CN106552266A - A kind of melphalan oral formulations - Google Patents

A kind of melphalan oral formulations Download PDF

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Publication number
CN106552266A
CN106552266A CN201510624259.8A CN201510624259A CN106552266A CN 106552266 A CN106552266 A CN 106552266A CN 201510624259 A CN201510624259 A CN 201510624259A CN 106552266 A CN106552266 A CN 106552266A
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CN
China
Prior art keywords
melphalan
preparation
pharmaceutical preparation
sodium
crospovidone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510624259.8A
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Chinese (zh)
Inventor
王志云
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
As Far As British Pharmaceutical Co
Original Assignee
As Far As British Pharmaceutical Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by As Far As British Pharmaceutical Co filed Critical As Far As British Pharmaceutical Co
Priority to CN201510624259.8A priority Critical patent/CN106552266A/en
Priority to PCT/IB2016/055691 priority patent/WO2017051362A1/en
Publication of CN106552266A publication Critical patent/CN106552266A/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The application provides a kind of melphalan oral formulations, and which includes the magnesium stearate of the melphalan of 2 0.3wt%, the polyvinylpyrrolidone of 50 96wt% or Microcrystalline Cellulose, the sodium lauryl sulfate of 0 10wt% and/or Poloxamer 188, the low-substituted hydroxypropyl cellulose of 2 10wt% and/or Croscarmellose Sodium/Crospovidone, the silicon dioxide of 0 5wt% and/or Talcum and 0 3wt%.The pharmaceutical preparation can be capsule form.The oral formulations have the stability of height, and provide good bioavailability.

Description

A kind of melphalan oral formulations
Technical field
The present invention relates to include the oral drug preparation of melphalan (melphalan), particularly capsule form Peroral dosage form, wherein melphalan have improved bioavailability.
Background technology
Melphalan, also referred to as Phenylalanin-Lost, melphalan, L-PAM or L- sand can Come new, be the phenylalanine derivative of chlormethine.Melphalan is active for some neoplastic disease Bifunctional alkylating agents.Which is referred to as 4- [double (2- chloroethyls) amino]-L-phenylalanine in chemistry.Molecule Formula is C13H18Cl2N2O2, molecular weight is 305.20.Structural formula is：
After oral melphalan, occurs the time (scope of medicine in blood plasma first：0 to 6 hour) and blood plasma Peak concentration (Cmax) these two aspects is alterable height.The mean absolute bioavailability of melphalan is also high Variable (the scope of degree：56% to 93%).It is (a kind of to become that these results are likely due to incomplete intestinal absorption Different " first to cross " hepatic metabolism) or caused due to fast hydrolyzing.The oral melphalan together with high fat diet Melphalan exposure (AUC) can be made to reduce 36% to 54%.Melphalan is mainly by chemical hydrolysis into a hydroxyl Base melphalan and dihydroxy melphalan and eliminate from blood plasma.In addition to these hydrolyzate, in human body Not yet it was observed that other melphalan metabolites.
The content of the invention
The oral drug preparation for describing in the present invention is intended to (1) stable crude drug so as to produce and stored Degraded in journey is minimized；(2) minimize the degraded during gastrointestinal absorption；(3) increase biological utilisation Transmutability in degree and reduction absorption process.Based on the related drugs dynamics research carried out in beasle dog And stability test, it was demonstrated that preparation described herein has at least one relative to existing dosage form on market Plant above-mentioned advantage.
According to the one side of the application, the melphalan of the oral formulations comprising 2-0.3wt% of the application, The polyvinylpyrrolidone or Microcrystalline Cellulose of 50-96wt%, the sodium lauryl sulfate of 0-10wt% and/or pool The low-substituted hydroxypropyl cellulose (L-HPC) and/or crosslinking carboxylic of Luo Shamu (poloximer) 188,2-10wt% The stearic acid of sodium carboxymethylcellulose pyce/Crospovidone, the silicon dioxide of 0-5wt% and/or Talcum and 0-3wt% Magnesium.
According to some embodiments of the application, said preparation is capsule form.
According to some embodiments of the application, polyvinylpyrrolidone of the said preparation comprising 76-96wt% or The crosslinking carboxylic first of Microcrystalline Cellulose, the sodium lauryl sulfate of 0-10wt% or Poloxamer 188,3-8wt% The magnesium stearate of base sodium cellulosate, the silicon dioxide of 0-3wt% and 0-3wt%.
According to some embodiments of the application, polyvinylpyrrolidone or micro- of the said preparation comprising 88wt% Crystalline cellulose, the sodium lauryl sulfate of 5wt% or Poloxamer 188, the cross-linked carboxymethyl cellulose of 3wt% The magnesium stearate of sodium or Crospovidone, the silicon dioxide of 1wt% and 1wt%.
According to some embodiments of the application, melphalan of the said preparation comprising 2wt%.
According to some embodiments of the application, said preparation includes the melphalan that amount is every capsule 2mg.
According to some embodiments of the application, the capsule shells that said preparation is used are gelatin and/or hydroxypropyl first The capsule shells of base cellulose (HPMC).
According to the another aspect of the application, the method for producing said preparation includes making activated feedstock medicine and excipient Mixing, and/or rolls and/or mills, finally and mix lubricant, encapsulation capsule or tabletting post package glue Capsule.
The oral formulations of the application have the stability of height, and provide good bioavailability.
Description of the drawings
Fig. 1 illustrates the preparation (formula of table 1) and marketed tablet Alkeran Tablets of the application in sky The comparison of the Dog Plasma melphalan characteristic under the conditions of abdomen.
Fig. 2 illustrate the preparation of the application and marketed tablet Alkeran Tablets on the feed under the conditions of ratio lattice The comparison of dog plasma melphalan characteristic.
Specific embodiment
The embodiment of merely illustrative purpose, is not intended to impose any restrictions the application below.
Embodiment
Prepare embodiment：
The representative composition of the application preparation is listed below respectively.
The representative composition of 1. melphalan preparation of table
The representative composition of 2. melphalan preparation of table
The representative composition of 3. melphalan preparation of table
The representative composition of 4. melphalan preparation of table
Bioavailability and stability experiment
1. the stability significantly improved after storing 4 weeks under the conditions of the accelerating storage of 40 DEG C/75%RH
When with marketed tablet Alkeran Tablets (AlkeranTM, 2mg tablets, lot number 403389, aspen) When being compared, degradation product I, J and active component of the preparation (formula of table 1) of the present invention is American and French The total losses amount of logical sequence is substantially few.It is well known that Alkeran Tablets need stored under refrigeration.Accelerate Condition of storage is intended to the difference for being disclosed in degradation product in the relatively short time cycle, and which does not represent business and produces The true condition of storage of product.
The net increase of the degradation product in the application preparation after stored under refrigeration 3 months of table 5.
Impurity The net increase of degradation product in preparation Acceptable value
B 0.000 0.3
D 0.000 3
I 0.107 0.2
J 0.000 0.5
G 0.000 1
H 0.032 0.5
The maximum amount of unknown single contaminant Nothing 0.1
The net increase of degradation product in the preparation of the invention after storing 3 months at 40 DEG C of table 6.
Impurity The net increase of degradation product in preparation Acceptable value
B 0.000 0.3
D 0.000 3
I 0.105 0.2
J 0.000 0.5
G 0.651 1
H 0.031 0.5
The maximum amount of unknown single contaminant 0.651 0.1
Note：
* net increase refers to the difference between preparation and crude drug melphalan
Net increases of the * less than 0 is according to 0% report.
2. it is remarkably improved compared with marketed tablet (Alkeran Tablets) and absorbs and internal with what is improved Transmutability
A) beasle dog absorbs crossing research methodology
Selection body weight is 10-11kg, the age is not exposed to any medicine for 3-5 year and in nearest 3 months Healthy male beagle dogs (N=3) carry out Absorption Study.For empty stomach condition, dog fasted overnight is made (not limit Water), then 3 capsules (6mg melphalan crude drug) are given via gavage, then give 100mL water, And continue 4 hours of fasting.In predetermined time point from the beginning venous puncture blood.Plasma sample is carried out Proper treatment to remove protein and interfering material, then using AB Sciex 4000Qtrap LC/MS/MS is analyzed.For fed condition, it is allowed to which dog is taken food after capsule 30min is taken.Institute There are other conditions to keep identical.
Dog Plasma of the application preparation (formula of table 1) relative to marketed tablet under the conditions of empty stomach Melphalan (average) characteristic relatively figure 1 illustrates.The application preparation is entering relative to marketed tablet Dog Plasma melphalan (average) characteristic under the conditions of food relatively figure 2 illustrates.Pharmacokinetics Illustrate in being characterized in table 7.
7. the application preparation of table is relative to marketed tablet in the pharmacokinetic parameter on an empty stomach and under fed condition
3. conclusion
The preparation exhibits of the application go out than marketed tablet (Alkeran Tablets) preferably stability and biology profit Expenditure, to show and have significant value promotion relative to universal acceptable commercial product, and significantly improve Product quality and potential effect, safety and patient compliance.

Claims (7)

1. a kind of oral drug preparation, which includes the polyethylene of the melphalan of 2-0.3wt%, 50-96wt% Ketopyrrolidine or Microcrystalline Cellulose, the sodium lauryl sulfate of 0-10wt% and/or Poloxamer 188,2-10 The low-substituted hydroxypropyl cellulose of wt%, Croscarmellose Sodium and/or Crospovidone, 0-5wt% The magnesium stearate of silicon dioxide and/or Talcum and 0-3wt%, wherein the pharmaceutical preparation is capsule form.
2. pharmaceutical preparation according to claim 1, wherein the U.S. of the preparation comprising 2-0.3wt% Method logical sequence, the polyvinylpyrrolidone of 76-96wt% or Microcrystalline Cellulose, the sodium lauryl sulfate of 0-10wt% And/or low-substituted hydroxypropyl cellulose, the Croscarmellose Sodium of Poloxamer 188,2-10wt% And/or the silicon dioxide and/or Talcum and the magnesium stearate of 0-3wt% of Crospovidone, 0-5wt%.
3. pharmaceutical preparation according to claim 1 and 2, wherein the preparation includes 2-0.3wt% Melphalan, the polyvinylpyrrolidone of 76-96wt% or Microcrystalline Cellulose, the lauryl sulfur of 0-10wt% Sour sodium or Poloxamer 188, the low-substituted hydroxypropyl cellulose of 3-8wt%, Croscarmellose Sodium And/or the magnesium stearate of the silicon dioxide and 0-3wt% of Crospovidone, 0-3wt%.
4. pharmaceutical preparation according to claim 3, wherein polyethylene of the preparation comprising 88wt% Ketopyrrolidine or Microcrystalline Cellulose, the sodium lauryl sulfate of 5wt% or Poloxamer 188, the crosslinking of 3wt% The magnesium stearate of sodium carboxymethyl cellulose or Crospovidone, the silicon dioxide of 1wt% and 1wt%.
5. the pharmaceutical preparation according to any one of claim 1-4, wherein the preparation includes 2wt% Melphalan.
6. pharmaceutical preparation according to claim 5, the amount of wherein melphalan is every capsule 2mg.
7. the pharmaceutical preparation according to any one of claim 1-6, wherein the capsule has gelatin And/or hydroxypropyl methylcellulose capsules shell.
CN201510624259.8A 2015-09-25 2015-09-25 A kind of melphalan oral formulations Pending CN106552266A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201510624259.8A CN106552266A (en) 2015-09-25 2015-09-25 A kind of melphalan oral formulations
PCT/IB2016/055691 WO2017051362A1 (en) 2015-09-25 2016-09-23 An oral formulation of melphalan

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510624259.8A CN106552266A (en) 2015-09-25 2015-09-25 A kind of melphalan oral formulations

Publications (1)

Publication Number Publication Date
CN106552266A true CN106552266A (en) 2017-04-05

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WO (1) WO2017051362A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4308286A1 (en) 2021-03-16 2024-01-24 Symrise AG Active substance capsules

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003092659A1 (en) * 2002-05-03 2003-11-13 Skyepharma Canada Inc. Oral dosage forms comprising fenofibrate
US20040034099A1 (en) * 2002-06-27 2004-02-19 Ramsey Beverly J. Pharmaceutical composition

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Application publication date: 20170405

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