfitinib utilisé comme principe pharmaceutiquement actif. Lorsque la présente invention est préparée, le poids et le volume de la formulation finale peuvent être optimisés en termes de commodité de dosage pour les patients et ladite formulation finale peut être administré à des patients présentant une intolérance au lactose.
PCT/KR2016/014300 2015-12-31 2016-12-07 Composition pharmaceutique contenant du géfitinib, pouvant être administrée à des patients présentant une intolérance au lactose, et présentant une commodité de dosage améliorée WO2017116031A1 (fr)

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KR1020150191215A KR101739731B1 (ko) 2015-12-31 2015-12-31 유당불내성 환자에게 투여가 가능하며, 복용편의성이 향상된 게피티니브를 함유하는 약제학적 조성물
KR10-2015-0191215 2015-12-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10792262B1 (en) 2019-07-29 2020-10-06 Saol International Limited Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives
US11654124B2 (en) 2019-07-29 2023-05-23 Amneal Pharmaceuticals Llc Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010132431A1 (fr) * 2009-05-11 2010-11-18 Jrs Pharma Gmbh+Co.Kg Excipient se désintégrant par voie orale
KR101002374B1 (ko) * 2002-02-26 2010-12-17 아스트라제네카 아베 수용성 셀룰로스 유도체를 포함하는 이레사의 약학 조제물
US20120156261A1 (en) * 2009-08-11 2012-06-21 Keiichi Fujiwara Disintegrating particle composition and orally rapidly disintegrating tablet
CN104586798A (zh) * 2015-01-04 2015-05-06 成都恒瑞制药有限公司 一种吉非替尼分散片及其制备方法
CN105168169A (zh) * 2014-06-18 2015-12-23 山东新时代药业有限公司 一种吉非替尼片剂及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101002374B1 (ko) * 2002-02-26 2010-12-17 아스트라제네카 아베 수용성 셀룰로스 유도체를 포함하는 이레사의 약학 조제물
WO2010132431A1 (fr) * 2009-05-11 2010-11-18 Jrs Pharma Gmbh+Co.Kg Excipient se désintégrant par voie orale
US20120156261A1 (en) * 2009-08-11 2012-06-21 Keiichi Fujiwara Disintegrating particle composition and orally rapidly disintegrating tablet
CN105168169A (zh) * 2014-06-18 2015-12-23 山东新时代药业有限公司 一种吉非替尼片剂及其制备方法
CN104586798A (zh) * 2015-01-04 2015-05-06 成都恒瑞制药有限公司 一种吉非替尼分散片及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10792262B1 (en) 2019-07-29 2020-10-06 Saol International Limited Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives
WO2021021277A1 (fr) * 2019-07-29 2021-02-04 Saol International Limited Formulations stabilisées de dérivés de l'acide butanoïque du type 4-amino-3-substitués
US11654124B2 (en) 2019-07-29 2023-05-23 Amneal Pharmaceuticals Llc Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives
US11931328B2 (en) 2019-07-29 2024-03-19 Amneal Pharmaceuticals Llc Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives

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