CN101247792A - Pharmaceutical compositions comprising a PH-dependent drug, a PH modifier and a retarding agent - Google Patents
Pharmaceutical compositions comprising a PH-dependent drug, a PH modifier and a retarding agent Download PDFInfo
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- CN101247792A CN101247792A CNA2006800306218A CN200680030621A CN101247792A CN 101247792 A CN101247792 A CN 101247792A CN A2006800306218 A CNA2006800306218 A CN A2006800306218A CN 200680030621 A CN200680030621 A CN 200680030621A CN 101247792 A CN101247792 A CN 101247792A
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Abstract
The present invention concerns pharmaceutical compositions comprising a pH-dependent drug compound and a pH modifier.
Description
The present invention relates to comprise the pharmaceutical composition of pH-dependent drug compound, the Use and preparation method of this pharmaceutical composition.
The pH-dependent drug compound demonstrates tangible pH-dependent solubility along gastrointestinal tract.They are expected in the fasting health volunteer and dissolve under the low pH of the stomach that occurs.Yet under higher intestinal pH environment, they may precipitate and/or dissolve not exclusively.In addition, food intake, Drug therapy and the Pathophysiology situation stomach pH that may raise, therefore, the medicine stripping may be lowered.Not exclusively stripping may cause between the patient of pH-dependent drug compound and bioavailability difference in height in the patient.
PH regulator agent, for example organic acid are mixed peroral dosage form to regulate microenvironment pH, increase drug solubility and drug dissolution thereby strengthen.In addition, can realize the pH-independent drug release.Yet, compare with medical compounds, the pH regulator agent be usually displayed on have higher solubility under the higher pH environment, be diffused into rapidly extraneous and therefore rapidly be present in solid dosage forms in the pH-dependent drug compound separate.Can use polymer to delay the rapid diffusion of pH regulator agent, maintain the target pH in the solid dosage forms thus.Yet the use of polymer makes the release of preparation change usually, and for example medicine discharged in the time period that prolongs, for example through 10 hours and longer.Medical compounds may highly depend on physiological condition from the absorption fully that this release changes in the preparation, and depends on medical compounds itself.For example only intestinal very specific, for example can show the difference in height opposite sex and impaired bioavailability between treatment target and in the treatment target than the medical compounds of top, for example little intestinal absorption.
Correspondingly, need comprise the pharmaceutical composition of pH-dependent drug compound, it has between the treatment target of reduction and the diversity in the treatment target and the bioavailability of increase.Surprisingly, the inventor has determined improved pharmaceutical composition, and it comprises pH-dependent drug compound and pH regulator agent, and wherein the pH regulator agent for example is present in the preparation in whole dissolution time, for example discharges simultaneously with medical compounds.
On the one hand, the invention provides a kind of pharmaceutical composition, it comprises pH-dependent drug compound, pH regulator agent and blocker, for example polymer as water-soluble polymer, wherein after 4 hours maximum dissolution time, for example in about 1 to the 4 hour dissolution time that contacts with gastro-intestinal Fluid, for example in 1 to 2 or 1 to 3 hour or about 2 to 4 hours, for example in 2 to 3 hours, the drug release in the pharmaceutical composition is complete.
The present invention further aspect, can use additional enteric coating, for example preventing the medicine in the stomach and any early stage diffusion of acid, and/or suppress stomach pH respectively and change, for example to guarantee medicine stripping uniformly in upper intestines such as small intestinal medicine and sour dissolved influence.
Provide contagion gown between acid core and the enteric coating again aspect further in the present invention, for example dissolved enteric coating to be provided among the intestinal pH approximately 〉=5.5.
The present invention more further aspect, described pharmaceutical composition is the form of multiparticle (multiparticulate) system, for example minitablets (minitablets) or piller (pellets).This many-particle system can show the advantage of relative triangular web, for example passes through repeatability and/or high degree of dispersion property improvement in digestive tract, causes in the treatment target and the diversity between treatment target reduces and the bioavailability improvement.
Those skilled in the art will understand and understand these and other feature of the present invention, advantage and purpose further by with reference to following description, claim and accompanying drawing.
The accompanying drawing summary
The accompanying drawing of incorporating this description into and constituting this description part has been set forth exemplary of the present invention.
Rate of release when Fig. 1 shows medicine and pH regulator agent.
Fig. 2 shows the influence of pH regulator agent to drug release.
Fig. 3 shows that drug release is independent of dissolution medium pH.
Composition of the present invention provides the short time modified release of pH-dependent drug compound, and particularly on the top of enteron aisle for example in the small intestine, it shows in treatment target and the otherness between treatment target reduces and the bioavilability improvement.
Detailed Description Of The Invention
Term " medicine " represents any compound, material, medicine, medicament or active component as used herein, and it has treatment or pharmacological action, and it is fit to be applied to for example people of mammal. This class medicine should be used with " treatment effective dose ".
Term " treatment effective dose " refers to a kind of amount or concentration as used herein, and it can effectively alleviate, eliminates, treats, prevents or control the symptom of the mammiferous disease of invasion and attack or illness. Term " control " means may slow down, interrupt, stop or stop all processes of the mammiferous disease of invasion and attack or illness process. Yet " control " must not show whole eliminations of all diseases or condition symptoms, and is intended to comprise prophylactic treatment.
The treatment effective dose that is fit to be it be known to those skilled in the art that because described amount with used treatment compound and for indication change.
Be particularly suitable for medicine of the present invention and salt thereof and be pH-dependent those, especially weakly basic drugs, for example any medicine of dissolubility difference＞100 between pH1 and the pH6.
Content of medicines can be up to about 1% to about 60% of about 60%, the composition weight of composition weight.Yet the selection of expected drug specified level will be determined according to the known factor of pharmaceutical field, comprise the size and the situation of method of application and treatment target.
The pH regulator agent that the present invention is fit to comprises acids, and mineral acid for example is as being solid water-soluble inorganic acid in ambient temperature, as sulfamic acid.
The organic acid that is fit to contains one or more acidic-groups, for example is selected from the acidic-group of carboxylic acid and sulfonic acid group, particularly ambient temperature be solid those.
The water-soluble organic acid that is fit to comprises and is selected from following water-soluble organic acid: single, two or polybasic carboxylic acid or single, two or three-sulfonic acid, for example it is a solid in ambient temperature.The solid, water soluble carboxylic acid that is fit to comprises aliphatic list or polybasic carboxylic acid, for example contains 2 to 8 carbon atoms, particularly 2 to 6 carbon atoms, for example contains 4 to 6, as complete-or the tricarboxylic acids of 4 carbon atoms, as saturated or undersaturated.The example of the solid, water soluble aliphatic monocarboxylic acid that is fit to comprises sorbic acid (2, the 4-hexadienoic acid).The example of the solid, water soluble aliphatic dicarboxylic acid that is fit to comprises adipic acid, malonic acid, succinic acid, 1,3-propanedicarboxylic acid, maleic acid or fumaric acid.Aliphatic carboxylic acid can choose wantonly by one or more, for example 1,2 or 3 can be identical or different the group that is selected from carboxyl, amino and hydroxyl replace.The solid, water soluble aliphatic carboxylic acid of the replacement that is fit to comprises lactic acid, hydroxyacetic acid or the ascorbic acid of aliphatic monocarboxylic acid that hydroxyl for example replaces such as gluconic acid, solid form; Aliphatic dicarboxylic acid such as malic acid, tartaric acid, hydroxymalonic acid (hydroxymalonic acid .) or glactaric acid (galactosaccharic acid) that hydroxyl replaces; Aliphatic tricarboxylic acid such as citric acid that hydroxyl replaces; Perhaps carry aminoacid such as the glutamic acid or the Aspartic Acid of acid side-chain.
The aromatic carboxylic acid that is fit to comprises and contains the water solublity aryl carboxylic acid that reaches 14 carbon atoms.The aryl carboxylic acid that is fit to comprises aryl, for example carries one or more carboxyls, as the phenyl or naphthyl of 1,2 or 3 carboxyl.This aryl optional by one or more groups, for example 1,2 or 3 can be identical or different the group that is selected from hydroxyl, (1-4C) alkoxyl such as methoxyl group and sulfonyl replace.The aryl carboxylic acid that is fit to comprises benzoic acid, phthalic acid, isophthalic acid, terephthalic acids or 1,2,4-benzenetricarboxylic acid (1,2, the 4-benzene tricarbonic acid).
Preferred pH regulator agent is selected from citric acid, fumaric acid, succinic acid, adipic acid and maleic acid.The preferred fumaric acid that uses.
Thereby it is more acid at medicine become indissoluble, the rate of release of insoluble pH value increase medicine from dosage form for example to be particularly suitable for pH regulator agent of the present invention and to be changing microenvironment pH.
The pH regulator agent constitute composition weight about 1% to about 60%, for example about 10% of composition weight to about 40%.In the present composition, the ratio of pH regulator agent and medical compounds can be for giving 0.2: 1 to about 2: 1, for example 1: 1.
As blocker, can use polymer, water-soluble polymer for example, for example cellulose derivative for example has the viscosity that is higher than about 100cps, for example has about 100 to about 100, the viscosity of 000cps.Preferably can use water-soluble polymer.
The polymer that is fit to includes but not limited to cellulose derivative, for example methylcellulose, hydroxypropyl emthylcellulose such as hydroxypropyl emthylcellulose k100LV, K 4M or hydroxypropyl emthylcellulose K15M, hydroxypropyl cellulose, hydroxyethyl-cellulose, sodium carboxymethyl cellulose, ethyl cellulose such as ethyl cellulose 100, cellulose acetate such as cellulose acetate CA-398-10NF, acetic acid phthalandione cellulose, cellulose-acetate propionate, cellulose acetate-butyrate, cellulose butyrate, celluloid, hydroxypropyl methyl cellulose phthalate, the hydroxypropyl emthylcellulose acetate succinate, propenyl derivatives is polyacrylate such as Acusol772 Acusol771 for example, methacrylic acid copolymer, polyvinyl is the polyvinylpyrrolidone class for example, polyvinyl acetate esters or polyvinyl acetate phthalate (polyvinyl acetatephthalates) and composition thereof, as selling with trade name Kollidon SR , polyethylene glycols, polyanhydrides, polysaccharide is xanthan gum class such as Xanthan gum for example, galactomannan, pectin and alginate.
Preferred polymer comprises hydroxypropyl emthylcellulose, for example Methocel K100LV, Methocel K4M and Methocel K100M.
Polymer constitute composition weight about 10% to about 60%, for example about 30% of composition weight to about 60%.
In some exemplary of the present invention, pharmaceutical composition can comprise visible other excipient in pharmaceutical composition usually, the example of this excipient includes but not limited to fluidizer, lubricant, antioxidant, antimicrobial, enzyme inhibitor, stabilizing agent, antiseptic, flavoring agent, sweeting agent and other composition, Handbook of Pharmaceutical Excipients for example, people such as Rowe edit, the 4th edition, Pharmaceutical Press (2003) is described, and it is quoted at this as a reference.
These other excipient can constitute about 0.05-11% of pharmaceutical composition gross weight, and for example about 0.5 of composition total weight to about 2%.Antioxidant, antimicrobial, enzyme inhibitor, stabilizing agent or antiseptic constitute about 0.05-1% of pharmaceutical composition gross weight usually.Sweeting agent or flavoring agent constitute about 2.5% or 5% of pharmaceutical composition gross weight usually.
The lubricant that is fit to includes but not limited to magnesium stearate, Talcum, castor oil hydrogenated, glycerylbehaptate, glyceryl monostearate, Polyethylene Glycol, ethylene oxide polymer, sodium lauryl sulfate, lauryl magnesium sulfate, enuatrol, sodium stearyl fumarate, DL-leucine, silica sol and other lubricant known in the art.Compositions of the present invention can comprise about 0 to 3%, about lubricant of 0.5 to 3%, for example 1% for example of composition weight.
For example for example starch hydrolysate or pregelatinized Starch of corn (corn) starch, wheaten starch, corn (maize) starch or potato starch, modified starch of the lactose, sugar, starch based that the filler that is fit to includes but not limited to for example anhydrous or hydrated form of lactose, mannitol, sorbitol, trehalose, maltose, anhydrous glucose; Inorganic salt, for example calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, orthophosphate or calcium sulfate, Celluloasun Microcrystallisatum, cellulose derivative and other filler known in the art.The present composition can comprise about 0 to 65%, about filler of 3 to 65% for example of composition weight.
The fluidizer that is fit to includes but not limited to Aerosil 200 or Talcum and other fluidizer known in the art.The present composition can comprise about fluidizer of 0 to 2% of composition weight.
The binding agent that is fit to includes but not limited to polyvinylpyrrolidone (PVP), for example PVP K30 or PVP K12, and it is for known and get from BASF AG is commercially available with trade name Povidone ; Perhaps hydroxypropyl emthylcellulose (HPMC), for example hang down the HMPC of apparent viscosity, for example 20 ℃ of determination of aqueous solution with 2% weight be lower than 100cps, for example be lower than 50cps, preferably be lower than 20cps, HPMC 3cps for example, it is for known and get from Shin-Etsu company is commercially available with trade name Pharmacoat 603.The present composition can comprise about 0 to 5%, about binding agent of 0.5 to 5% for example of composition weight.
The example of antioxidant includes but not limited to ascorbic acid and derivant, tocopherol and derivant thereof, butylated hydroxyanisole (BHA) and butylated hydroxytoluene.Vitamin E such as alpha-tocopherol are useful especially.
Of the present invention further aspect, the method of the pharmaceutical composition of preparation example minitablets form as indicated above is provided, this method comprises active component, organic acid, polymer and any other tabletting mixed with excipients, and water or organic solvent wet granulation.The dried granule that is used for preparation example such as minitablets form can sieve by 400 μ m sieve.Can add the foreign minister, it be by silicon dioxide, for example can form with magnesium stearate with trade name Aerosil, and fully mixes.This mixture can be pressed into diameter for example 1.5 to about 4mm, 1.7 to 2mm minitablets for example.The gained minitablets can be wrapped in the capsule, for example hard capsule or starch capsule, or be provided in the sachet.
Of the present invention more further aspect, the method of the pharmaceutical composition of preparation example piller form as indicated above is provided, and this method comprises by mixed active composition in planetary-type mixer, organic acid, polymer and for example microcrystalline Cellulose and prepares dry mixture.Can add purified water and obtain wet thing piece, use the sieve of the suitable size thing piece that should wet to extrude subsequently.Can be with this extrudate sphering in spheronizator, intensive drying is sieved to select being fit to size, obtains for example short time modified release pellets.
In the further embodiment of the present invention, enteric coating is applied to minitablets or piller.
As used herein term " enteric coating " be meant the protection dosage form in case under one's belt for example at pH1 to 2, up to the promptly dissolved coating in pH5 place.
This enteric coating according to the present invention can comprise following (with respect to the minitablets of final coating or the percent % of piller):
2-40% enteric coating polymer, hydroxypropyl methyl cellulose phthalate for example gets as known trade name HP50 or HP55 and from Shin Etsu is commercially available; The hydroxypropyl methyl cellulose acetate succinate is as getting from Shin Etsu is commercially available with trade name Aqoat H, M or L; Methacrylic acid-ethyl propylene acid copolymer (methacrylic acid copolymer, USP), for example with trade name Eudragit L, S, L100-55 or L30D from R hm Pharma commercially availablely get, from the Acryl-Eze of Colorcon or from Kollicoat MAE 30 DP of BASF; The cellulose acetate phthalate ester for example gets from FMC Biopolymer is commercially available with trade name Aquacoat CPD, perhaps from the polymer of Eastman Kodak; The polyvinyl acetate phthalate ester for example gets from Colorcon is commercially available with trade name Sureteric.
The polymer of 0-15% sub-coating (isolation coat between label and the enteric coating): hydroxypropyl emthylcellulose, for example with trade name Pharmacoat 603 or 606 commercially available getting; Ethyl cellulose for example gets from FMC Biopolymer is commercially available with trade name Aquacoat ECD, or from the Surelease of Colorcon, and they are with ethyl cellulose: HPMC=1: the mixture of 1 to 1: 10 ratio; Polyvinyl alcohol for example gets from Colorcon is commercially available with trade name Opadry II HP (model 85F).
0-10% plasticizer, for example glycerol triacetate, triethyl citrate, PEG4000, PEG6000, PEG8000, ethyl phthalate, ethyl sebacate, CitroflexA-2 etc.
The 0-15% antiplastering aid, silicon dioxide for example is as with commercially available getting such as trade name Aerosil 200, Syloid 244FP, Talcum, glyceryl monostearates.
Organic solvent or its contain and do not contain the mixture of water, and for example ethanol, acetone, isopropyl alcohol or water are according to need with dissolving or disperse the coating polymer and the excipient of coating solution.
The 0-0.5% sodium hydroxide is used for the polymer of redispersion aqueous enteric coating suspension, for example is used for redispersion Eudragit L100-55.
The further aspect of the present invention provides the method for coating pharmaceutical composition described herein, and this method can comprise:
Under the situation of organic enteric coating solution:
(1) enteric coating polymer and plasticizer are dissolved in the organic solvent and
(2) antiplastering aid is disperseed.
Under the situation of aqueous dispersion coating:
(1) with plasticizer dissolving or fine dispersion in water,
(2) antiplastering aid is disperseed, last
(3) add suspension (for example Aqoat or Eudragit L100-55) or the commercially available aqueous polymer dispersions that gets (for example Eudragit L30D, Acryl-Aze, Kollicoat MAE 30D) that redissolves.
Randomly can use isolation coat, it for example comprises the aqueous solution of suitable polymer, as hydroxypropyl emthylcellulose (HPMC) (4-8%), plasticizer (0-3%) and antiplastering aid (0-3%).Can add aqueous ethylcellulose dispersion, for example Aquacoat ECD or Surelease, its scope be 1: 10 to 1: 1 (ethyl cellulose: HPMC), to improve the isolation effect of sub-coating.According to the size of minitablets/pellets, the total amount of clothing of the used end can be 3-15% (may be 5-10% more).Be sub-coating effectively, can use the polyvinyl alcohol (Opadry II HP) of the heavy 2-10% of core.Again on the one hand, clothing can not use any other additive with the form use of the organic suspension in ethanol/acetone 1: 1 (every part of about 6-10% polymer of solvent) at the bottom of the HPMC.
Use optional coating pan or the fluidized-bed coating machine that utilizes the Wurster principle, enteric coating and/or end clothing can be applied as formulation weight 2 to 45%, the coatings of about 10-25% for example, for example for bolus, as have the bolus of about 5 to 15mm diameters; And the coatings of about 20-40% of formulation weight, for example for tabloid, as minitablets, as have about 1.5 to 4mm diameters, as the tabloid of 1.7 to 2mm diameters.Clothing layer of the described end can constitute about 2 to 15%, about 4-10% for example of formulation weight, for example for bolus; And about 8-15%, for example for tabloid, as minitablets or piller.Enteric coat layer can constitute about 5-40% of formulation weight, and for example about 8-20% is for example for bolus; And about 15-30%, for example for tabloid, as minitablets or piller.This layer can guarantee that the intestinal tolerance in simulated gastric fluid or 0.1N HCl solution (according to PhEur or USP) reaches 1-3 hour according to the size of minitablets/pellets.In addition, the expansion at stomach resistance test SMIS should reduce to minimum.
The further aspect of the present invention provides pharmaceutical composition mentioned above, it provides drug release completely, for example in the complete disintegrate that is no more than dosage form in 4 hours, for example through contacting with gastrointestinal tract, for example under the situation of non-enteric coated dosage forms under one's belt, perhaps under the situation of enteric coated dosage forms intestinal than top, small intestinal for example.For example can be provided in about 1 to 4 hour, for example in 1 to 3 or 1 to 2 hour or about 2 to 4 as 2 to 3 hours in complete drug release.
The effectiveness of all pharmaceutical compositions of the present invention can be observed in standard animal model and standard clinical tests, for example with the drug dose of the known indications that provides treatment active drug blood drug level, for example use the dosage of 2.5-1000mg for 75kg mammal such as per day for adults.The bioavailability of the increase of the medicine that is obtained by this compositions can be observed in standard animal experiment and clinical trial.
Following examples are illustrative, rather than are used to limit scope of the present invention described herein.Described embodiment only represents prompting enforcement method of the present invention.The amount of each composition that the percetage by weight of using among each embodiment with pharmaceutical composition is represented is listed in respectively in the form of each self-described.
Embodiment
1, minitablets
With medicine, organic acid, polymer and any other tabletting mixed with excipients, water or organic solvent wet granulation in mortar.After 40 ℃ of dryings, the dried particles that will be used to prepare minitablets sieves by 400 μ m sieve.Add the foreign minister who comprises silicon dioxide and magnesium stearate, fully mix.This mixture is pressed into minitablets with 1.7 to 2mm diameters.
| Embodiment 1 | ||
| [％] | The mg/ capsule | |
| Methocel K100LV | 30.0 | 75.00 |
| Dipyridamole | 10.0 | 25.00 |
| Fumaric acid | 20.0 | 50.00 |
| Lactose 200 orders | 34.0 | 85.00 |
| HPMC 3cps | 2.67 | 6.68 |
| Magnesium stearate | 1.33 | 3.33 |
| Aerosol 200 | 2.00 | 5.00 |
| 100.00 | 250.00 |
| Embodiment 2 | ||
| [％] | The mg/ capsule | |
| Methocel K100LV | 30.0 | 75.00 |
| Dipyridamole | 10.0 | 25.00 |
| Fumaric acid | 40.0 | 100.00 |
| Lactose 200 orders | 14.00 | 35.00 |
| HPMC 3cps | 2.67 | 6.68 |
| Magnesium stearate | 1.33 | 3.33 |
| Aerosol 200 | 2.00 | 5.00 |
| 100.00 | 250.00 |
| Embodiment 3 | ||
| [％] | The mg/ capsule | |
| Methocel K100LV | 30.0 | 75.00 |
| Lactose 200 orders | 54.0 | 135.00 |
| Dipyridamole | 10.0 | 25.00 |
| Fumaric acid | 0.00 | 0.00 |
| HPMC 3cps | 2.67 | 6.68 |
| Magnesium stearate | 1.33 | 3.33 |
| Aerosol 200 | 2.00 | 5.00 |
| 100.00 | 250.00 |
| Embodiment 4 | [％] | The mg/ capsule |
| Methocel K100LV | 30.0 | 75.00 |
| Dipyridamole | 10.0 | 25.00 |
| Succinic acid | 20.0 | 50.00 |
| Lactose 200 orders | 34.0 | 85.00 |
| HPMC 3cps | 2.67 | 6.68 |
| Magnesium stearate | 1.33 | 3.33 |
| Aerosol 200 | 2.00 | 5.00 |
| 100.00 | 250.00 |
| Embodiment 5 | ||
| [％] | The mg/ capsule | |
| Methocel K100LV | 30.0 | 75.00 |
| Dipyridamole | 10.0 | 25.00 |
| Succinic acid | 40.0 | 100.00 |
| Lactose 200 orders | 14.00 | 35.00 |
| HPMC 3cps | 2.67 | 6.68 |
| Magnesium stearate | 1.33 | 3.33 |
| Aerosol 200 | 2.00 | 5.00 |
| 100.00 | 250.00 |
| Embodiment 6 | ||
| [％] | The mg/ capsule | |
| Methocel K100LV | 30.0 | 75.00 |
| Dipyridamole | 10.0 | 25.00 |
| Fumaric acid | 20.0 | 50.00 |
| Lactose 200 orders | 34.0 | 84.99 |
| HPMC 3cps | 2.67 | 6.68 |
| Magnesium stearate | 1.33 | 3.33 |
| Aerosol 200 | 2.00 | 5.00 |
| 100.00 | 250.00 |
2. piller
Active component, organic acid, polymer and for example microcrystalline Cellulose are mixed the preparation dry mixture in planetary-type mixer.Add purified water, obtain wet thing piece, use the sieve of the suitable size thing piece that should wet to extrude subsequently.With this extrudate sphering, intensive drying is sieved with the size of selecting to be fit in spheronizator, obtains the short time modified release pellets.
| Embodiment 7 | ％w/w | The mg/ |
| Methocel K100LV | ||
| 30 | 75 | |
| Dipyridamole | 10 | 25 |
| |
20 | 50 |
| Lactose monohydrate 200 |
40 | 100 |
3. enteric coating:
Embodiment 1 to 4:
The preparation of end clothing:
This end clothing is by the aqueous solution preparation of polymer, plasticizer and antiplastering aid.Randomly add aqueous ethylcellulose dispersion (Aquacoat ECD or Surelease).Perhaps, the polymer organic suspension in preparation water or the ethanol/propanol 1: 1.
The preparation of enteric coating:
Under the situation of organic enteric coating solution, enteric coating polymer and plasticizer are dissolved in after the organic solvent, antiplastering aid is disperseed.Under situation by the aqueous dispersion coating, with plasticizer dissolving or fine dispersion in water, antiplastering aid is disperseed, add suspension (being Aqoat or Eudragit L100-55) or the commercially available aqueous polymer dispersions that gets (Eudragit L30D, Acryl-Aze, Kollicoat MAE 30D) that redissolves at last.
Coating method:
Use optional coating pan or the fluidized-bed coating machine that utilizes the Wurster principle, coating is applied as 2 to 45% coatings (for bolus is about 10-25%, is 20-40% for tabloid/minitablets).End clothing layer: 2-15% (bolus 4-10%, minitablets/pellets: 8-15%)/enteric coat layer: 5-40% (bolus: 8-20%, minitablets/pellets: 15-30%).This layer guarantees that according to the size of minitablets/pellets the intestinal tolerance in simulated gastric fluid or 0.1N HCl solution (according to Ph Eur or USP) reaches 1-3 hour.In addition, the expansion at stomach resistance test SMIS should reduce to minimum.
| Embodiment 1 | Part | ％ | The mg/250mg core | The mg/8mg core |
| End coating | ||||
| HPMC 3cps | 5.0 | 25.0 | 12.50 | 0.80 |
| Triethyl citrate | 0.5 | 2.5 | 1.25 | 0.08 |
| Talcum | 0.5 | 2.5 | 1.25 | 0.08 |
| Water is an amount of | ||||
| Enteric coating | ||||
| Eugragit L30D (doing) | 10.0 | 50.0 | 25.00 | 1.60 |
| PEG 6000 | 2.0 | 10.0 | 5.00 | 0.32 |
| Syloid 244 FP | 2.0 | 10.0 | 5.00 | 0.32 |
| Water is an amount of | ||||
| Amount to (doing) | 20.0 | 100.0 | 50.00 | 3.20 |
| |
Part | ％ | The mg/250mg core | The mg/8mg core |
| End coating | ||||
| HPMC 3cps | 6.0 | 26.67 | 15.0 | 0.960 |
| Aquacoat ECD (doing) | 2.0 | 8.89 | 5.0 | 0.320 |
| Triethyl citrate | 0.6 | 2.67 | 1.5 | 0.096 |
| Glyceryl monostearate | 0.4 | 1.77 | 1.0 | 0.064 |
| Water is an amount of | ||||
| Enteric coating | ||||
| HPMC AS(Aqoat)MF | 10.0 | 44.44 | 25.00 | 1.600 |
| Triethyl citrate | 2.5 | 11.11 | 6.25 | 0.400 |
| Talcum | 1.0 | 4.44 | 2.5 | 0.160 |
| Water is an amount of | ||||
| Amount to (doing) | 22.5 | 100.0 | 56.25 | 3.600 |
| Embodiment 3 | Part | ％ | The mg/250mg core | The mg/8mg core |
| End coating | ||||
| HPMC 3cps | 5.0 | 32.5 | 12.5 | 0.80 |
| Ethanol/acetone 1: 1 is an amount of | ||||
| Enteric coating | ||||
| HP 50 | 8.0 | 51.9 | 20.0 | 1.28 |
| Glycerol triacetate | 0.8 | 5.2 | 2.0 | 0.13 |
| Aerosil 200 | 1.6 | 10.4 | 4.0 | 0.26 |
| Ethanol/acetone 1: 1 is an amount of | ||||
| Amount to (doing) | 15.4 | 100.0 | 38.5 | 2.47 |
| Embodiment 3b | Part | ％ | The mg/250mg core | The mg/8mg core |
| Enteric coating | ||||
| HP 50 | 10 | 71.43 | 25.0 | 1.60 |
| Ethyl sebacate | 1 | 7.14 | 2.5 | 0.16 |
| Talcum | 3 | 21.43 | 7.5 | 0.48 |
| Ethanol/acetone 1: 1 is an amount of | ||||
| Amount to (doing) | 14 | 100.0 | 34.0 | 2.24 |
| Embodiment 4 | Part | ％ | The mg/250mg core | The mg/8mg core |
| End coating | ||||
| Opadry II HP | 4.00 | 21.46 | 10.00 | 0.640 |
| Water is an amount of | ||||
| Enteric coating |
| Eudragit L100-55 | 10.00 | 53.65 | 25.00 | 1.600 |
| Sodium hydroxide | 0.14 | 0.75 | 0.35 | 0.022 |
| Triethyl citrate | 2.50 | 13.41 | 6.25 | 0.400 |
| Syloid 244 FP | 2.00 | 10.73 | 5.00 | 0.320 |
| Water is an amount of | ||||
| Amount to (doing) | 18.64 | 100.0 | 46.60 | 2.982 |
| Embodiment 4b | Part | ％ | The mg/250mg core | The mg/8mg core |
| Enteric coating | ||||
| Eudragit L100-55 | 10 | 76.92 | 25.0 | 1.60 |
| Triethyl citrate | 1 | 7.69 | 2.5 | 0.16 |
| Syloid 244 |
2 | 15.38 | 5.0 | 0.32 |
| Isopropanol 97: 3 is an amount of | ||||
| Amount to (doing) | 13 | 100.0 | 32.5 | 2.08 |
4, study in vitro dissolution
Dissolution study carries out in USP1 type instrument (100rpm, 37 ℃ and 500ml dissolution medium).Tablet is exposed to constant pH medium, and (phosphate buffered solution pH=6.8) reaches 6 hours interval.0.1%SDS is added in the buffer solution to build sink condition (sink condition).From dissolution medium, extract the sample of predetermined space, filter by 0.45 μ m membrane filter.Sentence spectrophotography (Perkin Elmer UV/VIS) at the 410nm wavelength and analyze dipyridamole, by quantitatively acid release of HPLC.The fresh buffer that adds equivalent is to keep constant stripping volume.All tests are carried out in triplicate.
HPLC-analyzes
At Agilent HPLC, the enterprising circumstances in which people get things ready for a trip analysis of spectrum of HP1100 (be equipped with Chromeleon software and be used for data analysis).In initial 8 minutes, mobile phase consists of the 0.1M NH that is adjusted to pH2.7 with phosphoric acid
4H
2PO
4Buffer solution.Use gradient (acetonitrile/NH subsequently
4H
2PO
4Buffer solution (pH2.7)), removing fully may remaining medical compounds.Use Inertsil C8-3.5 μ m, 4.6*150mm (Erchatech AG, Switzerland) finishes separation.Use flow velocity 1ml/min, inject volume 5 μ L (FA) and 10 μ L (CA and SA), running time 15min.At 210nm place record chromatogram.
4.1 Fig. 1 proof discharges medical compounds dipyridamole 10% (dipyridamole is represented with hollow triangle among Fig. 1) and fumaric acid (variable concentrations) (fumaric acid is represented with filled circles among Fig. 1) from Methocel K4M 30% tablet of base material simultaneously.Leaching condition: a) phosphate buffered solution pH6.8, SDS0.1%; B) 0.01N HCl.Analyze medicine by UV spectrophotography (wavelength 410nm), analyze fumaric acid by HPLC.
4.2 Fig. 2 proves that the pH regulator agent is (in Fig. 2, fumaric acid 20%w/w shows with filled circles, succinic acid 20%w/w shows that with black triangle anacidity shows with open circles) be the influence that discharges the tablet of base material to medical compounds (dipyridamole 10%) from Methocel K100LV 30%.Leaching condition: a) phosphate buffered solution pH6.8; SDS 0.1%.Analyze medicine by UV spectrophotography (wavelength 410nm).
4.3 the pH-independence of Fig. 3 proof drug release when being with or without fumaric acid (in Fig. 3, have fumaric acid (pH6.8) to show with hollow triangle, have fumaric acid (pH2) to show with black triangle, no fumaric acid (pH2) shows with open squares).Leaching condition: a) phosphate buffered solution pH6.8, SDS0.1%; B) 0.01N HCl.Analyze medicine by UV spectrophotography (wavelength 410nm).
Under higher pH environment, the dissolution of pH dependent drug compound improves.Mix for example fumaric acid of pH regulator agent, can with solid dosage forms for example minitablets/pellets inside and the pH of close proximity change into more acid, thereby improve the dissolubility and the dissolution of medicine.Polymer helps to keep the inner or target pH on every side of dosage form.In whole stripping, realized rate of release in medicine and the pH regulator agent.
Be described in conjunction with describing in detail although should be appreciated that the present invention, above-mentioned explanation is illustrative and unrestricted the present invention, and scope of the present invention is determined by claims.Other aspect, advantage and modification all fall in the scope of the said claims.
Claims (12)
1, pharmaceutical composition, it comprises pH-dependent drug compound, pH regulator agent and blocker, and wherein after 1 to 4 hour maximum dissolution time, the drug release in the pharmaceutical composition is complete.
2, the pharmaceutical composition of claim 1, wherein after 2 to 4 hours maximum dissolution time, the drug release in the pharmaceutical composition is complete.
3, claim 1 or 2 pharmaceutical composition, wherein the pH regulator agent is the organic acid that is selected from citric acid, fumaric acid, succinic acid, adipic acid and maleic acid.
4, the pharmaceutical composition of any aforementioned claim, wherein blocker is a polymer, for example water-soluble polymer.
5, the pharmaceutical composition of any aforementioned claim, its Chinese medicine and pH regulator agent discharge in pharmaceutical composition simultaneously.
6, the pharmaceutical composition of any aforementioned claim, it comprises enteric coating.
7, the pharmaceutical composition of claim 6 further is included in the contagion gown between acid core and the enteric coating.
8, the pharmaceutical composition of any aforementioned claim is the form of minitablets or piller.
9, pharmaceutical composition, it comprises pH dependent drug, fumaric acid and cellulose derivative.
10, the pharmaceutical composition of any aforementioned claim provides in the object of reduction and the purposes of the bioavailability of object differences and increase.
11, each pharmaceutical composition of claim 1 to 9 is provided at the purposes that medicine discharges fully after 1 to 4 hour the maximum dissolution time in pharmaceutical composition.
12, each pharmaceutical composition of claim 1 to 9 is provided at the purposes that intestinal discharges in pharmaceutical composition fully than the top medicine.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0517204.4 | 2005-08-22 | ||
| GB0517204A GB0517204D0 (en) | 2005-08-22 | 2005-08-22 | Organic compounds |
| GB0518359A GB0518359D0 (en) | 2005-09-08 | 2005-09-08 | Organic compounds |
| GB0518359.5 | 2005-09-08 | ||
| PCT/EP2006/008243 WO2007022956A2 (en) | 2005-08-22 | 2006-08-22 | Pharmaceutical compositions comprising a ph-dependent drug, a ph modifier and a retarding agent |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011101278307A Division CN102198273A (en) | 2005-08-22 | 2006-08-22 | Pharmaceutical compositions comprising a pH-dependent drug, a pH modifier and a retarding agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101247792A true CN101247792A (en) | 2008-08-20 |
| CN101247792B CN101247792B (en) | 2011-07-06 |
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ID=35098109
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800306218A Expired - Fee Related CN101247792B (en) | 2005-08-22 | 2006-08-22 | Pharmaceutical compositions comprising a PH-dependent drug, a PH modifier and a retarding agent |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101247792B (en) |
| GB (1) | GB0517204D0 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107666914A (en) * | 2015-06-04 | 2018-02-06 | 辉瑞公司 | Pa Boxini solid dosage forms |
| CN110251475A (en) * | 2019-07-25 | 2019-09-20 | 沈阳东星医药科技有限公司 | A kind of 9-hydroxy-risperidone tablet and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2470599A1 (en) * | 1979-12-07 | 1981-06-12 | Panoz Donald | IMPROVEMENTS IN PROCESSES FOR THE PREPARATION OF GALENIC SHAPES WITH DELAYED ACTION AND PROGRAMMED RELEASE AND GALENIC FORMS OF MEDICAMENTS THUS OBTAINED |
| DE3000979A1 (en) * | 1980-01-12 | 1981-07-23 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW DIPYRIDAMOL RETARD FORMS AND METHOD FOR THEIR PRODUCTION |
| DE3124090A1 (en) * | 1981-06-19 | 1983-01-05 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW ORAL DIPYRIDAMOL FORMS |
-
2005
- 2005-08-22 GB GB0517204A patent/GB0517204D0/en not_active Ceased
-
2006
- 2006-08-22 CN CN2006800306218A patent/CN101247792B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107666914A (en) * | 2015-06-04 | 2018-02-06 | 辉瑞公司 | Pa Boxini solid dosage forms |
| CN113616606A (en) * | 2015-06-04 | 2021-11-09 | 辉瑞公司 | Solid dosage forms of palbociclib |
| TWI763881B (en) * | 2015-06-04 | 2022-05-11 | 美商輝瑞股份有限公司 | Solid dosage forms of palbociclib |
| CN110251475A (en) * | 2019-07-25 | 2019-09-20 | 沈阳东星医药科技有限公司 | A kind of 9-hydroxy-risperidone tablet and preparation method thereof |
| CN110251475B (en) * | 2019-07-25 | 2021-07-16 | 沈阳信康药物研究有限公司 | Paliperidone tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101247792B (en) | 2011-07-06 |
| GB0517204D0 (en) | 2005-09-28 |
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