CN101167695A - Composition with improved light stability - Google Patents
Composition with improved light stability Download PDFInfo
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- CN101167695A CN101167695A CNA2006101635820A CN200610163582A CN101167695A CN 101167695 A CN101167695 A CN 101167695A CN A2006101635820 A CNA2006101635820 A CN A2006101635820A CN 200610163582 A CN200610163582 A CN 200610163582A CN 101167695 A CN101167695 A CN 101167695A
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Abstract
The invention provides a light-stabilized solid composition for oral administration which can conveniently prevent the discoloration and decomposition caused by light of nallose atabrine and other salt which is acceptable in pharmacy. The solid composition for oral administration contains nallose atabrine and other salt and ferric oxide which is acceptable in pharmacy, and has no coating layer.
Description
Technical field
The present invention relates to contain Orally-administered solid composition and preparation that the light stability of Amlodipine improves.
Background technology
Dihydropyridines calcium antagonists Amlodipine is being played the part of the role of core owing to have abundant and constant vasorelaxation action and be difficult to cause tachycardic character in the blood pressure lowering therapy.But Amlodipine is the chemical compound that is difficult to tolerate photolysis in the dihydropyridine compounds, decomposes but produce sometimes under the more situation of irradiation dose, causes reducing as the effect of active substance.Therefore, in containing the Orally-administered solid composition of Amlodipine, need to be used to guarantee the technology of photostability.
At present, about the preparationization to the photo-labile medicine, the whole bag of tricks that is used for the medicine stabilisation is known.For example, in patent documentation 1, disclose in the soft capsule that in epithelium, has disperseed coloring agent and to have enclosed preventing the medicine nifedipine of photo-labile because the soft capsule of decomposition that light causes and rotten nifedipine.In addition, the capsule preparations that makes active form Cholecalciferol class stabilisation by the hard capsule that contains tar class pigment and iron oxide red etc. is disclosed in patent documentation 2.These technology all are the methods that contain coloring agent in the film, capsule that covers the photo-labile medicine, are difficult to be applicable to tablet, granule, microgranule, powder etc.
On the other hand, in patent documentation 3, disclose by apply on the tablet of dihydrogen pyridine derivative that the thin film mixed ferrum oxide forms to the stable tablet of light.Yet, in this technology, having increased operation in order to implement coating, its needed time and labour force increase, and cost raises.In addition, in the tablet that must cut apart, easily owing to apply and cause troubles such as cut-off rule is buried, after cutting apart, divisional plane can expose, and therefore can't expect Photostabilised effect.In addition, in the preparation that can't apply, can't use this technology owing to some reason.For example, in the intraoral disintegration type preparation, under the situation that preparation is totally implemented to apply, intraoral immediately disintegrable, fast dissolubility is impaired, can't realize its function.In addition, by only applying the former medicine in the preparation or contain the granule of former medicine, though can keep immediately disintegrable as preparation, in this case, can predict these parts that apply preparations can't disintegrate in the oral cavity, dissolving, therefore is difficult to take.In addition, in patent documentation 4, disclose contain as the titanium oxide of opacifier and as edible yellow No. 5 of coloring agent, iron sesquioxide, yellow iron sesquioxide to the stable pyridine compounds and their of light.Yet, in the document, the feature of actual disclosure be by appropriate excipients with the preparation of Amlodipine solid dispersionization on spraying contain the coating liquid of coloring agent and opacifier, therefore, the final document in fact also discloses the preparation (referring to patent documentation 4 page 2 the 1st hurdle the 50th row～the 2 hurdle the 4th row and page 2 the 2nd hurdle the 32nd row～page 3 the 4th hurdle the 5th row embodiment) with coat.
As the Photostabilised method of the tablet of not implementing to apply, granule, microgranule, powder etc., the compositions of the light stability raising that mixes the material more than a kind that is selected from yellow and red stain in unsettled fat-soluble medicine is disclosed in patent documentation 5.In addition, in patent documentation 6, disclose in the powder body that is containing the photo-labile medicine and added coloring agent, carried out the wet type pelletize and the Orally-administered solid composition that forms.In addition, in non-patent literature 1, put down in writing when in nifedipine, adding yellow iron sesquioxide, can suppress because the growing amount of the caused oxysome of light and the reduction of drug content.Yet, in these documents, do not have record about Amlodipine.
Patent documentation 1: the spy opens clear 55-22645 communique
Patent documentation 2: the spy opens flat 4-46122 communique
Patent documentation 3: the spy opens the 2003-104888 communique
Patent documentation 4: the spy opens the 2003-104887 communique
Patent documentation 5: the spy opens the 2000-7583 communique
Patent documentation 6: the spy opens the 2000-191516 communique
Non-patent literature 1:International Journal of Pharmaceutics, 103 (1994) 69-76
Summary of the invention
The problem that the present invention will solve is to provide and prevents Amlodipine or its pharmaceutically acceptable salt easily owing to light produces variable color and decomposition, Photostabilised Orally-administered solid composition.
Because Amlodipine is as dihydropyridine compounds and light stability is higher, the content in the scope of using as conventional pharmaceuticals reduces can not cause any problem substantially.The inventor finds different with nifedipine, in Amlodipine, considers detecting owing to can observe variable color in the scope that the content that light caused reduces, and prevents this painted problem that becomes a needs solution.Owing in above-mentioned non-patent literature 1,, do not hint the record of such problem itself certainly for variable color not record fully yet.The problem of the document is to improve following problem: if to the light of 400 foot one candle light of nifedipine tablet irradiation 14 days, then generate and reach 45% analyte.On the other hand, test as described later shown in the example, because the oxysome that generates in the Amlodipine tablet is about 1%, therefore the degree of decomposing is different fully.Therefore clearly, the major subjects in Amlodipine is to prevent paintedly, and it belongs to diverse phenomenon with the content reduction problem as major subjects in nifedipine.
In addition, the inventor finds that painted character self also is diverse in nifedipine and Amlodipine.That is, confirm actually when making tablet, under the tablet of nifedipine of making equally and Amlodipine places situation under the fluorescent lamp, demonstrate diverse painted character.In the situation of nifedipine, from the beginning the color of nifedipine self be the tablet of xanchromatic nifedipine after a few hours, tablet surface begins to fade, and is coloured to mottled brown afterwards.On the other hand, in the situation of Amlodipine, be white at the beginning, compare with nifedipine, be coloured to little yellow very lentamente.Show that thus the coloring reaction of nifedipine and the coloring reaction of Amlodipine belong to diverse character, this obvious explanation can't infer fully whether the method that raising nifedipine photostability goes for Amlodipine.On the other hand, in above-mentioned patent documentation 5 and 6, what confirm actual effect is menatetrenone and sofalcone, not only is not Amlodipine nor is the dihydropyridines medicine with same skeleton, therefore more is difficult to predict effect in Amlodipine by these documents.
In addition, the inventor finds, tests as described later shown in the example, under the situation of mixed oxidization titanium, can promote on the contrary because the decomposition that light causes can't improve stability in Amlodipine.In addition, stabilization agent as the inhibited oxidation decomposition, antioxidant such as dibenzylatiooluene, butylated hydroxyanisole (BHA) is well-known, though find that these antioxidants can suppress because the growing amount of the analyte that the oxidation of Amlodipine produces can not suppress variable color fully.That is, find that the decomposition that causes owing to light at least may not necessarily demonstrate identical character with variable color in Amlodipine.Therefore, can not infer that fully the variable color when in Amlodipine blending iron oxide suppresses effect.
In recent years, enter aging society, because physiological each underactivity or senile dementia etc., the reduction of food intake function (chew, swallow etc.) or exist the person at advanced age of obstacle increasing.For such elderly patient, carry out under the case of oral administration at tablet, produce the problem take difficulty etc.On the other hand, in busy modern society, but because therefore selection time and local advantage of taking require exploitation not need water when taking, stable, low capacity, and oral formulations easy to carry.The inventor has obtained the intraoral disintegration type preparation of the improved Amlodipine of taking after various researchs.Yet, as mentioned above,, still can not realize the Photostabilised effective ways of Amlodipine for the preparation that can't apply after this function of realizations such as Orally disintegrating tablet.Therefore, just do not need to apply the tablet of the stable Amlodipine of light, just can be applied in Orally disintegrating tablet etc. as long as the inventor thinks to provide.
The inventor has carried out meticulous research, found that by blending iron oxide in Amlodipine or its pharmaceutically acceptable salt, do not need to be used for the Orally-administered solid composition that Photostabilised coat just obtains containing Photostabilised Amlodipine very easily.Find in addition: by using this technology, blending iron oxide in Amlodipine or its pharmaceutically acceptable salt can be realized intraoral disintegration type preparation Photostabilised of taking excellence very easily, thereby finish the present invention.
That is, the present invention relates to following content.
[1] a kind of Orally-administered solid composition, it contains (a) Amlodipine or its pharmaceutically acceptable salt and (b) ferrum oxide, and does not have coat.
[2] as [1] described Orally-administered solid composition, it is the Orally-administered solid composition that is substantially devoid of titanium oxide.
[3] as [1] or [2] described Orally-administered solid composition, it is the intraoral disintegration type preparation.
[4] as each described Orally-administered solid composition of [1]～[3], it contains the composition of following (a)～(d):
(a) Amlodipine or its pharmaceutically acceptable salt
(b) ferrum oxide
(c) mannitol
(d) corn starch.
[5] as each described Orally-administered solid composition of [1]～[4], it further contains the fumaric acid sodium stearyl ester, and Orally-administered solid composition is an Orally disintegrating tablet.
[6] as [5] described Orally-administered solid composition, wherein:
(a) Amlodipine or the content of its salt in Orally-administered solid composition are counted 2～5 weight % with Amlodipine,
(b) content of ferrum oxide in Orally-administered solid composition is 0.03～2 weight %,
(c) content of mannitol in Orally-administered solid composition is 70～90 weight %,
(d) content of corn starch in Orally-administered solid composition is 5～15 weight %, and
(e) content of fumaric acid sodium stearyl ester in Orally-administered solid composition is 1～3 weight %.
[7] as each described Orally-administered solid composition of [1]～[6], wherein ferrum oxide is yellow iron sesquioxide.
[8], wherein contain (a) Amlodipine or its pharmaceutically acceptable salt and (b) mixture of ferrum oxide as each described Orally-administered solid composition of [1]～[7].
[9], wherein contain by with (a) Amlodipine or its pharmaceutically acceptable salt and (b) compositions that obtains of the mixture pelleting of ferrum oxide as each described Orally-administered solid composition of [1]～[8].
The invention effect
According to the present invention, can provide very easily the stable Orally-administered solid composition that contains Amlodipine of light.In addition, thus, can provide by to easy taking preparation Photostabilised and can keep quality such as the Orally disintegrating tablet of the Amlodipine that can't apply, though advanced age dysphagia such as people the patient and the people of busy social life also can easily take in all cases to the stable Amlodipine Orally-administered solid composition of light.
The specific embodiment
Amlodipine [2-(2-amino ethoxy methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-picoline-3,5-dicarboxylic acids 3-ethyl ester 5-methyl ester] owing to have the optical activity center, therefore have (S)-(-) body and (R)-(+) body, the present invention can use any or mixture of these optically active bodies.Preferred (S)-(-) body and the racemic modification of using.
As the pharmaceutically acceptable salt of Amlodipine, can list salt with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, succinic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid.Preferably enumerate the salt with benzenesulfonic acid, i.e. the benzenesulfonic acid Amlodipine.
As the ferrum oxide among the present invention, can list yellow iron sesquioxide, yellow iron oxide, iron sesquioxide, iron oxide red and black iron oxide.Preferably enumerate yellow iron sesquioxide, yellow iron oxide, iron sesquioxide.Further preferably enumerate yellow iron sesquioxide.
The suitable combined amount of these ferrum oxides is according to blended ferrum oxide, the kind of dosage form and different, for example, under the situation of the tablet that contains yellow iron sesquioxide, if macro-mixing, then when beating sheet, can produce black splotch and damage quality,, then can't obtain enough effects if combined amount is very few, therefore as preferred addition, 0.01～10 weight % can be enumerated,, 0.01～5 weight % can be enumerated as preferred addition, as further preferred addition, 0.03～2 weight % can be enumerated,, 0.03～1 weight % can be enumerated as preferred addition, as particularly preferred addition, can enumerate 0.05～0.5 weight %.
The particle diameter of ferrum oxide among the present invention if as pharmaceuticals qualitatively can be in Orally-administered solid composition homodisperse, blended size, just have no particular limits, can enumerate is 0.01～1.0 μ m using laser diffraction and scattering formula particle size distribution device to survey periodic volume average particle size for example, more preferably 0.01～0.5 μ m, further preferred 0.1～0.5 μ m.
As the Orally-administered solid composition among the present invention, can enumerate the preparation of dosage forms such as gel, gum, dry syrup, powder, microgranule, granule equigranular preparation, tablet, masticatory, intraoral disintegration type preparation.More preferably owing to do not need water when taking, therefore can selection time, place gel, gum, masticatory, the intraoral disintegration type preparation taken.Further preferred intraoral disintegration type preparation particularly preferably is Orally disintegrating tablet.
The so-called coat of the present invention is meant the outermost layer of the unit of direct covering oral administration, does not comprise the packing of PTP sheet material etc.
Specifically; for example can enumerate with dry type pelletizes such as principal agent, excipient, disintegrating agent, binding agent or wet type pelletize etc.; beat as required obtained by molding such as sheet to Orally-administered solid composition on spraying film property macromolecular solution; drying etc., thus execute in the outside of this Orally-administered solid composition by with the form skin that form different with this Orally-administered solid composition.In the film property macromolecular solution, in the scope that can not hinder common thin film to form, add various additives.So-called coating is meant the formation of such coat.
As other coat, can enumerate capsules such as soft capsule and hard capsule.
Content to Amlodipine among the present invention or its pharmaceutically-acceptable salts has no particular limits, owing to common 1 day administration 2.5～5mg of Amlodipine, therefore consider the size of preparation, expectation mixes Amlodipine or its pharmaceutically-acceptable salts, make as Amlodipine, contain 0.1～10 weight %.More preferably mix Amlodipine or its pharmaceutically-acceptable salts, make, contain 0.25～6.25 weight %, further preferably mix, especially preferably mix by containing 2～5 weight % by containing 1～6.25 weight % as Amlodipine.
So-called intraoral disintegration type preparation among the present invention, be can not need water just can be in the oral cavity dissolving or disintegrate and take fast, also can the same preparation of taking with water with common preparation.As dosage form, can enumerate powder, microgranule, granule equigranular preparation and tablet.
Intraoral disintegration type granular preparation among the present invention, Orally disintegrating tablet can be enumerated in the time of dissolved in oral cavity or disintegrate and be generally in 1 minute, are preferably in 45 seconds, more preferably in 30 seconds.
In the intraoral disintegration type preparation,,, preferably add water soluble excipient in the present invention as excipient from the viewpoint of taking.As water soluble excipient, can enumerate the water solublity sugar alcohol, the saccharide that have good sweet taste when taking, have the amino acids of sweet taste and the mixture of these materials, preferably enumerate the mixture of water solublity sugar alcohol, saccharide, glycine and these materials, especially preferably enumerate the water solublity sugar alcohol.
So-called water solublity sugar alcohol among the present invention can be set forth in the water and to add the 1g sugar alcohol, 20 ℃ of strong joltings in following per 5 minutes 30 seconds, and at about 30 minutes during with interior dissolving, the sugar alcohol of necessary water shortage 30ml etc.As the example of water solublity sugar alcohol, can enumerate Sorbitol, mannitol, maltose alcohol, reduction starch saccharification thing, xylitol, reduction paratinose, erithritol etc., these materials also can will mix use according to proper proportion more than 2 kinds.As preferred water solublity sugar alcohol, can enumerate mannitol, xylitol, erithritol, further preferred mannitol, erithritol, preferred especially mannitol.Content as water solublity sugar alcohol among the present invention has no particular limits, and can enumerate for example 50～99.9 weight %, preferably enumerates 70～97 weight %, more preferably enumerates 70～90 weight %, especially preferably enumerates 75～85 weight %.
In the intraoral disintegration type preparation, especially, preferably contain disintegrating agent in the present invention from the viewpoint of disintegrative.As disintegrating agent, can enumerate for example starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, low degree of substitution hydroxy propyl cellulose, carboxymethyl starch sodium, low degree of substitution carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, these materials also can will mix use according to proper proportion more than 2 kinds.Preferably enumerate starch, carboxymethylcellulose calcium, low degree of substitution hydroxy propyl cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone.More preferably enumerate starch, low degree of substitution hydroxy propyl cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, further preferably enumerate starch, low degree of substitution hydroxy propyl cellulose.Especially preferably enumerate starch.
So-called starch among the present invention comprises all starch from all native starches that can be used for pharmaceuticals.Can enumerate for example potato starch, corn starch, wheaten starch, rice starch and soluble starch, part alphalysed starch, alphalysed starch, hydroxypropyl starch etc., preferably enumerate corn starch.As these contents of starch, for example mix 1～50 weight %, preferably mix 2～30 weight %, more preferably mix 3～20 weight %, further preferred 5～15 weight % that mix.
In the present invention in the intraoral disintegration type preparation, there is no particular limitation to binding agent, can enumerate starch (comprising the part alphalysed starch), hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, polyvinyl pyrrolidone, gelatin, methylcellulose, gum arabic powder, polyvinyl alcohol, alkyl hydroxy ethyl cellulose etc.From the viewpoint of disintegrative, the material beyond the starch is not used in expectation basically.Basically so-called, be meant so long as can be this intraoral disintegration type preparation, especially in intraoral dissolving or disintegration rate, and the amount that exerts an influence of Photostabilised effect of the present invention, just can mix other binding agents.
In Orally-administered solid composition of the present invention, except mentioned component, can also add normally used avirulence and inert additive in the pharmaceutical field.As these additives, can enumerate basically and can not influence effect of the present invention, usually as the additive material of pharmaceuticals, can enumerate for example excipient such as lactose, corn starch, mannitol, xylitol, Sorbitol, erithritol, glycine, Talcum, Kaolin, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, crystalline cellulose; Lubricants such as stearic acid, magnesium stearate, calcium stearate, fumaric acid sodium stearyl ester; Disintegrating agents such as carboxymethylcellulose calcium, low degree of substitution hydroxy propyl cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium; Binding agents such as hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, polyvinyl pyrrolidone, gelatin, methylcellulose, gum arabic powder, polyvinyl alcohol, alkyl hydroxy ethyl cellulose, other coloring agent, correctives, spice, adsorbent, antiseptic, stabilization agent, wetting agent, antistatic agent, pH regulator agent etc.
Lubricant especially uses when making tablet of the present invention, wherein, and preferred magnesium stearate and fumaric acid sodium stearyl ester.
In addition, can also cooperate flavouring agent spice such as aspartame, acesulfame, glucide, saccharin sodium, stevioside, the contour sugariness artificial sweetening of sucralose and Herba Menthae, Herba Menthae Rotundifoliae, menthol, Fructus Citri Limoniae, orange, grapefruit, パ イ Application, fruit, yoghourt, especially be under the situation of spice cooperating aspartame and Herba Menthae, can obtain the preferred sense of taking.
Manufacture method as Orally-administered solid composition of the present invention, can enumerate known method, for example as comminution granulation, extruding pelletization method, broken comminution granulation, dry type compacting comminution granulation, fluosolids comminution granulation be can enumerate, rotate comminution granulation, fluosolids comminution granulation, high-speed stirred comminution granulation rotated, as beating the sheet method, can enumerate wet type and beat the sheet method, directly beat sheet method etc.
Below, carry out more specific description by embodiment and comparative example, but the present invention is not limited in these examples.
Embodiment 1
Tablet formulation (mg)
| Form | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | Comparative example 6 | Comparative example 7 | Comparative example 8 |
| The benzoic acid Amlodipine | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 | 7 |
| Mannitol 1 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Corn starch 2 | 11 | 11 | 11 | 11 | 11 | 11 | 11 | 11 | 11 | 11 | 11 |
| The fumaric acid sodium stearyl ester 3 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 |
| Yellow iron sesquioxide 4 | 0.12 | 1.2 | - | - | - | - | - | - | - | - | - |
| Iron sesquioxide 5 | - | - | 0.12 | - | - | - | - | - | - | - | - |
| Titanium oxide 6 | - | - | - | - | 1.2 | - | - | - | - | - | - |
| Butylated hydroxyanisole (BHA) 7 | - | - | - | - | - | 12 | - | - | - | - | - |
| Dibenzylatiooluene 8 | - | - | - | - | - | - | 12 | - | - | - | - |
| Edible yellow No. 5 9 | - | - | - | - | - | - | - | 0.12 | - | - | - |
| Edible yellow No. 5 aluminum color lakes 10 | - | - | - | - | - | - | - | - | 12 | - | - |
| Edible red No. 3 11 | - | - | - | - | - | - | - | - | - | 0.12 | - |
| Edible red No. 102 12 | - | - | - | - | - | - | - | - | - | - | 0.12 |
1. trade name D-mannitol (Kyowa Hakkokogyo Co., Ltd)
2. trade name corn starch (XX16) W (Japan Food Chemical Co., Ltd)
3. trade name プ Le-Block (Penwest Pharmaceuticals society (U.S.))
4. the yellow iron sesquioxide (changing into Co., Ltd. the sixth of the twelve Earthly Branches in the last of the ten Heavenly stems) of trade name
5. trade name iron sesquioxide (changing into Co., Ltd. the sixth of the twelve Earthly Branches in the last of the ten Heavenly stems)
6. trade name refined dearsenization titanium oxide (ザ Network ト レ-ベ Application ケ ミ エ society (De イ Star))
7. trade name 3-t-Butyl-4-hydroxyanisole (Na カ ラ イ テ ス Network Co., Ltd.)
8. trade name 2,6-di-t-butyl-paracresol (Na カ ラ イ テ ス Network Co., Ltd.)
9. trade name eats yellow No. 5 (three Rong Yuan エ Off エ Off ア イ Co., Ltd.)
10. trade name eats yellow No. 5 aluminum color lakes (three Rong Yuan エ Off エ Off ア イ Co., Ltd.)
11. trade name eats red No. 5 (three Rong Yuan エ Off エ Off ア イ Co., Ltd.)
12. trade name eats red No. 102 (three Rong Yuan エ Off エ Off ア イ Co., Ltd.)
About embodiment 1～3 and comparative example 1～8, according to the prescription of table 1, after each compositions of 12 times of amounts of prescription fully mixed, take by weighing 1 formula ratio in mortar, use hydraulic type press (reason development), the pressure compression with 50kgf obtains the tablet that diameter is 7mm.
The test example
Preparation to embodiment 1～3 and comparative example 1～8 carries out the light stability test.With the result of the fluorescent lamp 4000 luxs * outward appearance in 2 weeks and the growing amount of oxysome shown in the table 2.In addition, oxysome (2-[(2-amino ethoxy) methyl]-4-(neighbour-chlorophenyl)-6-methyl-3,5-dipicolinic acid 3-ethyl ester 5-methyl ester) quantitatively analyze by liquid chromatography.
The HPLC analytic process
Post: octadecyl conjunction type silicon gel (mean diameter 5 μ m, internal diameter 4.6 * long 150mm) (the Na カ ラ イ テ ス Network trade name COSMOSIL 5C18 of Co., Ltd.)
A liquid: 30mmol/L phosphate buffer (pH6.0)/methyl alcohol mixed liquor (1: 1)
B liquid: methanol/30mmol phosphate buffer (pH6.0) mixed liquor (19: 1)
B liquid: 80% → 0% gradient
Detector: UV
Detect wavelength: 237nm
[table 2]
(the oxidation scale of construction be the numerical value that on the area fraction values of HPLC, multiply by augmenting factor 2 (this be since the UV absorption intensity of oxysome be Amlodipine 1/2))
As shown in Table 2, it is bigger on cosmetic variation that comparative example 1 does not carry out Photostabilised preparation fully, and the growing amount of oxysome also surpasses 1%.On the contrary, contain in the preparation of titanium oxide at comparative example 2, not only can't suppress variable color, the oxysome growing amount increases on the contrary.As by applying Photostabilised that coat carries out, usually use the coating of the strong titanium oxide of shaded effect, but find that by titanium oxide being mixed with principal agent and excipient etc. light stability worsens on the contrary for Amlodipine to replace applying the preparation of making.Hence one can see that, mixes this method with principal agent and excipient etc. and can realize that Photostabilised this common considering can not be applicable to Amlodipine will applying the strong material of power.
In addition, comparative example 3 and 4 is to add as the butylated hydroxyanisole (BHA) of antioxidant and the preparation of dibenzylatiooluene, comparative example 6 is the preparations that add edible yellow No. 5 aluminum color lakes, and these comparative examples are the growing amount of energy inhibited oxidation body all, but can't suppress cosmetic variation.Hence one can see that, and it also is invalid adding antioxidant and adding pigment.
In adding other yellow, red colour system pigment edible yellow No. 5, the comparative example 5,7 and 8 of edible yellow No. 3 and edible red No. 102 preparation respectively, also can't suppress cosmetic variation and oxysome growing amount.Hence one can see that, adds pigment and also can't obtain Photostabilised effect usually.
As mentioned above, find generation and/or cosmetic variation that opacifier, antioxidant, pigment usually all can't the inhibited oxidation bodies, in contrast, find to contain in the preparation of yellow iron sesquioxide or iron sesquioxide, can suppress cosmetic variation, oxysome growing amount simultaneously at embodiment 1～3.Therefore, in usual way, can't suppress cosmetic variation and oxysome growing amount simultaneously, and with Amlodipine and the specific like this combination of ferrum oxide, and can suppress cosmetic variation and oxysome growing amount first.
Industrial applicability
By the present invention, can provide a kind of Amlodipine or its pharmaceutically acceptable salt of preventing easily owing to the caused variable color of light and decomposition, Photostabilised Orally-administered solid composition. Thus, in the quality of the intraoral disintegration type preparation of seeking to improve Amlodipine or its pharmaceutically acceptable salt, can make the packaged form of simpler Portability excellence, even People and busy modern society also can carry anywhere, need not drink water and just can take easily in all cases Amlodipine or its pharmaceutically acceptable salt.
Claims (9)
1. Orally-administered solid composition, it contains (a) Amlodipine or its pharmaceutically acceptable salt and (b) ferrum oxide, and does not have coat.
2. Orally-administered solid composition as claimed in claim 1, it is substantially free of titanium oxide.
3. Orally-administered solid composition as claimed in claim 1 or 2, it is the intraoral disintegration type preparation.
4. as each described Orally-administered solid composition of claim 1～3, it contains the composition of following (a)～(d):
(a) Amlodipine or its pharmaceutically acceptable salt;
(b) ferrum oxide;
(c) mannitol; With
(d) corn starch.
5. as each described Orally-administered solid composition of claim 1～4, further contain the fumaric acid sodium stearyl ester, and Orally-administered solid composition is an Orally disintegrating tablet.
6. Orally-administered solid composition as claimed in claim 5, wherein:
(a) Amlodipine or the content of its salt in Orally-administered solid composition are counted 2～5 weight % with Amlodipine,
(b) content of ferrum oxide in Orally-administered solid composition is 0.03～2 weight %,
(c) content of mannitol in Orally-administered solid composition is 70～90 weight %,
(d) content of corn starch in Orally-administered solid composition be 5～15 weight % and
(e) content of fumaric acid sodium stearyl ester in Orally-administered solid composition is 1～3 weight %.
7. as each described Orally-administered solid composition of claim 1～6, wherein ferrum oxide is yellow iron sesquioxide.
8. as each described Orally-administered solid composition of claim 1～7, it contains (a) Amlodipine or its pharmaceutically acceptable salt and (b) mixture of ferrum oxide.
9. as each described Orally-administered solid composition of claim 1～8, it contains by with (a) Amlodipine or its pharmaceutically acceptable salt and (b) compositions that obtains of the mixture pelleting of ferrum oxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101635820A CN101167695A (en) | 2006-10-27 | 2006-10-27 | Composition with improved light stability |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101635820A CN101167695A (en) | 2006-10-27 | 2006-10-27 | Composition with improved light stability |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101167695A true CN101167695A (en) | 2008-04-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101635820A Pending CN101167695A (en) | 2006-10-27 | 2006-10-27 | Composition with improved light stability |
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| Country | Link |
|---|---|
| CN (1) | CN101167695A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102300563A (en) * | 2009-01-29 | 2011-12-28 | 大日本住友制药株式会社 | Orally disintegrating tablet having inner core |
| CN103251566A (en) * | 2013-05-22 | 2013-08-21 | 中国人民解放军第二军医大学 | Tablet and preparation method thereof |
-
2006
- 2006-10-27 CN CNA2006101635820A patent/CN101167695A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102300563A (en) * | 2009-01-29 | 2011-12-28 | 大日本住友制药株式会社 | Orally disintegrating tablet having inner core |
| CN106344533A (en) * | 2009-01-29 | 2017-01-25 | 大日本住友制药株式会社 | Orally disintegrating tablet having inner core |
| CN103251566A (en) * | 2013-05-22 | 2013-08-21 | 中国人民解放军第二军医大学 | Tablet and preparation method thereof |
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Open date: 20080430 |