CN108653234A - It is loaded with the solid particulate matter and double enteric solid preparations comprising the particulate matter, preparation method and the usage of polypeptide protein class drug - Google Patents
It is loaded with the solid particulate matter and double enteric solid preparations comprising the particulate matter, preparation method and the usage of polypeptide protein class drug Download PDFInfo
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- CN108653234A CN108653234A CN201710212881.7A CN201710212881A CN108653234A CN 108653234 A CN108653234 A CN 108653234A CN 201710212881 A CN201710212881 A CN 201710212881A CN 108653234 A CN108653234 A CN 108653234A
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/23—Calcitonins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
Abstract
The present invention relates to a kind of solid particulate matter being loaded with polypeptide protein class drug, comprising double enteric solid preparations of the solid particulate matter, as well as preparation method and application thereof.The solid particulate matter includes polypeptide protein class drug, sorbefacient and protease inhibitors.Double enteric solid preparations prepared by the present invention can resist the degradation of hydrochloric acid in gastric juice and gastrointestinal enzyme to polypeptide protein class drug when oral, while have site specific DDS for colon effect, can effectively facilitate absorption of the polypeptide protein class drug in enteron aisle.
Description
Technical field
The present invention relates to field of biological pharmacy, more specifically to a kind of solid being loaded with polypeptide protein class drug
Grain object, double enteric solid preparations comprising the solid particulate matter, as well as preparation method and application thereof.
Background technology
Polypeptide protein class drug, if insulin, human growth hormone (HGH), calcitonin are administered with the approach of injection.But it injects
There are many disadvantages for administration, and the biological half-life such as insulin is short, and daily 1-2 times injection of insulin can make patient generate part
The side effects such as redness, subcutaneous nodule, lipoatrophy bring greatly pain and inconvenience to patient.Therefore, research safety
Convenient, inexpensive effective oral administration preparation will greatly facilitate patient to replace injection.
But the polypeptide proteins class drug such as insulin, if directly oral without special embedding technical finesse, easily by stomach
Proteolytic degradation in acidic environment degradation, gastrointestinal tract, while pharmaceutical molecular weight is big, fat-soluble difference, it is difficult to penetrate alimentary canal
Epithelial cell barriers, bioavilability only have 0.1%~2%, thus the oral medication of polypeptide protein class drug be faced with it is huge
Big challenge.
Recent study shows that suitable drug-loading system is used to be helped again with certain protease inhibitors, sorbefacient,
Can effectively improve polypeptide protein class drug gastrointestinal tract absorptivity.The liposome pancreas islet researched and developed such as Diasome companies
Element has the function of that liver cell is directly targeted, and blood glucose can be not only reduced rapidly by liver physiology approach, and make peripheral blood pancreas
Island element concentration maintains normal level.But since the stability of preparation is poor, it will take time for clinical application.Emisphere companies
Develop a series of sorbefacient (such as N- (8- [2- (2-hydroxybenzoyl)] of micromolecular compounds as polypeptide protein class drug
Amino) Sodium Caprylate (SNAC), WO 2008/028859), it is used to take orally the clinical research of macromolecular administration by more companies,
Such as the research of the oral Suo Malu peptides and oral insulin of Novo Nordisk Co., Ltd, the research of the oral insulin of Oramed companies,
But that there is also sorbefacient dosages is big for its oral tablet, the shortcomings of being easily diluted to reduce drug effect in body.Also
Insulin is dissolved in hydrophobic solvent or oil phase by researcher, and oral preparation is made, as in patent WO 95/13795 that insulin is molten
In oil phase formulation, using rotary evaporation, spray drying, or freezing 48h removings are hydrophilic under less than the vacuum condition of 0.1Mpa
Property solvent.Generally speaking, preparation process is more complicated, limits the scale of production, also increases cost.
Therefore, simple preparation method, mild, property stabilization are designed and polypeptide protein class Oral drug absorption can be promoted
Oral preparation be a problem that formulation scientist faces always.
Invention content
The purpose of the present invention is to solve above-mentioned problem, provide it is a kind of it is safe and reliable, be easily accepted by patients
And the oral double enteric solid preparations for being loaded with polypeptide protein class drug can be used for.
According to an aspect of the present invention, a kind of solid particulate matter being loaded with polypeptide protein class drug is provided comprising：
The parts by weight of 0.5 parts by weight~90, the polypeptide protein class drug of the parts by weight of preferably 1 parts by weight~50；
The parts by weight of 0.5 parts by weight~90, the sorbefacient of the parts by weight of preferably 5 parts by weight~50；
The parts by weight of 0 parts by weight~50, the protease inhibitors of the parts by weight of preferably 1 parts by weight~30；And
The parts by weight of 5 parts by weight~90, the enteric material of the parts by weight of preferably 10 parts by weight~90.
The present invention's is loaded in the solid particulate matter of polypeptide protein class drug, it is preferable that the solid particulate matter is averaged
Grain size is about 0.1~2000 μm；And/or the grain size of 90% particle of institute's solid particulate matter is no more than 2000 μm, more preferably institute
The average grain diameter of solid particulate matter is stated about in the range of 0.1~1000 μm.
The present invention's is loaded in the solid particulate matter of polypeptide protein class drug, it is preferable that the polypeptide protein class drug is
Polypeptide protein class drug with pharmacological activity, by insulin and the like, Exenatide, calcitonin, recombined human first shape
Glandular hormone, hematopoietin, Filgrastim, human growth hormone (HGH), interleukins, cyclosporin, table
Skin growth factor, GLP-1 analogs or interferon etc., more preferably insulin, Exenatide or salmon calcitonin.
The present invention's is loaded in the solid particulate matter of polypeptide protein class drug, it is preferable that the sorbefacient can be：N-
(8- [2- (2-hydroxybenzoyl)s] amino) octanoic acid and its derivative (such as N- [8- (2- hydroxy benzoyls) amino] Sodium Caprylate
(SNAC), N- (10- [2- hydroxy benzoyls -] amino) sodium caprate (SNAD)), medium chain fatty acid and its esters (such as capric acid
Sodium), bile acid and its derivative, ethylenediamine tetra-acetic acid (EDTA) or its salt or combination thereof, more preferably SNAC, SNAD
Or sodium caprate.
The present invention's is loaded in the solid particulate matter of polypeptide protein class drug, it is preferable that the protease inhibitors can be
Trypsin inhibitor, cystatin, serine/threonine protein enzyme inhibitor, asparaginic acid protease inhibitors and
Metal protease inhibitors etc..More preferably soybean trypsin inhibitor (SBTI), Aprotinin or ovomucoid.
The present invention's is loaded in the solid particulate matter of polypeptide protein class drug, it is preferable that the enteric material can use
All enteric-coating materials are without limiting, such as cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose O-phthalic
Acid esters (HPMCP), polyvinyl acetate phthalate (PVAP), crylic acid resin (such as Eudragit S100,
Eudragit L100), one or more of shellac etc. mixing material, preferably Eudragit S100, Eudragit
L100, HPMCP or combination thereof.
According to another aspect of the present invention, the preparation side of the solid particulate matter for being loaded with polypeptide protein class drug is provided
Method comprising following steps：
1) polypeptide protein class drug, sorbefacient, protease inhibitors are dissolved in aqueous phase solution, it is molten forms (A)
Liquid, wherein polypeptide protein class drug and sorbefacient mass ratio are about 100:1~1:100, preferably from about 1:10~1:40, it is more
Peptide protein medicaments and protease inhibitors mass ratio are about 100:1~1:100, preferably from about 1:1~1:10；
2) Enteric Materials are dissolved in solvent, form (B) solution, the concentration of enteric material is about 1mg/mL~200mg/
ML, preferably from about 5~100mg/mL；And
3) (A) solution is added into (B) solution at room temperature, (A) solution and the volume ratio of (B) solution are about 1:10~1:
100, preferably from about 1:5~1:25, form uniform solution, after be dried the solid particulate matter be prepared.
Aqueous phase solution in the step 1) of above-mentioned preparation method can be to be made in the pharmaceutically acceptable solvent in this field
It is standby.The aqueous phase solution is preferably the aqueous solution of water, phosphate buffer, ethanol water, the aqueous solution of acid or alkali；The alkali
Aqueous solution be preferably sodium hydroxide, potassium hydroxide or ammonia aqueous solution；The aqueous solution of the acid is preferably hydrochloric acid, phosphoric acid or vinegar
The aqueous solution of acid.Wherein, the acid-base property of the aqueous phase solution and concentration can do adjustment appropriate with the change of material.
Solvent in the step 2) of above-mentioned preparation method can be water, ethyl alcohol, the tert-butyl alcohol, dichloromethane or theirs is arbitrary
The combination of ratio.
In the step 3) of above-mentioned preparation method, it is preferable that atomizing freeze drying method, spray drying may be used in the drying
Method or boulton process etc..
Optionally, the preparation method of the solid particulate matter for being loaded with polypeptide protein class drug may also include the steps of：
1) by polypeptide protein class drug, sorbefacient, that protease inhibitors is dissolved in the water phase containing surfactant is molten
In liquid, (A) solution is formed；Wherein polypeptide protein class drug and sorbefacient mass ratio are about 100:1~1:100, preferably
About 1:10~1:40；Polypeptide protein class drug and protease inhibitors mass ratio are about 100:1~1:100, preferably from about 1:1~
1:10；
2) enteric material is dissolved in solvent, forms (B) solution, the concentration of enteric material is about 1mg/mL~200mg/
ML, preferably from about 5~100mg/mL；
3) (A) solution is added into (B) solution at room temperature, (A) solution and the volume ratio of (B) solution are about 1:1~1:
100, preferably from about 1:1~1:50, form W/O water-in-oil emulsions (C)；
4) lotion (C) that step 3) obtains is slowly added into the solvent containing surfactant (D), lotion (C) with it is molten
The volume ratio of agent (D) is about 1:1~1:100, preferably from about 1:5~1:25, organic solvent solidification is added after stirring under room temperature
Grain；And
5) solid particulate matter will be obtained after particle drying in step 4).
The solution of step 1) the polypeptide protein class drug of above-mentioned preparation method can be by by polypeptide protein class drug
It is dissolved in pharmaceutically acceptable solvent and prepares.The pharmaceutically acceptable solvent is preferably water, phosphate buffer, second
The aqueous solution of alcohol solution, the aqueous solution of acid or alkali；The aqueous solution of the alkali is preferably the water of sodium hydroxide, potassium hydroxide or ammonia
Solution；The aqueous solution of the acid is preferably the aqueous solution of hydrochloric acid, phosphoric acid or acetic acid.
Solvent in the step 2) of above-mentioned preparation method can be the tert-butyl alcohol, dichloromethane, chloroform etc. or they and water, second
The combination of the arbitrary proportion of alcohol, and
Above-mentioned steps 4) in solvent in the solvent (D) containing surfactant can be that paraffin, cottonseed oil, soybean oil etc. are non-aqueous
Solvent phase solvent.
The step 1) of above-mentioned preparation method and 4) in, it is preferable that the surfactant can be anion surface active
Agent, cationic surfactant or nonionic surfactant, more preferably polysorbas20, sorbester p18 or sorbester p17.
In the step 4) of above-mentioned preparation method, it is preferable that the solvent can be common organic solvent, more preferably just
Pentane, n-hexane or normal heptane.
In the step 5) of above-mentioned preparation method, it is preferable that atomizing freeze drying method, spray drying may be used in the drying
Method or boulton process etc..
According to another aspect of the present invention, a kind of double enteric solid preparations of oral polypeptide protein class drug are provided, are wrapped
Containing solid particulate matter as described above and site specific DDS for colon material.
In accordance with a further aspect of the present invention, a kind of preparation of double enteric solid preparations of oral polypeptide protein class drug is provided
Method comprising the step of preparing the above-mentioned solid particulate matter for being loaded with polypeptide protein class drug, and by prepared solid
The step of grain object and site specific DDS for colon material preparation are at solid pharmaceutical preparation.
In the preparation method of double enteric solid preparations of the present invention, it is preferable that by prepared solid particulate matter and colon
The step that locator material is prepared into solid pharmaceutical preparation is selected from following any type methods：
A) by the solid particulate matter, optionally with medical additive, after pouring into common gelatine capsule, using site specific DDS for colon
One or more of material mixture is coated, and is prepared into capsule.Preferably, a) described in medical additive choosing
From the pharmaceutically acceptable additive such as mannitol, starch, lactose, microcrystalline cellulose；
B) by the solid particulate matter, optionally with medical additive, the capsule shells of the material containing site specific DDS for colon are poured into, are made
For at capsule.Preferably, b) described in medical additive be selected from mannitol, starch, lactose, microcrystalline cellulose etc. and pharmaceutically may be used
The additive of receiving；
C) it is carried out using one or more of site specific DDS for colon material mixture after the solid particulate matter being pelletized
Coating, is prepared into enteric-coated micro-pill；
D) it by the solid particulate matter, is optionally mixed with medical additive, after tabletting, using in site specific DDS for colon material
One or more kinds of mixtures are coated, and prepare piece agent.Preferably, d) described in the medical additive be selected from it is micro-
The pharmaceutically acceptable additive such as crystalline cellulose, starch, povidone and magnesium stearate；Or
E) by the solid particulate matter and site specific DDS for colon material, optionally and medical additive, after mixing tabletting be prepared into
Enteric coatel tablets.Preferably, e) described in the medical additive be selected from microcrystalline cellulose, starch, povidone and magnesium stearate etc.
Pharmaceutically acceptable additive.
In the preparation method of above-mentioned double enteric solid preparations, it is preferable that the site specific DDS for colon material can be pH sensibility
(such as shell is poly- for polymer (such as crylic acid resin, such as Eudragit S100, Eudragit L100), natural polysaccharide substance
Sugar, pectin, Pectin calcium) and one or more of azobenzene polymer class etc. mixture.Preferably Eudragit S100,
Pectin or Pectin calcium.
According to another aspect of the present invention, purposes of the solid particulate matter in medicine preparation is provided.
According to a further aspect of the invention, a kind of pharmaceutical composition is provided, it includes the solid particulate matters or described
Double enteric solid preparations.
Advantageous effect
The double enteric solid preparations of the present invention for being loaded with polypeptide protein class drug have to be stablized in acid condition,
The characteristics of being dissolved under conditions of pH >=7.And the pH of alimentary canal Stomach duodenum, upper part of small intestine is respectively less than 6.5, so described double
Enteric solid preparation cannot be dissolved destruction at above-mentioned position, avoid the drug release in advance of preparation, be effectively protected polypeptide protein
Class drug improves stability of the drug in enteron aisle from the proteasome degradation in enteron aisle.
Sorbefacient and protease inhibitors are added in the solid particulate matter, polypeptide protein class medicine can be effectively facilitated
Object cross-film inhibits polypeptide protein class drug by the degradation of protease in enteron aisle, to improve the oral life of polypeptide protein class drug
Object curative effect.
Method of the present invention have preparation process it is simple, it is easy to implement, it is required at low cost the features such as.
Description of the drawings
Fig. 1 displays prepare the SEM figures of the insulin granule prepared in embodiment 1；
Fig. 2 is shown in the release in vitro result figure for preparing the insulin granule capsulae enterosolubilis prepared in embodiment 9；
Fig. 3 is shown in the internal blood sugar decreasing effect figure for preparing the insulin granule capsulae enterosolubilis prepared in embodiment 9；
Fig. 4 is shown in the internal rush assimilation effect figure for preparing the insulin granule capsulae enterosolubilis prepared in embodiment 9；
Fig. 5 is shown in the internal hypoglycemic figure for preparing the Exenatide particle capsulae enterosolubilis prepared in embodiment 10.
Specific implementation mode
The present invention is described in further detail with reference to specific embodiment, and with reference to data.It should be understood that these embodiments are
In order to demonstrate the invention, it is intended to illustrate specific formula composition, preparation method and its function and the effect of the present invention, rather than with
Any mode limits the scope of the invention.In the examples below, the various processes and method not being described in detail are in this field
Well known conventional method.
In the present invention, agents useful for same, the source of equipment and trade name are indicated on the first appearance, used thereafter identical
Reagent is unless otherwise specified, identical as the content indicated for the first time, and the conventional reagent that do not mark has purchased from Chinese medicines group chemical reagent
Limit company.Wherein, insulin is purchased from Xuzhou Wanbang Jinqiao Pharmaceutical Co., Ltd., N- [8- (2- hydroxy benzoyls) amino] octanoic acids
Sodium (SNAC) is purchased from Shanghai Bo Shi Pharmaceuticals Ltds, and Exenatide, salmon calcitonin are purchased from Aladdin reagent Co., Ltd, press down peptide
Enzyme, trypsin inhibitor are purchased from Aladdin reagent Co., Ltd, and sodium taurocholate is purchased from traditional Chinese medicines agent radical Co., Ltd, hydroxypropyl first
Cellulose phthalate (HPMCP) is purchased from straight Jiangjin factory of Shin-Etsu Chemial Co., Ltd, Utech (Eudragit
S100, L100) purchased from wound industrial group is won, Pectin calcium is purchased from upper Hisense's sail biology scientific research institution.
Experimental animal：Healthy SD rat 36, male, weight 200-220g, source are that the experiment of Shanghai institute of materia medica is dynamic
Object center.Animal subject carries out adaptability raising in 1-2 weeks a few days ago in experiment in test site.All zooperies obtain Shanghai
The approval of the IACUC committees of institute of materia medica.
Prepare embodiment
Prepare the preparation of the insulin granule of 1 Eudragit S100 packages of embodiment
100mg SNAC are dissolved in the NaOH of 1mL 0.01M, and 10mg insulin (Ins) is dissolved in 1mL 0.01M's
It is added to after NaOH aqueous solutions in SNAC solution and forms uniform solution (A)；500mg Eudragit S100 are added to 48mL's
It is appropriate to heat in the tert-butyl alcohol (water containing 5mL), so that it is fully dissolved and forms uniform solution (B)；A is slowly added into B, with
After 500r/min vortex mixeds form uniform solution, the pancreas of Eudragit S100 packages is prepared using atomizing freeze drying technology
Island crude granule.
Prepare the preparation of the insulin granule containing protease inhibitors of 2 Eudragit S100 packages of embodiment
100mg SNAC are dissolved in the NaOH of 1mL 0.01M, and 10mg Ins and 10mg Aprotinins are dissolved in 1mL 0.01M
NaOH aqueous solutions after be added in SNAC solution formed uniform solution (A)；500mg Eudragit S100 are added to 23mL
The tert-butyl alcohol in (water containing 2mL), it is appropriate to heat, so that it is fully dissolved and form uniform solution (B)；A is slowly added into B, with
After 500r/min vortex mixeds form uniform solution, the pancreas of Eudragit S100 packages is prepared using atomizing freeze drying technology
Island crude granule.
Prepare the preparation of the insulin granule containing protease inhibitors of 3 Eudragit S100 packages of embodiment
200mg SNAC are dissolved in the NaOH of 1mL 0.01M, and 10mg Ins and 10mg Aprotinins are dissolved in 1mL 0.01M
NaOH aqueous solutions after be added in SNAC solution formed uniform solution (A)；400mg Eudragit S100 are added to 23mL
The tert-butyl alcohol in (water containing 2mL), it is appropriate to heat, so that it is fully dissolved and form uniform solution (B)；A is slowly added into B, with
After 500r/min vortex mixeds form uniform solution, the pancreas of Eudragit S100 packages is prepared using atomizing freeze drying technology
Island crude granule.
Prepare the preparation of the insulin granule containing protease inhibitors of embodiment 4 HPMCP packages
200mg SNAC are dissolved in the NaOH of 1mL 0.01M, and 10mg Ins and 10mg Aprotinins are dissolved in 1mL 0.01M
NaOH aqueous solutions after be added in SNAC solution formed uniform solution (A)；400mg HPMCP are added in 48mL water, are fitted
Work as heating, so that it is fully dissolved and form uniform solution (B)；A is slowly added into B, is formed with 500r/min vortex mixeds
After one solution, the insulin granule of HPMCP packages is prepared using spray drying technology.
Prepare the preparation of the Exenatide particle containing protease inhibitors of 5 Eudragit S100 packages of embodiment
200mg SNAC are dissolved in the NaOH of 1mL 0.01M, and 10mg Exenatides and 100mg Aprotinins are dissolved in 4mL
It is added to after the NaOH aqueous solutions of 0.01M in SNAC solution and forms uniform solution (A)；400mg Eudragit S100 are added
It is appropriate to heat to (water containing 2mL) in the tert-butyl alcohol of 25mL, so that it is fully dissolved and forms uniform solution (B)；A is slowly added into B
In, after forming uniform solution with 500r/min vortex mixeds, Eudragit S100 packages are prepared using atomizing freeze drying technology
Exenatide particle.
Prepare the preparation of the Exenatide particle containing protease inhibitors of 6 Eudragit S100 packages of embodiment
400mg SNAC are dissolved in the NaOH of 1mL 0.01M, and 10mg Exenatides and 100mg Aprotinins are dissolved in 4mL
It is added to after the NaOH aqueous solutions of 0.01M in SNAC solution and forms uniform solution (A)；400mg Eudragit S100 are added
It is appropriate to heat to (water containing 2mL) in the tert-butyl alcohol of 25mL, so that it is fully dissolved and forms uniform solution (B)；A is slowly added into B
In, after forming uniform solution with 500r/min vortex mixeds, Eudragit S100 packages are prepared using atomizing freeze drying technology
Exenatide particle.
Prepare the insulin granule containing protease inhibitors that 7 emulsion process of embodiment prepares Eudragit S100 packages
40mg SNAC are dissolved in the NaOH aqueous solutions of 0.5mL 0.01M, and 2mg Ins and 2mg Aprotinins are dissolved in
It is added in SNAC solution after the NaOH aqueous solutions (containing 1% polysorbas20) of 0.5mL 0.01M and forms uniform solution (A)；By 80mg
Eudragit S100 are added in the ethanol/dichloromethane of 4mL (ethyl alcohol：Dichloromethane=1:4), fully dissolving is formed
One solution (B)；A is slowly added into B, after 500r/min vortex mixeds formation W/O lotions after (C), (C) is slowly added dropwise
W/O/O microballoons are formed to (1% sorbester p17 is contained) in 50mL atoleines；N-hexane solidified microsphere is added, continues to stir 1.5h, just
Hexane cleans 3 times, and microballoon is put into the insulin granule that vacuum drying chamber drying obtains Eudragit S100 packages afterwards for 24 hours.
Prepare the preparation of the salmon calcitonin particle of 8 Eudragit L100 packages of embodiment
300mg sodium taurocholates are dissolved in 5mL H2O, and 10mg salmon calcitonins and 100mg trypsin inhibitors are dissolved in 5mL
It is added to after the NaOH aqueous solutions of 0.01M in sodium cholate solution and forms uniform solution (A)；400mg Eudragit L100 are added
Enter into the tert-butyl alcohol of 50mL (water containing 10mL), it is appropriate to heat, so that it is fully dissolved and forms uniform solution (B)；A is slowly added to
Into B, after forming uniform solution with 500r/min vortex mixeds, Eudragit L100 are prepared using atomizing freeze drying technology
The salmon calcitonin particle of package.
Prepare the preparation of capsulae enterosolubilis of the embodiment 9 equipped with insulin granule
Take the preclinical capsules of filling No. 9 Pccaps of insulin granule (Capsugel, the U.S. for preparing and being prepared in embodiment 2,3
State), capsule is then put into coating pan and is coated with 15% Eudragit S100 ethanol solutions.Average weight gain is 15%.
Prepare the preparation of capsulae enterosolubilis of the embodiment 10 equipped with Exenatide particle
Take prepare embodiment 5,6 in prepare No. 9 preclinical capsules of Pccaps of Exenatide granule filling (Capsugel,
The U.S.), capsule is then put into coating pan and is coated with 10% pectin solution.Average weight gain is 10%.
Prepare the preparation of enteric coatel tablets of the embodiment 11 equipped with insulin granule
With pressure after taking the insulin granule for preparing and being prepared in embodiment 2 to be mixed with starch, microcrystalline cellulose and magnesium stearate
Piece machine is tabletted, and tablet is then put into coating pan is coated with 15% Eudragit S100 ethanol solutions.It is average
Weightening is 15%.
Prepare the preparation of enteric coatel tablets of the embodiment 12 equipped with insulin granule
The insulin granule for preparing and being prepared in embodiment 2 is taken to be mixed with Pectin calcium, starch, microcrystalline cellulose and magnesium stearate
40 mesh sieve is crossed afterwards, it is tabletted with tablet press machine.
Each medicinal ingredient and its content in the solid particulate matter for preparing and being prepared in embodiment 1-8 are listed in the following table 1
And prepare the preparation method of double enteric solid preparations prepared by embodiment 9-12 and final dosage form.
Table 1
EXPERIMENTAL EXAMPLE
EXPERIMENTAL EXAMPLE 1
Insulin granule form and grain size
The insulin granule for preparing the Eudragit S100 packages prepared in embodiment 1 is taken to carry out ion sputtering process plated film
It uses scanning electron microscope Electronic Speculum SEM (Phenom XL, Netherlands) to observe afterwards, finds insulin granule form spherical in shape, specifically
As a result Fig. 1 is referred to.Wherein the grain size of 90% particle of solid particulate matter is no more than 500 μm, and Average Particle Diameters are about 10 μm.
EXPERIMENTAL EXAMPLE 2
Insulin granule encapsulation rate and drugloading rate measure
1, instrument：1200 high performance liquid chromatographs of Agilent (Agilent companies of the U.S.)；Supercentrifuge (Allegra
64R, Beckman Coulter, the U.S.).Reagent：Insulin granule (is prepared) according to herein described method；Acetonitrile (chromatography
It is pure, sigma, the U.S.)；Water is Milli-Q ultra-pure waters, and other reagents such as phosphoric acid are that analysis is pure.
2, chromatographic condition：Chromatographic column：Grace Vydac 218TP C18 columns (250mm × 4.6mm, 5 μm, U.S.'s Grace
Company)；Mobile phase：0.1M disodium hydrogen phosphates buffer solution (phosphoric acid tune pH=3.0):Acetonitrile (72:28, v/v)；Flow velocity：1mL/
min；Column temperature：40℃；Detection wavelength：214nm.
3, assay method：It takes the present invention to prepare insulin granule 10mg obtained in embodiment 1 and is dissolved in 95% ethyl alcohol of 1mL
(containing 100 μ L 0.01M NaOH) makes microballoon dissolving release Ins, with the pancreas islet that HPLC detections are wrapped after adding mobile phase to be acidified
Cellulose content.
Measurement result：The encapsulation rate for preparing the insulin granule drug prepared in embodiment 1 is about 90.66%, drugloading rate
About 14.68%.
EXPERIMENTAL EXAMPLE 3
By the insulin solid particle prepared in embodiment 2 and prepare the capsulae enterosolubilis loading dialysis prepared in embodiment 9
It is respectively put into bag in the buffer solution that 500mL pH value is 1.2, buffer solution is placed under the conditions of 37 DEG C and is stirred with 100rpm, in 2h
Respectively at 30min, 60min, 90min, 120min point in time sampling buffering is measured in the HPLC methods described in EXPERIMENTAL EXAMPLE 2
Insulin content in liquid.Bag filter is taken out to be put into the buffer solution of pH 4.5 after 2h and detects different time points insulin releasing
Amount.Identical method detects burst size of the insulin in pH 6.8,7.4 buffer solutions respectively.
As a result it is shown in Fig. 2, insulin solid particulate matter can discharge insulin in the buffered environment of pH 6.8.In order to anti-
Only insulin discharges in advance, therefore insulin solid particulate matter is packed into conventional capsule and carries out secondary coating.The result shows that
Eudragit S100 enteric coated capsules in the acidic environment of pH 1.4,4.5 and in the weak acid environment of pH6.8 not
Insulin is discharged, and can smoothly release insulin in the environment of pH 7.4, the insulin of release about 90% in 1h.As a result
Show that insulin granule capsulae enterosolubilis of the present invention can protect insulin preparation to resist the acidic environment in stomach, is not released in stomach
It puts, and starts to discharge insulin after entering colon.
EXPERIMENTAL EXAMPLE 4
After 12 Sprgue-dawley rats are weighed, STZ (streptozotocin) is weighed by the dosage of 65mg/kg, is used
0.1M citrate buffers (pH=4.5) dissolve, immediately in intraperitoneal injection to rat body.Raising after a week, surveys blood glucose, blood glucose value
Rat higher than 16.67mM is used for subsequent experimental.Experimental animal is randomized into 3 groups, and fasting 12h, can't help water before being administered.First
Group is oral insulin control group (30IU/kg) (control group), is given mixed equipped with insulin, sorbefacient, Aprotinin physics
Close the Eudragit S100 enteric coating capsulae enterosolubilis of object；Second group is the insulin granule for preparing embodiment 9 and preparing
Eudragit S100 enteric coated capsule groups (30IU/kg, SNAC:Ins=10:1)；Third group is to prepare embodiment 9 to prepare
Insulin granule Eudragit S100 enteric coated capsule groups (30IU/kg, SNAC:Ins=20:1)；Respectively 0h, 1h, 2h,
3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h tail vein take blood, and blood glucose level, statistics insulin drop are measured with blood glucose meter
Hypoglycemic effect.
As a result it is shown in Fig. 3, compared with the control group for not being prepared into enteric coated particles, is loaded with the Eudragit of insulin granule
S100 coated capsules (double capsulae enterosolubilis) are there are significant blood sugar decreasing effect, and blood glucose reduces about 40% in 12h.And this drop
Sustainable 10 hours of the effect of blood glucose.
EXPERIMENTAL EXAMPLE 5
After 12 Sprgue-dawley rats are weighed, STZ (streptozotocin) is weighed by the dosage of 65mg/kg, is used
0.1M citrate buffers (pH=4.5) dissolve, immediately in intraperitoneal injection to rat body.Raising after a week, surveys blood glucose, blood glucose value
Rat higher than 16.67mM/L is used for subsequent experimental.Experimental animal is randomized into 4 groups, and fasting 12h, can't help water before being administered.The
One group is subcutaneous insulin injections solution group (5IU/kg)；Second group is the insulin granule for preparing embodiment 9 and preparing
Eudragit S100 enteric coated capsule groups (30IU/kg, SNAC:Ins=10:1)；Third group is to prepare embodiment 9 to prepare
Insulin granule Eudragit S100 enteric coated capsule groups (30IU/kg, SNAC:Ins=20:1).Respectively 0h, 1h, 2h,
Orbital venous plexus takes blood when 3h, 4h, 5h, 6h, 8h, 10h and 12h, and serum insulin is detected with insulin ELISA kit
Concentration draws pharmacokinetic curve.
As a result it is shown in Fig. 4, the results showed that the double capsulae enterosolubilis of Eudragit S100 coatings for being loaded with insulin granule exist
SNAC:Ins=20:Significantly improve the concentration of serum insulin when 1, when 4h can detect serum insulin concentration it is notable on
It rises, when 5h reaches peak value.Its bioavilability of relative insulin solution hypodermic injection group is about 7%.
EXPERIMENTAL EXAMPLE 6
After 12 normal Sprgue-dawley rats are weighed, 4 groups are randomly divided into, fasting 12h, can't help water before being administered.
First group is blank control group, is not administered；Second group is hypodermic injection Exenatide physiological saline group (10ug/kg)；Third group
For oral Exenatide particle Eudragit S100 enteric coated capsule groups (30IU/kg, the SNAC for preparing embodiment 10 and preparing:
Exenatide=20:1)；4th group is the oral Exenatide particle Eudragit S100 enteric packets for preparing embodiment 10 and preparing
Clothing Capsules group (30IU/kg, SNAC:Exenatide=40:1).Each group rat simulates meal in the glucose solution of 0h gavages 1g/kg
State afterwards, and the drug administration by injection of 10 μ g/kg is carried out to injection group rat.Oral group 2h gavages enteric glue before gavage glucose
Capsule.Each group rat tail vein when respectively in 0h, 0.5h, 1h, 1.5h, 2h, 3h, 4h takes blood, and blood glucose is measured with blood glucose meter
Level counts each group of blood sugar decreasing effect.
As a result be shown in Fig. 5, be loaded with Exenatide particle Eudragit S100 coated capsules (double capsulae enterosolubilis) its control
Hypoglycemic effect is similar with injection group, wherein SNAC:Exenatide=40:1 group of control hypoglycemic effect is best.
Claims (10)
1. a kind of solid particulate matter being loaded with polypeptide protein class drug comprising：
The polypeptide protein class drug of the parts by weight of 0.5 parts by weight~90；
The sorbefacient of the parts by weight of 0.5 parts by weight~90；
The protease inhibitors of the parts by weight of 0 parts by weight~50；And
The enteric material of the parts by weight of 5 parts by weight~90, and
Wherein, the average grain diameter of the solid particulate matter is 0.1~2000 μm.
2. solid particulate matter according to claim 1, wherein
The polypeptide protein class drug is the polypeptide protein class drug with pharmacological activity, such as insulin and the like, Ai Sai
That peptide, calcitonin, recombinant human parathyroid hormone, hematopoietin, Filgrastim, life length swash
Element, interleukins, cyclosporin, epidermal growth factor, GLP-1 analogs or interferon；And/or
The sorbefacient is N- (8- [2- (2-hydroxybenzoyl)s] amino) octanoic acids and its derivative, medium chain fatty acid and its salt
Class, bile acid and its derivative, ethylenediamine tetra-acetic acid or its salt or combination thereof；And/or
The protease inhibitors be trypsin inhibitor, cystatin, serine/threonine protein enzyme inhibitor,
Asparaginic acid protease inhibitors or metal protease inhibitors；And/or
The enteric material is the combination of a kind of enteric material or two or more enteric materials, is preferably selected from phthalic acid second
Acid cellulose, hypromellose phthalate, polyvinyl acetate phthalate, Eudragit S100,
Eudragit L100 and shellac it is one or more.
3. a kind of method preparing solid particulate matter as claimed in claim 1 or 2 comprising following steps：
1) polypeptide protein class drug, sorbefacient, protease inhibitors are dissolved in aqueous phase solution, form (A) solution,
Middle polypeptide protein class drug is 100 with sorbefacient mass ratio:1~1:100, polypeptide protein class drug and protease inhibitors
Mass ratio is 100:1~1:100；
2) Enteric Materials are dissolved in solvent, form (B) solution, a concentration of 1mg/mL~200mg/mL of enteric material；With
And
3) (A) solution is added into (B) solution at room temperature, the volume ratio of (A) solution and (B) solution is 1:10~1:100, shape
At uniform solution, after be dried the solid particulate matter be prepared.
4. according to the method described in claim 3, wherein,
Aqueous phase solution in step 1) is the aqueous solution of water, phosphate buffer, ethanol water, the aqueous solution of acid or alkali, excellent
The aqueous solution of selection of land, the alkali be the aqueous solution of sodium hydroxide, potassium hydroxide or ammonia and the aqueous solution of the acid be hydrochloric acid,
The aqueous solution of phosphoric acid or acetic acid；And/or
Solvent in step 2) is the combination of water, ethyl alcohol, the tert-butyl alcohol, dichloromethane or their arbitrary proportion.
5. a kind of method preparing solid particulate matter as claimed in claim 1 or 2 comprising following steps：
1) polypeptide protein class drug, sorbefacient, protease inhibitors are dissolved in the aqueous phase solution containing surfactant,
Form (A) solution；Wherein polypeptide protein class drug and sorbefacient mass ratio are 100:1~1:100；Polypeptide protein class drug
It is 100 with protease inhibitors mass ratio:1~1:100；
2) enteric material is dissolved in solvent, forms (B) solution, a concentration of 1mg/mL~200mg/mL of enteric material；
3) (A) solution is added into (B) solution at room temperature, the volume ratio of (A) solution and (B) solution is 1:1~1:100, shape
At W/O water-in-oil emulsions (C)；
4) lotion (C) that step 3) obtains is slowly added into the solvent containing surfactant (D), lotion (C) and solvent (D)
Volume ratio be 1:1~1:100, organic solvent (E) cured granulate is added after stirring under room temperature；And
5) solid particulate matter will be obtained after particle drying in step 4).
6. according to the method described in claim 5, wherein,
Aqueous phase solution in step 1) is the aqueous solution of water, phosphate buffer, ethanol water, the aqueous solution of acid or alkali, excellent
The aqueous solution of selection of land, the alkali be the aqueous solution of sodium hydroxide, potassium hydroxide or ammonia and the aqueous solution of the acid be hydrochloric acid,
The aqueous solution of phosphoric acid or acetic acid；And/or
Solvent in step 2) be the tert-butyl alcohol, dichloromethane, chloroform etc. or they and water, ethyl alcohol arbitrary proportion combination；With/
Or
The solvent in solvent (D) described in step 4) containing surfactant is paraffin, cottonseed oil, soybean oil；And/or
The organic solvent (E) in step 4) is selected from pentane, n-hexane or normal heptane.
7. a kind of double enteric solid preparations of oral polypeptide protein class drug, it includes solid particles as described in claim 1
Object and site specific DDS for colon material.
8. double enteric solid preparations according to claim 7, wherein
The site specific DDS for colon material is one kind in pH sensitive polymers, natural polysaccharide substance and azobenzene polymer class
Or two or more mixture.
9. a kind of preparation method of double enteric solid preparations as claimed in claim 7 comprising following any method：
A) it by solid particulate matter described in claim 1, optionally with medical additive, after pouring into common gelatine capsule, uses
One or more of site specific DDS for colon material mixture is coated, and is prepared into capsule；
B) by solid particulate matter described in claim 1, optionally with medical additive, the capsule of the material containing site specific DDS for colon is poured into
Shell is prepared into capsule；
C) using the mixing of one or more of site specific DDS for colon material after solid particulate matter described in claim 1 being pelletized
Object is coated, and is prepared into enteric-coated micro-pill；
D) it by solid particulate matter described in claim 1, is optionally mixed with medical additive, after tabletting, using site specific DDS for colon
One or more of material mixture is coated, and prepares piece agent；Or
E) by solid particulate matter described in claim 1 and site specific DDS for colon material, optionally and medical additive, tabletting after mixing
It is prepared into enteric coatel tablets.
10. a kind of purposes of solid particulate matter as claimed in claim 1 or 2 in medicine preparation.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110974943A (en) * | 2019-12-09 | 2020-04-10 | 广东药科大学 | Oral insulin pharmaceutical preparation and preparation method thereof |
| CN111643478A (en) * | 2020-06-29 | 2020-09-11 | 上海舒泽生物科技研究所 | Preparation method of acrylic resin-coated recombinant human auxin microcapsule |
| CN112587496A (en) * | 2020-12-16 | 2021-04-02 | 江苏海洋大学 | Exenatide enteric capsule and preparation method thereof |
| CN112956699A (en) * | 2021-01-27 | 2021-06-15 | 上海海洋大学 | Hypoglycemic peptide enteric solid dispersion and preparation method thereof |
| CN113117050A (en) * | 2021-05-06 | 2021-07-16 | 合肥天汇孵化科技有限公司 | Polypeptide composition and application thereof |
| CN113230232A (en) * | 2021-05-14 | 2021-08-10 | 中国药科大学 | PH-sensitive degradable zwitterionic microcapsule and preparation method and application thereof |
| CN114903865A (en) * | 2021-01-29 | 2022-08-16 | 中国科学院过程工程研究所 | Oral capsule and preparation method and application thereof |
| WO2023065231A1 (en) * | 2021-10-21 | 2023-04-27 | Guangzhou Dazhou Biomedicine Ltd. | Oral delivery of therapeutic agents |
| WO2023098777A1 (en) * | 2021-12-01 | 2023-06-08 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of glp-1 and gip receptor dual agonist and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557282A (en) * | 2004-01-17 | 2004-12-29 | 浙江大学 | Modified water-soluble medicine and vaccine embedded macromolecule microsphere preparation method |
| WO2008132727A2 (en) * | 2007-04-26 | 2008-11-06 | Technion Research And Development Foundation Ltd | Oral delivery of proteins and peptides |
| CN102274190A (en) * | 2010-06-11 | 2011-12-14 | 上海现代药物制剂工程研究中心有限公司 | Paclitaxel alhumin submicron for injection and preparation method thereof |
| CN102123697B (en) * | 2008-08-18 | 2015-06-10 | 安特拉贝欧有限公司 | Methods and compositions for oral administration of proteins |
-
2017
- 2017-04-01 CN CN201710212881.7A patent/CN108653234B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557282A (en) * | 2004-01-17 | 2004-12-29 | 浙江大学 | Modified water-soluble medicine and vaccine embedded macromolecule microsphere preparation method |
| WO2008132727A2 (en) * | 2007-04-26 | 2008-11-06 | Technion Research And Development Foundation Ltd | Oral delivery of proteins and peptides |
| CN102123697B (en) * | 2008-08-18 | 2015-06-10 | 安特拉贝欧有限公司 | Methods and compositions for oral administration of proteins |
| CN102274190A (en) * | 2010-06-11 | 2011-12-14 | 上海现代药物制剂工程研究中心有限公司 | Paclitaxel alhumin submicron for injection and preparation method thereof |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110974943A (en) * | 2019-12-09 | 2020-04-10 | 广东药科大学 | Oral insulin pharmaceutical preparation and preparation method thereof |
| CN111643478A (en) * | 2020-06-29 | 2020-09-11 | 上海舒泽生物科技研究所 | Preparation method of acrylic resin-coated recombinant human auxin microcapsule |
| CN112587496A (en) * | 2020-12-16 | 2021-04-02 | 江苏海洋大学 | Exenatide enteric capsule and preparation method thereof |
| CN112956699A (en) * | 2021-01-27 | 2021-06-15 | 上海海洋大学 | Hypoglycemic peptide enteric solid dispersion and preparation method thereof |
| CN114903865A (en) * | 2021-01-29 | 2022-08-16 | 中国科学院过程工程研究所 | Oral capsule and preparation method and application thereof |
| CN114903865B (en) * | 2021-01-29 | 2024-01-16 | 中国科学院过程工程研究所 | Oral capsule and preparation method and application thereof |
| CN113117050A (en) * | 2021-05-06 | 2021-07-16 | 合肥天汇孵化科技有限公司 | Polypeptide composition and application thereof |
| CN113117050B (en) * | 2021-05-06 | 2022-04-26 | 合肥天汇孵化科技有限公司 | Polypeptide composition and application thereof |
| CN113230232A (en) * | 2021-05-14 | 2021-08-10 | 中国药科大学 | PH-sensitive degradable zwitterionic microcapsule and preparation method and application thereof |
| WO2023065231A1 (en) * | 2021-10-21 | 2023-04-27 | Guangzhou Dazhou Biomedicine Ltd. | Oral delivery of therapeutic agents |
| WO2023098777A1 (en) * | 2021-12-01 | 2023-06-08 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of glp-1 and gip receptor dual agonist and use thereof |
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