CN107308159A - One kind improves isradipine bioavilability pharmaceutical composition - Google Patents
One kind improves isradipine bioavilability pharmaceutical composition Download PDFInfo
- Publication number
- CN107308159A CN107308159A CN201710635695.4A CN201710635695A CN107308159A CN 107308159 A CN107308159 A CN 107308159A CN 201710635695 A CN201710635695 A CN 201710635695A CN 107308159 A CN107308159 A CN 107308159A
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- China
- Prior art keywords
- isradipine
- antioxidant
- pharmaceutical composition
- sodium
- medicine
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Abstract
The invention discloses the isradipine pharmaceutical composition that bioavilability is improved.Present invention firstly provides a kind of method for improving isradipine drug bioavailability, this method includes：The isradipine medicine of effective dose is used in combination with antioxidant or complexing of metal ion agent；The present invention still further provides the pharmaceutical composition using isradipine medicine as active component that a kind of bioavilability is improved, wherein including antioxidant.Described antioxidant includes but is not limited to free base absorbant, metal ion chelation agent, oxygen scavenger, peroxide decomposer or enzyme antioxidant.
Description
Technical field
The present invention relates to isradipine pharmaceutical composition, more particularly to the isradipine drug regimen that bioavilability is improved
Thing, belongs to isradipine field of pharmaceutical preparations.
Background technology
Isradipine (Isradipine) is a kind of new dihydropyridine calcium channel blocker.It is by expanding blood
Pipe, reduces peripheral vascular resistance, increases coronary blood flow, improves myocardial oxygen delivery function and reaches the purpose reduced blood pressure.The medicine
Developed, pushed away first by Britain's vapour bar-Jia Ji (Ciba-Geigy) company by Switzerland mountain pass scholar (Sandoz) company within 2 months 1989
Upper market.
Isradipine medicine is known in the treatment of hypertension and coronary heart disease and in other applications highly effective fruit
Compound.But isradipine medicine water solubility is relatively low (dissolubility is poor), causes the bioavilability of active component relatively low,
Not only there is certain difficulty on the pharmaceutical preparation of medical domain, and because isradipine drug bioavailability is low, lead
Cause its curative effect in clinical practice not ideal enough, there is to be solved.
The content of the invention
An object of the present invention is to provide a kind of method for improving isradipine drug bioavailability；
The second object of the present invention is to provide the isradipine pharmaceutical composition that a kind of bioavilability is improved
To achieve the above object, the technical solution used in the present invention is：
The present invention has found metal ion (such as Fe with oxidisability first3+) in acid condition, can be by isradipine medicine
Thing is aoxidized；According to the literature, it is in most foods to contain Fe more3+, for example, Fe in the skin of soya-bean milk3+Account for total iron more than 40%, purple
Fe in dish3+Account for total iron more than 60%, wherein 100g seaweeds Fe containing more than 30mg3+；Therefore, patient contains Fe edible3+Food
Afterwards, the Fe in small isradipine medicine, food is taken3+In acid condition (hydrochloric acid in gastric juice) can rapidly by isradipine oxidation of drug,
The curative effect that medicine should originally be played not only is lost, adverse reaction is can also result in.
The present invention is further had found by zoopery, has been gavaged ascorbic Beagle dogs and has been gavaged isradipine again
Piece, is detected with LC-MS/MS and gathers blood sample drug concentration at different time points；Testing result is found, compared to not gavaging dimension
Raw element C normal group, increase vitamin C can effectively improve the bioavilability of isradipine before isradipine is gavaged；
The Beagle dogs for having gavaged seaweed gavage isradipine piece again, and the bioavilability of isradipine is substantially lower will.
Thus, present invention firstly provides a kind of method for improving isradipine drug bioavailability, this method includes：
The isradipine medicine of effective dose is used in combination with antioxidant or complexing of metal ion agent；It is wherein, described to be used in combination,
Can be by isradipine medicine and antioxidant or complexing of metal ion agent and meanwhile use or first using antioxidant or
Complexing of metal ion agent, reuses isradipine medicine.
Described antioxidant includes but is not limited to free base absorbant, metal ion chelation agent, oxygen scavenger, peroxidating
Thing distintegrant or enzyme antioxidant etc..For example, it may be ascorbic acid, sodium ascorbate, arabo-ascorbic acid, arabo-ascorbic acid
The derivatives such as sodium, ascorbyl palmitate, glutathione, vitamin E, Tea Polyphenols, anthocyanidin, β-carrotene, tomato red
Element, cysteine hydrochloride, niter cake, sodium metabisulfite, sulfurous acid vitamin-c palmitate sodium, butylhydroxy anisole
(BHA), butylated hydroxytoluene (BHT), propylgallate, tocopherol, citric acid, EDTA, reduced sugar glucose or lactose
Deng.
The present invention still further provides the medicine using isradipine medicine as active component that a kind of bioavilability is improved
Compositions, wherein containing antioxidant.
Described antioxidant includes but is not limited to free base absorbant, metal ion chelation agent, oxygen scavenger, peroxidating
Thing distintegrant or enzyme antioxidant etc..For example, it may be ascorbic acid, sodium ascorbate, arabo-ascorbic acid, arabo-ascorbic acid
The derivatives such as sodium, ascorbyl palmitate, glutathione, vitamin E, Tea Polyphenols, anthocyanidin, β-carrotene, tomato red
Element, cysteine hydrochloride, niter cake, sodium metabisulfite, sulfurous acid vitamin-c palmitate sodium, butylhydroxy anisole
(BHA), butylated hydroxytoluene (BHT), propylgallate, tocopherol, citric acid, EDTA, reduced sugar glucose or lactose etc..
Described pharmaceutical composition can include pharmaceutically acceptable salt or ester.
Described pharmaceutical composition may further include pharmaceutically acceptable carrier or diluent.Suitably in drug regimen
Carrier, diluent and the excipient used in thing is known in the field.
Described pharmaceutical composition can further include one or more reagents, and the reagent is selected from：Antiseptic, tension force
Conditioning agent or assistant for emulsifying agent
The assistant for emulsifying agent can be selected from：Glycerine (or glycerine), poloxamer (poloxamers),
CremophorTM, the husky amine (poloxamine) in pool Lip river, stearic acid polyoxyethylene, Polyoxyethylene Sorbitol Fatty Acid Esters, sorbierite
Fatty acid ester, polysorbate, tocopheryl succinate PEG, cholic acid, deoxycholic aicd, oleic acid and its pharmaceutically acceptable salt.
Suitable pharmaceutical preparation can be made in the pharmaceutical composition of the present invention, such as oral, sublingual, intranasal, eye
Interior, rectum, transdermal, mucous membrane, the preparation of part or parenteral.Parenteral can include intracutaneous, subcutaneous, intramuscular, quiet
Arteries and veins, abdominal cavity, intra-arterial, in marrow, in heart, intra-articular (joint), intrasynovial (joint fluid region), encephalic, in backbone and intrathecal
(spinal fluid).Any device suitable for parental injection or infusion pharmaceutical preparation may be incorporated for such administration.For example, can be by
Pharmaceutical composition is placed in sterile precharging type syringe.
In some other embodiments, according to the invention provides the preparation method of the medicine.The preparation method
It can include mixing isradipine and pharmaceutically acceptable carrier or diluent.The preparation method can also be included her
Horizon is drawn to be mixed with lipid, emulsifying agent and water.
Preferably, the isradipine or its pharmaceutically acceptable salt or ester.Methods described, which may further include, to be added
Enter one or more reagents selected from the group being made up of antiseptic, tension regulator, antioxidant and assistant for emulsifying agent；Regulation mixing
The pH of thing is placed in sterile precharging type syringe to about 6.0-8.8, or by the medicine.
, just can be very by binding activity compound and pharmaceutical carrier well known in the art or excipients for oral
Corresponding oral drug preparation is readily prepared, for example, piece agent, powder, pill, dragee, capsule, liquid can be prepared
Preparation, gel, supensoid agent etc.；
Appropriate carrier or excipients can be adhesive, wetting agent, filler, diluent, disintegrant or glidant etc.；
Spices, dehydrating agent, colouring agent, sweetener, coating agent, preservative etc. can also be included.
For example, described diluent can be calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, sucrose, sweet dew
Sugar or D-sorbite etc.；
Described adhesive can be carboxymethyl cellulose, sodium carboxymethylcellulose, microcrystalline cellulose, gelatin, hydroxypropyl
Methylcellulose, carboxyethyl cellulose or carboxylic propyl methocel etc.；
Described disintegrant can be sodium carboxymethylcellulose, calcium carboxymethylcellulose, calcium phosphate, polyvinylpyrrolidine
Ketone, agar or alginic acid etc..
The wetting agent can be Macrogol 4000, Macrogol 6000, lauryl sodium sulfate, starch (corn shallow lake
Powder, wheaten starch, farina etc.), talcum etc.；
The glidant can be calcium silicates, starch, powdery cellulose etc..
Brief description of the drawings
Fig. 1 is mean blood plasma concentration-time plot in each group dog plasma of LC-MS/MS measure different time points.
Embodiment
The invention will now be further described with reference to specific embodiments, advantages of the present invention and feature will be with description and
It is apparent.It should be understood that the embodiment is only exemplary, any limitation is not constituted to the scope of the present invention.This area
Technical staff should be understood that without departing from the spirit and scope of the invention can to the details of technical solution of the present invention and
Form is modified or replaced, but these modifications or substitutions each fall within protection scope of the present invention.
Experimental example 1
Health Beagle dogs 12 are selected, three groups is randomly divided into, every group 4, respectively feeds normal group, seaweed and (contain Fe3
+ ion) organize and vitamin C group.During experiment, Beagle dog overnight fastings are not cut off the water supply (feed deionized water) at least 12h, collection
Venous blood, separated plasma is used as 0h blood concentration sample.Then start according to experiment packet feeding, normal group dog not feeding
Thing, seaweed group dog gavage 100ml seaweed soups, and vitamin C group dog gavages vitamin C piece 0.1g (1,0.1g/ pieces).30min
Afterwards, every dog gavages isradipine piece 5mg (2,2.5mg/ pieces) respectively.After administration, respectively in 0.25h, 0.5h, 1h,
1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h gather blood sample, are placed in anticoagulant tube containing EDTA, 3000r/min centrifugations
10min, takes blood plasma, and -20 DEG C of preservations are to be measured.Its blood plasma drug concentration is surveyed with LC-MS/MS.
Testing result is shown in Table 1 and Fig. 1.
The LC-MS/MS of table 1 determines each group dog plasma drug concentration of different time points
Note：ND represents not measure or less than lower limit of quantitation without standard measure
Visible according to the testing result of table 1 and Fig. 1, when using isradipine vitamin C being used in combination can effectively carry
The bioavilability of high felodipine.
Claims (8)
1. a kind of method for improving isradipine drug bioavailability, this method includes：By the isradipine medicine of effective dose
It is used in combination with antioxidant.
2. in accordance with the method for claim 1, it is characterised in that：Described being used in combination is by isradipine medicine and antioxygen
Agent is used simultaneously, or first uses antioxidant, reuses isradipine medicine.
3. according to the method described in claim 1 or 2, it is characterised in that described antioxidant includes but is not limited to free radical
Absorbent, metal ion chelation agent, oxygen scavenger, peroxide decomposer or enzyme antioxidant.
4. in accordance with the method for claim 3, it is characterised in that described antioxidant is selected from ascorbic acid, ascorbic acid
Sodium, arabo-ascorbic acid, sodium isoascorbate, ascorbyl palmitate, glutathione, vitamin E, Tea Polyphenols, anthocyanidin, β-
Carrotene, lycopene, cysteine hydrochloride, niter cake, sodium metabisulfite, sulfurous acid vitamin-c palmitate sodium, uncle
Butylated hydroxy anisole, butylated hydroxytoluene, propylgallate, tocopherol, citric acid, EDTA, reduced sugar glucose or breast
Any one of sugar or more than one mixtures constituted according to arbitrary proportion.
5. the pharmaceutical composition using isradipine medicine as active component that a kind of bioavilability is improved, it is characterised in that contain
There is antioxidant.
6. according to the pharmaceutical composition described in claim 5, it is characterised in that described antioxidant includes but is not limited to freedom
Base absorbant, metal ion chelation agent, oxygen scavenger, peroxide decomposer or enzyme antioxidant.
7. according to the pharmaceutical composition described in claim 5 or 6, it is characterised in that described antioxidant be selected from ascorbic acid,
Sodium ascorbate, arabo-ascorbic acid, sodium isoascorbate, ascorbyl palmitate, glutathione, vitamin E, Tea Polyphenols,
Anthocyanidin, beta carotene, lycopene, cysteine hydrochloride, niter cake, sodium metabisulfite, sulfurous acid ascorbic acid palm fibre
Palmitic acid acid sodium, butylhydroxy anisole, butylated hydroxytoluene, propylgallate, tocopherol, citric acid, EDTA, reduced sugar Portugal
Any one of grape sugar or lactose or more than one mixtures constituted according to arbitrary proportion.
8. according to the pharmaceutical composition described in claim 5-6 any one, it is characterised in that described pharmaceutical composition also includes
Pharmaceutically acceptable salt or ester；Described pharmaceutical composition further comprises pharmaceutically acceptable carrier or excipients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710635695.4A CN107308159A (en) | 2017-07-28 | 2017-07-28 | One kind improves isradipine bioavilability pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710635695.4A CN107308159A (en) | 2017-07-28 | 2017-07-28 | One kind improves isradipine bioavilability pharmaceutical composition |
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| Publication Number | Publication Date |
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| CN107308159A true CN107308159A (en) | 2017-11-03 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710635695.4A Pending CN107308159A (en) | 2017-07-28 | 2017-07-28 | One kind improves isradipine bioavilability pharmaceutical composition |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1911233A (en) * | 2005-08-11 | 2007-02-14 | 鲁南制药集团股份有限公司 | Medicine composite contg. Moxabilli and antioxidant |
| CN101180040A (en) * | 2005-05-20 | 2008-05-14 | 奥默罗斯公司 | Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures |
| CN102292070A (en) * | 2009-01-23 | 2011-12-21 | 韩美控股株式会社 | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability |
| WO2017068532A1 (en) * | 2015-10-23 | 2017-04-27 | Ftf Pharma Private Limited | Oral solution of dihydropyridine derivatives |
-
2017
- 2017-07-28 CN CN201710635695.4A patent/CN107308159A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180040A (en) * | 2005-05-20 | 2008-05-14 | 奥默罗斯公司 | Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures |
| CN1911233A (en) * | 2005-08-11 | 2007-02-14 | 鲁南制药集团股份有限公司 | Medicine composite contg. Moxabilli and antioxidant |
| CN102292070A (en) * | 2009-01-23 | 2011-12-21 | 韩美控股株式会社 | Solid pharmaceutical composition comprising amlodipine and losartan with improved stability |
| WO2017068532A1 (en) * | 2015-10-23 | 2017-04-27 | Ftf Pharma Private Limited | Oral solution of dihydropyridine derivatives |
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Application publication date: 20171103 |
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