CN1213739C - Granular product or tablet containing an effervescent system and an active pharmaceutical substance, as well as a method for its preparation - Google Patents
Granular product or tablet containing an effervescent system and an active pharmaceutical substance, as well as a method for its preparation Download PDFInfo
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- CN1213739C CN1213739C CN95191882.6A CN95191882A CN1213739C CN 1213739 C CN1213739 C CN 1213739C CN 95191882 A CN95191882 A CN 95191882A CN 1213739 C CN1213739 C CN 1213739C
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- effervescent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
Abstract
In accordance with this invention, there is provided a granular product with an effervescent system which comprises acid-sensitive pharmaceutically active substances, such as, for example, beta-carotene, cimetidine, ranitidine or cisapride, which is specially useful to prevent antacid action, having an acid-binding capacity below about 5meq, at a weight of about 1.6 to about 2.3 grams. The effervescent grains are made from carrier crystals of at least one solid, edible organic acid, preferably citric acid, and are present as a granular product, separate from the pharmaceutically active substance, and are coated with at least one layer of a neutral substance which is soluble in water and/or alcohol and which is able to bring about a melting point depression of the acid grains at their surface, such as, for example, a water-soluble polymer, a higher alcohol, a carbohydrate and/or a hydrocolloid. A second coating contains at least a part of the alkali and/or alkaline earth carbonate or bicarbonate provided for the total dosage.
Description
Invention field
The present invention relates to a kind of granulated drug preparation or a kind of tablet of more specifically saying so, it contains the medical substance of a kind of effervescent system and a kind of preferred acid labile, such as: cisapride, beta-carotene, a kind of H2 blocker such as cimetidine or ranitidine, and/or a kind of material with the administration of effervescent pharmaceutical dosage forms, this preparation has effervescence component or a kind of lower and sour degree of neutralization in a small amount.
Background of invention
Up to the present, what may accomplish only is the medicine of acid labile to be joined in effervescent tablet or the instant pelletized product of effervescent with stable form very difficultly, because this with the such compositions hydrolysis of effervescent system or the acidity after decomposing relevant, that is, they are not stable structures.In addition, no matter when, so a kind of material also influences the surface tension of water, foaming has appearred, and this foaming is very unwanted for the consumption of effervescent solution, in any case perhaps, the hydrophobic particles of this medicine is tending towards creep rising on glass.On the other hand, in some cases, for many medicines, a kind of antiacid side effect of effervescent tablet does not meet the requirements.Therefore, purpose of the present invention is exactly will provide a kind of to avoid the effervescent system of above-mentioned defective and provide probability for patient accepts medical substance, the material that is included in acid labile in the effervescent solution that is easy to take is interior, and these materials have hydrophobic property or influence the tensile character of horizontal plane.For fear of the antiacid effect that does not meet the requirements, further purpose of the present invention is to create a kind of effervescent tablet or a kind of instant effervescent pelletized product, the sour conjugation that they have is lower than 5 milliequivalents, and for all H2 blocker, this is particularly advantageous.At last, needed is when temperature is about 15-20 ℃, and tablet or pelletized product should be dissolved in water rapidly to be less than about 2 minutes time.
Summary of the invention
Can finish solution with a kind of according to wonderful easy, low cost of the present invention and effective and efficient manner to an above-mentioned difficult problem.For example, at first basically, acid particle is wrapped up with a kind of compositions, said composition comprises at least a neutral substance, this neutral substance causes that acid particles reduces at the fusing point of their surfaces, then thereon in conjunction with at least a second integument, it contains a kind of alkali metal and/or alkaline earth metal carbonate and/or bicarbonate, and the partial reaction product of a kind of carbonate or bicarbonate and identical or a kind of different organic acids can also be arranged.
The present invention is specifically related to following aspect:
(1) a kind of being suitable for by drinking oral administration and medication combined effervescent product acid labile, it comprises the crystallization of at least a solid edible organic acid carrier, it is characterized by this carrier crystallization and comprise the ground floor coatings and second coatings, wherein first coatings contains at least a water-soluble polymer that is selected from, sugar alcohol, the neutral substance of carbohydrate and hydrocolloid, the amount of neutral substance is from 0.05 to 1.0% weight with respect to the carrier crystallization, and second coatings contains and is selected from alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal carbonate, alkali metal bicarbonates, at least a material at least a solid edible organic acid alkali metal salt and at least a solid edible organic acid alkali salt.
(2) according to the effervescent product of (1), it is characterized by it contain be selected from alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal carbonate and alkali metal bicarbonates at least a material as outer coatings.
(3) according to the effervescent product of (1) or (2), it is granule or tablet form.
(4) according to the effervescent product of (1) or (2), it is characterized by it and contain a kind of moisture bonding agent that is selected from natrium carbonicum calcinatum and sodium sulfate.
(5) according to the effervescent product of (4), it is characterized by the content of moisture bonding agent, with respect to total mixture, be 4 to 10% weight.
(6) according to the effervescent product of (1) or (2), it is characterized by it and contain at least one coatings, coatings contains the material that is selected from solid edible organic acid alkali metal salt and/or alkali salt, chooses wantonly to comprise a kind of described neutral substance.
(7) according to the effervescent product of (1) or (2), it is characterized by it and contain the part of at least a antifoaming agent, perhaps contain at least a antifoaming agent with the pelletized product form of separating as at least one described coatings.
(8) effervescent product of basis (3), it is characterized by the antifoaming agent that it also contains active medicinal matter and is selected from dimethyl polysiloxane and simethicone, and with respect to total mixture, the content of antifoaming agent is from 0.005 to 0.5% weight, or, be from 0.05 to 2.0% weight with respect to active medicinal matter.
(9) according to the effervescent product of (3), it is characterized by, when gross weight is no more than 2.6 grams, measure according to the test 103 of USP XXIII, what it had is lower than 5 milliequivalents with sour degree of neutralization.
(10) according to the effervescent product of (9), it is characterized by, measure according to the test 103 of USP XXIII, described sour degree of neutralization is lower than 3 milliequivalents.
(11) according to the effervescent product of (3), it is characterized by, when gross weight was no more than 2.5 grams, it was lower than 180 seconds in the dissolution time in water under the room temperature.
(12) according to the effervescent product of (3), it is characterized by when gross weight is no more than 2.0 grams, it is lower than 120 seconds in the dissolution time in water under the room temperature.
(13) effervescent product of basis (3), it is characterized by comprise a kind of hydrophobic active medicinal matter and wherein hydrophobic substance be present in the isolating granule of effervescence component in, in these granules, hydrophobic substance is coated or is combined at least a material that is selected from suspending agent and neutral substance.
(14) according to the effervescent product of (13), it is characterized by described neutral substance and be selected from mannitol and sorbitol.
(15) according to the effervescent product of (13), it is characterized by granule and also contain at least a component, this component is selected from binding agent, a kind of surfactant and alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate and alkali metal bicarbonates.
(16) according to the effervescent product of (15), it is characterized by described binding agent and be selected from polyvinylpyrrolidone, the surface-active agent of living is selected from dioctyl sodium sulphosuccinate and sodium lauryl sulphate.
(17) according to (3) effervescent product, it is characterized by with respect to total mixture, it contains the cimetidine of 2 to 30% weight, a kind of solid edible organic acid of 30 to 60% weight; At least a alkali metal of 12 to 40% weight or alkaline earth metal carbonate or bicarbonate, wherein 2 to 10% weight are the sodium carbonate as the moisture bonding agent; The sweetener of 1 to 4% weight; 0.01 to a kind of neutral substance of 30% weight, wherein 0.01 to 0.05% weight is used for the neutral substance coating; 0.005 to a kind of antifoaming agent of 0.5% weight and the fumet of 0.1 to 3% weight.
(18) according to the effervescent product of (17), it is characterized by described neutral substance and contain the sorbitol of 3 to 20% weight and the mannitol of 2 to 10% weight.
(19) according to the effervescent product of (3), it is characterized by, with respect to total mixture, it contains following component: the cisapride of 0.4 to 4.5% weight; 0.4 suspending agent to 4.5% weight; 0.1 binding agent to 1% weight; 0.03 surfactant to 0.35% weight; A kind of solid edible organic acid of 30 to 55% weight; At least a alkali metal of 12 to 40% weight or alkaline earth metal carbonate or bicarbonate, wherein 2 to 10% weight are the sodium carbonate as the moisture bonding agent; 0.3 sweetener to 2.5% weight; 0.02 to the neutral substance of 55% weight, wherein 0.02 to 0.1% weight is used for the neutral substance coating; 0.005 antifoaming agent to 0.05% weight; Fumet with 0.2 to 5% weight.
(20) effervescent product of basis (19), it is characterized by binding agent is polyvinylpyrrolidone, surfactant is a dioctyl sodium sulphosuccinate, the edible organic acid is a citric acid, neutral substance is selected from maltodextrin, lactose and mannitol, and antifoaming agent is selected from dimethyl polysiloxane and simethicone.
(21) according to the effervescent product of (3), it is characterized by, with respect to total mixture, it contains following component:
The beta-carotene of-0.1 to 0.5% weight (100%);
The alpha-tocopherol acetate of-0 to 2% weight (100%);
The solid edible organic acid of-35 to 70% weight;
At least a alkali metal of-11 to 38% weight or alkaline earth metal carbonate or bicarbonate;
The sweetener of-1 to 4% weight;
The neutral substance of-0.1 to 35.0% weight, wherein 0.1 to 0.5% weight is used for the neutral substance coating; With
The fumet of-0.3 to 3% weight.
(22) according to the effervescent product of (21), it is characterized by the ascorbic acid that the solid edible organic acid comprises 0 to 10% weight, the malic acid of the citric acid of 35 to 55% weight and 0 to 5% weight.
(23) according to the effervescent product of (21), it is characterized by described alkali metal or alkali metal bicarbonates and comprise the calcium carbonate of 5 to 15% weight and the sodium bicarbonate of 5 to 20% weight.
(24) according to the effervescent product of (3), it is characterized by, with respect to total mixture, it contains following component: the hydrochloric acid ranitidine of 3 to 14% weight is equivalent to each dosage 75-300mg; The citric acid of 30 to 50% weight; The monosodium citrate of 0 to 20% weight; The sodium bicarbonate of 10 to 30% weight; The sodium carbonate of 2 to 10% weight; The sweetener of 1 to 3% weight; 0.05 to the neutral substance that is used for first coating of 0.2% weight and the additional neutral substance of 0 to 15% weight; The anti-foam granule of 0 to 8% weight and the fumet of 0.1 to 4% weight.
(25) effervescent tablet of basis (1) or (2), it is characterized by except neutral substance, it also contains at least a solid edible organic acid or this organic acid alkali metal salt, and perhaps both all contain, and wherein the crystalline acid of organic acid and carrier is identical or different.
(26) according to the effervescent product of (3), it is characterized by and contain cisapride, and when gross weight was lower than 2 grams, what it had was lower than 5 milliequivalents with sour degree of neutralization as active medicinal matter.
(27) according to the effervescent product of (26), it is characterized by when gross weight is lower than 1.6 grams, it is that have to be lower than 3 milliequivalents with degree of neutralization acid.
(28), it is characterized by the cimetidine that comprises as active medicinal matter, and when gross weight was lower than 2.5 grams, what it had was lower than 5 milliequivalents with sour degree of neutralization according to the effervescent product of (3).
(29) according to the effervescent product of (28), it is characterized by when gross weight is lower than 2.0 grams, be lower than 3 milliequivalents with the degree of neutralization of acid.
(30) according to the effervescent product of (3), it is characterized by and comprise ranitidine, and it is when gross weight is lower than 2.6 grams as active medicinal matter, what it had is lower than 3 milliequivalents with sour degree of neutralization.
(31) according to the effervescent product of (30), it is characterized by when gross weight is lower than 2.0 grams, it is that have to be lower than 2 milliequivalents with degree of neutralization acid.
(the preparation method of the effervescent product of 32. 1 kinds of bases (1), the crystallization of wherein at least a solid edible organic acid carrier provides in vacuum tank, under agitation with its be selected from water-soluble polymer, sugar alcohol, the aqueous solution of a kind of neutral substance of carbohydrate and hydrocolloid and moistening, the amount of neutral substance is from 0.05 to 1.0% weight with respect to the carrier crystallization, thereby form crystalline first coatings of carrier, a kind of alkali metal of powder type and/or alkaline earth metal carbonate and/or bicarbonate are disperseed equably and be combined on the surface layer of the first coatings humidity by mixing, thereby form crystalline second coatings of carrier, subsequently that the effervescent granule of preparation is dry and mixes with a kind of active medicinal matter and medicinal acceptable adjuvant, and choose wantonly it is pressed into tablet.
(33) according to the method for (32), wherein said active medicinal matter is a kind of medicine of acid labile.
(34) according to the method for (32), wherein said active medicinal matter is selected from H2 blocker, cimetidine, ranitidine, cisapride and solatene.
(35) method of basis (32), wherein said water solublity is except that containing neutral substance, also contain at least a solid edible organic acid or this organic acid alkali metal salt or the two all contains, the crystalline acid of wherein said organic acid and carrier is identical or different.
(36) method of basis (32) or (35), wherein by solution-wet with buffer substance, at least a additional coatings is added on the effervescent granule, and described buffer substance is selected from alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal carbonate, alkali metal bicarbonates, at least a solid edible organic acid alkali metal salt and at least a solid edible organic acid alkali salt.
(37) according to the method for (35), wherein solution further comprises a kind of neutral substance, and this neutral substance is selected from a kind of water-soluble polymer, a kind of sugar alcohol, a kind of carbohydrate and a kind of hydrocolloid.
(38) according to the method for (32), wherein except medicine, effervescent granule also mixes with a kind of pelletized product, and this pelletized product is to make by a kind of antifoaming agent in appropriate solvent being added in also dry this solvent of neutral substance particle surface.
(39) according to the method for (32), wherein that exsiccant effervescent granule is moistening with ethanol, this effervescent granule preferably contains a kind of dissolved antifoaming agent, and with this effervescent granule after drying, removes remaining moisture by ethanol evaporation.
(40) according to the method for (32), wherein before active medicinal matter is sneaked into effervescent system, with a kind of binding agent and/or a kind of surfactant, use and be dispersed on a kind of suspending agent granule and drying it with the form of solution.
(41) method of basis (32), wherein before active medicinal matter is sneaked into effervescent system, with it and at least a neutral substance, at least a suspending agent and at least a being selected from: alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal carbonate, alkali metal bicarbonates, at least a solid edible organic acid alkali metal salt, the material of at least a solid edible organic acid alkali salt mixes, after this, the solution of at least a binding agent and/or a kind of surfactant is coated and is dispersed on the compound particles at least once and drying.
The present invention will specifically more intactly be discussed below, in addition, also has the discussion and the explanation of several preferred embodiment.
Detailed Description Of The Invention
Neutral substance of the present invention comprises water-soluble and/or alcoholic acid polymer, such as polyvinylpyrrolidone; Carbohydrate, such as sucrose, tetramethylolmethane, glucose and fructose are (only under the minimal effect of integument to alkali effervescent particle surface of bicarbonate, both take place Mei Lade (Maillard) reaction and cause their flavescence in the back, so they are not particularly preferred in this article); Hydrocolloid, such as maltodextrin, dextrin and the like; Preferred especially higher alcohol, such as xylitol, mannitol and sorbitol.
Definite is that WO 93/00886 discloses a kind of external acid, may be Fructus Vitis viniferae acid delta-lactone, and it is hydrolyzed into gluconic acid, this external acid can be added in the acid carrier crystal surface, thereby has disturbed lattice and realized that fusing point reduces.Yet a kind of like this method can not provide enough protections for the active substance of acid labile certainly.The active substance that therefore also can not in practice the invention of WO 63/00886 be used for acid labile so far.
Apply for that (British patent 1270781) is the crystallization of effervescent tablet outsourcing acid carrier with a kind of thin polymeric layers, such as using polyvinylpyrrolidone, carboxymethyl cellulose or like that.Yet this can produce the prolongation of the dissolution time that does not meet the requirements, and is under 1 to 5% the situation, also can produce the difficult problem that foam forms by weight at polyvinylpyrrolidone as be shown in the examples.In addition, when being used for coating by ethanol or aqueous solution, some acid always in solution by carrier crystalline transition stratification, the active substance of the acid labile that therefore can not adequately protect.In addition, in any case, those skilled in the art have had more than 20 year and have solved a difficult problem unsatisfactorily, Here it is not only in constitutionally stable mode, and heavily adapting to the active substance of acid labile in the effervescent system with smaller sheet, described less sheet heavily has very low sour conjugation and very short dissolution time.When the dissolving of tablet ingredients (or suspending fully) when being less than 120 seconds, preferred 90 seconds or still less, it is rapid especially that effervescent tablet is considered to usually.
Yet, according to the present invention, after will be only preferred neutral substance in a small amount is used for acid particle, alkali metal and/or alkaline earth metal carbonate and/or the combination on the acid particle surface of bicarbonate particle, thus limited interaction between acid and the active substance.
In addition, the method of applying among the EP-A1-415326 is used for the acid carrier crystallization with the sugar of several times of amounts together with the sodium bicarbonate coating, thereby reach slight twinge effect, because a kind of agent or lozenge chewed, can not solve the problem or the work of combination, a kind of like this system can not react fully so that a kind of effervescent tablet reasonably is being dissolved in water in the time.The purpose of described EP-A1 is the reaction between the acid plus carbonate of will slowing down, so that do not produce a kind of undesirable high effervescent effect in mouth.
As disclosed in the prior art (US-A-4127645); if have acid with a kind of; the tablet of the heart portion that bicarbonate and calcium are formed is with a kind of neutral substance coating in addition; for example use the aqueous solution of sorbitol; ethanol or water/alcoholic solution, a kind of so like this tablet can not provide reliable protection for the material of the acid labile that contains in heart portion.Yet if (for example, maltodextrin is if necessary with a kind of mixture (US-A-4650669) that has sugar with a kind of neutral substance with this mixture; The sorbitol (US-A-5223264) that has vitamin, they only are suitable for doing a kind of chewable tablet with sensation of pricking) suppress to obtain tablet, any in two kinds of reactants will together be wrapped or undesirable agglutinating particle will occur so.In two kinds of situations, undesirable increase has appearred in the mistake that the solubilizing reaction of tablet takes place slow and dissolution time thus, or solution has contained undesirable a large amount of sugar.In addition, in agglutinating particle, acid particle also is present in unprotect ground the surface of agglutinating particle probably; Yet for concerning acid-sensitive active substance, this has caused bigger unstability.
In No. 4867942, United States Patent (USP), introduced a kind of method, in the method, the solution as buffer agent of a kind of solid edible organic acid carrier crystallization with a kind of reaction is in advance covered, particularly use a kind of acid alkali metal of a kind of solid edible organic acid and/or alkali salt.Therefore, more acidic crystallization and an amount of carbonate or bicarbonate mutually combine on this coatings.By a kind of final processing of carrying out with ethanol and vacuum drying remove various in and the water that discharges in the partial reaction.Yet, a kind of like this technology has defective, and Here it is for the medicine of acid labile, on the acidic crystallization surface, a kind of additional acid enters into a kind of and reaction alkali carbonate simultaneously, and reaction is carried out too fastly and must be carried out full and uniformly inadequately thus.Therefore, because acidic crystallization is attached on the particulate surface, so the product that is formed by this method can not be avoided the medicine of a kind of acid labile of sneaking into and its reaction fully.
On the contrary, according to the present invention, the structure of effervescent system not only can avoid a kind of medicine to sensitivity directly to contact with acidic crystallization, a kind of have the basically more effervescent tablet or the pelletized product of rock-steady structure are provided thus, and the structure of this effervescent system can also prepare littler basically tablet, that is, when dissolving, those tablets that have a small amount of effervescence component produce a kind of buffer system.Therefore, according to this tablet of the present invention, can keep far below 5 millinormal and sour degree of neutralization, this buffer system with antiacid effervescent formulation is different.In addition, according to the preparation of product, obtain a kind of blocked reaction and better go into the sheet compressibility.According to the present invention, can prepare a kind of effervescent tablet, it contains a kind of medicine of acid labile first, such as cisapride, or a kind of such as the such H2 blocker of cimetidine, and this effervescent tablet for only be have 1.6 to 2.3g tablet (or pelletized product) weight with at the bottom of the sour degree of neutralization in 5 milliequivalents.
Furtherly, the particularly preferred instantiation according to the present invention, with acidic crystallization with a kind of neutral substance coating after, at least provide the carbonate of full dosage and/or the part in the bicarbonate particle can be applicable to this coating, make and form effervescent granule by acidic crystallization, on acidic crystallization, formed first coatings of neutral substance, be second coatings of carbonate and/or bicarbonate thereon, in some cases, these carbonate and/or bicarbonate partly with acid reaction.
The present invention can be used for especially expediently as EP-B1-76340, product or the method described in US-A-4867942 and the WO 93/00886, and their description and claim have been regarded as openly in this article.
The application of neutral substance, for example, particularly a kind of sorbitol solution, the fusing point that can cause the citric acid crystal surface reduces, therefore, and on the one hand, bonding force for next step coatings has increased, this coatings contains alkali metal or alkaline earth metal carbonate and/or bicarbonate, shows slower and the more even thus and better passivation of reaction of citric acid crystal surface simultaneously, makes the medicine of acid labile be subjected to the etch of effervescent granule.On the other hand, fusing point reduces the time of the citrate recrystallize that has prolonged citric acid or formed, and this shows that effervescent granule all has better compressibility in a very long time.
Because the maximum that is dissolved in the aqueous solution is 50-70% by weight, so the amount that is applicable to the crystalline neutral substance of acid carrier is with the quantitative changeization of solvent that can moistening acid.Therefore, % by weight, is 0.05 to 1.0% with the acid preferred amount that adds that is as the criterion, preferred especially 0.07 to 0.8%.According to the present invention, the amount of adding then only has weak effect less than 0.07, and the amount that adds is less than 0.05, and then not have the effect of being correlated with: the active substance stability of structure of acid labile has reduced.The amount that adds surpasses 0.8, generally begins to have a kind of interference effect, and 1.0 when above, the activity of citric acid and effervescent system has reduced significantly.
Yet, owing to tend to need long dissolution time, be introduced in the water so that make that granule is heavy and only be used for dissolved reaction, so with regard to granule, difficulty may be lacked thereafter.In addition, use, and the solution that can prepare is 50% that so maximum 70% solution is the used neutral substance of the quantitative determination of the solution by can the moistening citric acid amount of citric acid for example because neutral substance is actually in solution.Can not carry out moistening with the unlimited a large amount of water and the solvent of back the citric acid crystallization.
In some cases, if particularly carbonate and/or the combination on neutral coatings of bicarbonate particle, so this neutral coatings also can contain solid edible organic acid in a small amount, and containing a kind of acid in some cases, this acid is different from a kind of in forming of carrier crystallization, this point is open in context, but here, still fusing point reduces and/or reaction of control effervescent and rate of dissolution in order to aggravate.
Every kind of such effervescent granule, from itself, it is actually a kind of little effervescent " tablet ", and is effervescive by itself.Therefore, if desired, can reach short dissolution time, less amount and lower and sour degree of neutralization.
Finish without citric acid by using monosodium citrate, a kind of experiment with little effervescent tablet of snap action is failed, because because the reaction of monosodium citrate and sodium bicarbonate is slower, and the effervescent reaction of having slowed down significantly, and the common acid consumption degree of such tablet surpasses 5 milliequivalents.
On the other hand, according to the present invention, a kind of very thin sodium dihydrogen citrate coatings, particularly as the 3rd or the 4th layer, if desired, it can contain a kind of additional neutral substance, play a part favourable because the 1mol monosodium citrate is in conjunction with the 1mol water of crystallization and help drying or keeping dry property like this.In addition, under any circumstance, can be once more or do not cover the surface of citric acid more completely with bicarbonate.
In addition, because the sense of taste that shows of many materials is bad, particularly those show the material of bitterness, so must keep final effervescent solution in pH value is 3.8 to 4.6 scope, are the liquid of Gong drinking because of it especially.Experiment shows, in this scope, bitter especially material more effectively can be sheltered.
Although be not essential, preferably in particulate preparation process, remove remaining water in the reaction particles by alcoholic acid a kind of final processing.Ethanol can destroy the associative key of water of crystallization, because in dry run, by evaporation the moisture of remnants is removed with ethanol.Also antifoaming agent in a small amount can be joined in the ethanol, thereby quicken the dissolving of final tablet.
Many above-mentioned medicines, particularly cimetidine and cisapride often cause foaming in effervescent tablet.Yet this is not because such as the foaming that causes because of surfactant.In other words, when stirring entry, itself does not foam activating agent.And when the effervescent particle in the tablet dissolves, formed the carbon dioxide bubble.
These bubbles break and make CO
2Break away from from the surface, now, if material a kind of indissoluble or more hydrophobic exists, so insoluble particle can be sealed CO
2Bubble, and successfully avoided breaking rapidly of bubble by forming a kind of like this thin film, thus make the bubble that has this thin film assemble from the teeth outwards and formed " foam " thus.Yet this " foam " that has formed between effervescent granule disturbs the reaction that continues, and disturbs tablet or particulate rapid dissolving thus.According to this invention, stop this situation by at least a antifoaming agent that adds very in a small amount, thereby, any " foam " beginning collapse immediately that reaction forms as effervescent.
The preferred addition of antifoaming agent is 0.005-0.5% by weight, and to comprise any filler, the total amount of flavoring agent etc. is as the criterion, or 0.05-2.0% by weight, and is as the criterion with active substance.According to the present invention, addition is less than 0.005, does not then have correlation effect; Addition then has problems or unacceptable side-effects more than 0.5.
With regard to the solubility active substance, although be to be difficult for dissolving, as about cimetidine, used percentage ratio be 0.1-0.3% (by weight, be as the criterion with active substance) simethicone, this equates and use 0.016-0.028% (about 0.03%) (heavily being as the criterion) with total sheet.With regard to such as the so insoluble hydrophobic active substances of cisapride (used is monohydrate), some difference of this situation, use therein is 1% simethicone (being as the criterion with active substance), and when the sheet with 1.6g heavily serve as on time, the amount of use is 0.006%.Cisapride needs a large amount of antifoaming agent to suppress foam as a kind of sl. sol. hydrophobic active substances obviously, and the actual minimizing of amount of filler that needs and effervescent substrate used simethicone in causing every, thereby make ratio transform.
With regard to the solubility active substance, such as cimetidine and ranitidine, requirement to simethicone is very little, in order that in the dissolved local response of effervescent tablet, suppress less foaming trend, and with regard to cisapride already mentioned above, the trend of foaming be basically increase and principle also therefore slightly different.
If a large amount of the use, after the effervescent tablet dissolving, the thin film of simethicone forms and just occurs in the surface so.Particularly with regard to insoluble active substance, because the particles aggregate of active substance also keeps suspension, thereby produced unnoticed dissolution properties, this thin film also tends to form a kind of ring on the glass wall of cup.
Yet, in some cases, also add surfactant very in a small amount, for example, docusate sodium (docusate sodium).Because they have wettable characteristic, such drug particle dissolves sooner and no longer is adhered to foamy bubble.Must accurately measure the ratio of this material, thereby reach needed dissolution characteristics.
Although in some cases, antifoaming agent can be applicable to effervescent system and/or medicine, and according to the present invention, it also is not preferred.In first kind of situation, be enough to reach the seldom amount antifoaming agent of required effect if not use, it can cause that undesirable dissolving is slowed down and the reaction of effervescence component.Under second kind of situation, only comprise those medicines, promptly when 40 ℃, when guiding to above them from a kind of solution, they do not lose any solubility or stability with a kind of form (for example, methyl ethyl ketone and acetone) of solvent with antifoaming agent.In addition, in the process of utilizing fine powdered medicine to produce, add antifoaming agent and can cause bad dispersion, because drug particle itself is attached on the antifoaming agent drop.
According to the present invention, preferably at first carry out thus forming a kind of typical pelletized product by antifoaming agent and a kind of neutral substance, thereafter with this product and effervescent system and medicament mixed, if necessary, (for example add additional adjuvant, aromatic, sweetener and the like), then this mixture is pressed into tablet form.
In the preparation process of effervescent system, discharge moisture by neutralization reaction, and can not be with this moisture by heating and/or application of vacuum and fully remove, and in storage, can from air, absorb moisture, therefore preferably the moisture combination particularly can be used natrium carbonicum calcinatum (every mol can absorb the water of 10mol) or sodium sulfate by adding a kind of moisture bonding agent.Perhaps be applicable in the crystalline coatings of carrier that by this bonding agent being joined one or more perhaps by it is joined in the total mixture, moisture can combine with this bonding agent like this.Because the activating agent of acid labile further is suppressed or avoids fully owing to the minimizing of moisture with the reaction of acid, so this has just increased the shelf life.Yet excessive this moisture bonding agent is unwanted (for example, sodium carbonate), because it can delay the effervescent reaction.
Therefore, sodium carbonate should not cover effervescent granule fully as a kind of desiccant, because only be effective dry with coming the moisture to remnants in a small amount only preferably, or delay reaction in the production process, and avoid the prolongation of undesirable tablet dissolved time.So, because the reason of the size (being approximately 0.1-0.05mm) of quantity and particle, the final sodium carbonate that adds shall not be applied to and covers (or a kind of tablet coating layer) fully, and it is unsuitable for producing a kind of successive coatings thus, and this coatings is on the sodium bicarbonate that has existed.Yet it partly depends on effervescent granule.Yet, also may after dry run, just add sodium carbonate.
In principle, the percentage amounts of sodium carbonate is with several factors vary, such as the amount of used effervescent base, the amount of used filler and type, such as the existence of other carbonate of calcium carbonate etc. in every kind of tablet.
Moisture bonding agent, particularly sodium carbonate, the preferred amount that adds is between 1 and 10, and particularly (% (is as the criterion with total amount, comprises any filler, flavoring agent etc.) 4-6 by weight).The amount that adds is less than 4, then only has a kind of weak effect, and the amount that adds is less than 1, then is that the increase of dry effect and stability is too small, and they are not according to respective effects of the present invention.The amount that adds surpasses 6, generally begins to occur a kind of result of cumbersome, because sodium carbonate dissolves slowlyer and the reaction is more difficult; The amount that adds surpasses 10%, and dissolution time is significant prolongation, because the sodium carbonate leader absorbs water (reaching 10 moles water of crystallization) in the dissolved process of effervescent tablet, that is, and with the sodium carbonate calcining, then with itself and citric acid reactions.
Here every mol that requires emphasis, in the sorbitol layer or above carry out improved independent sodium citrate and can combine with the 1mol water of crystallization, although and have the moisture of many remnants to exist, the sorbitol layer can avoid or stop any to the deleterious acid of medicine.
According to the present invention, if undertaken, even use the material that is considered to difficulty by the step of all regulations, can produce effervescent tablet so, for example, sheet heavily is 1.6g, its dissolution time will reach and be lower than 100 seconds.It shall yet further be noted that particularly cimetidine, because its hydrophobic property, under other identical condition, dissolution time has prolonged than other medicines are further.
For example,, do not add a kind ofly, make dissolving rapidly with the sorbitol solution granulating in the essential external acid of others according to WO 93/00886.
In addition, in preparation effervescent system process of the present invention, and itself with regard to tablet, the step that adopts according to the present invention can be controlled the reaction that occurs in single crystallization or particle surface place, and form a kind of partial structurtes thus, and in course of dissolution, above-mentioned required advantage all will realize in whole process.
Native system also is particularly suitable for processing material acid labile and that be slightly soluble in water.Such material shows unfavorable character in suspension, such as being example with the cisapride.As mentioned above,, be adhered to the glass wall of cup, form nonconforming ring and on the surface of drinkable liquid, tend to caking because they are tending towards foaming with effervescent system.
Can solve all above-mentioned difficult problems effectively by preparing isolating granule.For this purpose, in another instantiation of the present invention, provide a kind of carrier, it can be by a kind of Aerosil
And/or a kind of aqueous substance composition, on carrier, preferably medicine is used in partly soluble carrier particle surface, and/or is used for bonding agent and/or surfactant (if desired), and be dried, or medicine is combined with carrier surface by binding agent.
It is at most 8 that the amount of suspended material is limited to, and preferably is at most that 4.5 (% (is as the criterion with total mixture) by weight).For example, for cisapride, the sinking that produces the granule particle because amount is big after tablet dissolved increases.On the other hand, the amount of adhesive therefor was limited in for 1% (by weight) too, because otherwise it will cause the granule of active substance, suspended material and binding agent undesirable caking to occur, and they dissolve comparatively difficultly and are sink to the bottom, that is, hindered required suspension.
To do more complete description and understand the present invention the present invention with reference to following preferred specific embodiment.Yet, these embodiment only are used for explaining invention obviously, for those skilled in the relevant art, many other specific embodiments and variation obviously are easily, and they also limit scope of the present invention or claim never in any form or derive from this spirit.
On the other hand, can also be in methyl ethyl ketone or acetone and should medicinal mannitol with this medicine dissolution, Aerosil
(R)With the sodium bicarbonate coating.
Embodiment 1: contain the preparation of 200mg cimetidine effervescent tablet
A) preparation of effervescent system
The citric acid that 102 parts (by weight) thick citric acid and 25 parts (by weight) is fine powdered is (when powder particle provides when slightly making a list face; on the powder particle rough surface; have an appointment at most 30% sodium bicarbonate in conjunction with); so the preferred latter improves in the effervescent granule or a kind of pre-warmed vacuum tank of tartaric acid suction that forms in the carrier crystallization, and under agitation they is heated to about 60 ℃.Next, with a kind of solution 1 (being made by the water and the sorbitol that are 36 parts (by weight) equally) of 0.85 part (by weight), 21 parts of (by weight) citric acids and 7 parts of (by weight) sodium bicarbonate suction also are dispersed on the citric acid by mixing.Thereafter, 52.5 parts of (by weight) sodium bicarbonate and 4.4 parts of (by weight) aspartames are joined in this mixture, then this mixture is stirred and carry out drying by the vacuum that is up to 200 millibars, after this, with 1.9 parts of (by weight) sodium carbonate suction and by stirring it be dispersed in this mixture, then this mixture carried out drying by the vacuum that is up to 15 millibars.
Next, with other 0.6 part (by weight) described solution suction and by mixing it is dispersed in this mixture.The effervescent granule of gained is under agitation carried out drying in being up to 20 millibars vacuum.If necessary, also use the ethanol of 0.25 part of (by weight) 96% to come dry this mixture, and with its suction.Then, again the sodium carbonate of 9.3 parts (by weight) is combined on the effervescent granule surface.After final drying again, product is sieved.
B) preparation of granular antifoaming agent
Having bushing temperature is in 80 ℃ the vacuum blending tank, and the sorbitol powder that adds 7.7 parts (by weight) also is heated to 50 ℃.Then,, mix by jolting it is stirred, and when temperature is 45 ℃ at least,, be dried reducing under 15 millibars the vacuum condition with 30% butanone/acetone mixture (5: 3) suction of 0.2 part of (by weight) simethicone.
C) preparation of total mixture
In a kind of blender, with the cimetidine of 20 parts (by weight) and 178.4 parts (by weight) a) in the effervescent system of preparation mix 10 minutes (sorbitol powder that can add if desired, 21.1 parts (by weight)) when the 6rpm.Then with 7 parts of (by weight) b) in the Fructus Citri Limoniae fumet of antifoaming agent granule preparation and that sift out through 0.6mm and 4.5 parts (by weight) add mixing 5 minutes when 6rpm again.Final mixture is pressed into the tablet that weighs 2.3g, and this tablet contains the 200mg cimetidine and has the hardness of 6-8kp.
Embodiment 2: contain the 200mg cimetidine and contain the preparation of the effervescent tablet of Fructus Citri Limoniae and malic acid in effervescent granule
In a kind of pre-heated vacuum tank, with 102 parts (by weight) thick citric acid, 25 parts of (by weight) Powdered citric acids and 1.1 parts of (by weight) malic acids under agitation are heated to 60 ℃.A kind of solution suction that to form by 0.4 part of (by weight) water, 0.22 part of (by weight) sorbitol and 0.22 part of (by weight) malic acid and they are dispersed on the citric acid then by mixing.Next, in being up to 200 millibars vacuum, 52.5 parts of (by weight) sodium bicarbonate and 4.4 parts of (by weight) aspartames being joined in the said mixture and by stirring carry out drying.Next, the sodium carbonate suction of 1.9 parts (by weight) is dispersed in it in this mixture by stirring, carries out vacuum drying reducing under 15 millibars the condition then.At last, can carry out final drying by enough ethanol, and the sodium carbonate of 9.3 parts (by weight) is added in this mixture.All the other processes are with embodiment 1.
Embodiment 3: contain the 400mg cimetidine and as the effervescent tablet of the mannitol of neutral substance
To also under agitation be heated to 60 ℃ in the citric acid suction one pre-heated vacuum tank of 49 parts (by weight).Then, be dispersed on the citric acid with a kind of solution 1 (by the mannitol preparation of 0.25 part of (by weight) water and 0.20 part (by weight)) suction of 0.45 part (by weight) and by mixing, after this 14.7 parts of (by weight) sodium bicarbonate and 3.2 parts of (by weight) aspartames added.Reaction uses the vacuum up to 200 millibars to carry out drying from stirring then.Next with the sodium carbonate suction of 0.5 part (by weight) and by dispersed with stirring in said mixture, carry out drying with 15 millibars vacuum then.A kind of solution 2 (preparing by add the monosodium citrate of 0.16 part (by weight) in solution 1) with 0.5 part (by weight) is pumped in this mixture and by mixing and disperses subsequently.Thus obtained effervescent granule also stirs through 20 millibars vacuum drying, and is last, with the sodium carbonate adding of 2.8 parts (by weight).In this mixture, add 17.3 parts of (by weight) cimetidines, 4.3 part (by weight) mannitol, 8 parts of (by weight) sorbitol, 0.9 part of (by weight) fumet and 4 parts (by weight) are according to embodiment 1b) the antifoaming agent granule of preparation, up to being uniformly dispersed.
Embodiment 4: contain the 300mg cimetidine and as the effervescent tablet of the maltodextrin of neutral substance
With embodiment 3, for the cimetidine effervescent tablet of 300mg, select 50% maltodextrin solution, used amount is identical with the amount of 400mg form.
In all embodiment that contain 100 to 400mg cimetidines, sheet is heavy can be 2.3g.Preferred 60 to 150 seconds of dissolution time that tablet has and buffer capacity are below 5 milliequivalents, and it is according to USP XXII, and by adding 30ml, 1.0N HCl back titration (with 0.5 N NaOH) is dissolved in the effervescent tablet of 70ml water and measures.
Below to provide numerical value in the table 1 be the percent that is used for explaining one pack system in the special total mixture of preferred specific embodiment, their preferable range is as follows:
Table 1
Cimetidine 2-30% is (corresponding to a kind of 50 to 600mg first cyanogen miaows that contain
The effervescent tablet of guanidine)
Citric acid 30-60% sorbitol 5-20%
Sodium bicarbonate 10-30% mannitol 2-20%
Sodium carbonate 2-10% simethicone 0.005-0.15%
Aspartame 1-4% fumet 0.11-3%
With gross weight is 2.31 grams, contain 100,200,300 and the cimetidine effervescent tablet of the cimetidine of 400mg or the preferred percentage composition of granule capsule be summarized in the following table 2:
Table 2
100mg 200mg 300mg 400mg
Cimetidine 4.30 8.70 13 17.3
Citric acid 50 50 48.2 48.2
Sodium citrate 0.04 0.04 0.04 0.04
Radix Asparagi acyl phenylpropyl alcohol 1.74 1.64 2.54 3.24
The propylhomoserin methyl ester
Sorbitol 12.5 12.5 12.8 8.00
Sodium bicarbonate 20.7 20.7 14.7 14.7
Sodium carbonate 4.4 4.4 3.5 3.3
Mannitol 4.3 4.3 4.3
HMA Fructus Citri Limoniae 2.0 2.0 0.9 0.9
Fumet
Simethicone 0.02 0.02 0.02 0.02
Embodiment 5: the cisapride effervescent tablet
A) preparation of effervescent granule
With 655 parts of (by weight) crystallization citric acids, 70 parts of (by weight) citric acid powder and 8 parts of (by weight) saccharin sodium mixing also are heated to 60 ℃.Then a kind of solution of 2.8 parts (by weight) is pumped in this mixture and by mixing and disperses, this solution is by 0.6 part of (by weight) sorbitol, 0.3 part (by weight) trisodium citrate, 0.5 part of (by weight) citric acid and 1.6 parts of (by weight) water are formed.Next, the sodium bicarbonate of 340 parts (by weight) and the aspartame of 2 parts (by weight) are added and reaction.Before the drying, add 77 parts of (by weight) sodium carbonate, subsequently under slowly stirring with this mixture vacuum drying to 15 millibar.
B) preparation of granulated drug
As described below, insoluble hydrophobic cisapride is attached to the material of suspension by the surfactant of a kind of binding agent and a kind of a small amount of: contain 10 parts of (by weight) cisaprides with a kind of in 1 part of (by weight) ethanol and 40 parts of (by weight) acetone, the solution effects of 2 parts of (by weight) polyvinylpyrrolidones and 0.8 part of (by weight) docusate sodium is in 10 parts of (by weight) Aerosil
(R), make it evenly to loose and drying when stirring.Granule is crossed the sieve of 0.1-0.3mm.
C) preparation of final mixture
In 1152 parts of (by weight) effervescent granules, add 50 parts of (by weight) maltodextrins, 100 parts of (by weight) lactose, 184 parts of (by weight) mannitols, 40 parts of (by weight) fumet, part 50.2 (by weight) anti-foam granule (0.2 part of (by weight) simethicone is wrapped on 50 parts of (by weight) mannitols) and b) in the granulated drug of preparation, mix and carry out 15 minutes so that homodisperse, then the compacting of this mixture is formed the tablet of 1.6g, this tablet have with sour degree of neutralization only be 2 milliequivalents.Up to the present have so low and cisapride effervescent tablet sour degree of neutralization the unknown.
Embodiment 6: the beta-carotene effervescent tablet
To acid and the highstrung material of oxidation, must be noted that coverture to this with good especially acid.Surface and contact area at beta-carotene must keep alkalescence.Therefore effervescent granule is covered with calcium carbonate at least in part, to guarantee a kind of basic surface.Yet this has caused long slightly dissolution time really, and needs in this case, because when tablet dissolved, β-Hu Luo element needs the time to suspend.Described in the US-A-5223264 that begins as this paper, a large amount of sorbitol never is applicable to the beta-carotene effervescent tablet of planning in water dissolving or suspending.
A) preparation of effervescent granule
With 1315 parts of (by weight) citric acids, 7 parts of (by weight) saccharin sodium and 45 parts of (by weight) sodium cyclamate are heated to 50 ℃ in a kind of vacuum tank.A kind of solution is by 19 parts of (by weight) citric acids of 3.6 parts of (by weight) calcium carbonate, 12 parts of (by weight) sorbitol and 45 parts of (by weight) water prepare, and with this solution stirring adding of 16.8 parts (by weight) and by mixing it are dispersed on the citric acid.Next, 400 parts of (by weight) calcium carbonate and 190 parts of (by weight) citric acids are added and this mixture under agitation is heated to 60 ℃.Then carry out the granulating second time, and after disperseing and mixing, add the sodium bicarbonate of 403 parts (by weight), before drying, also will add the sodium carbonate of 52 parts (by weight) with 44 parts of (by weight) above-mentioned solution.Then with this mixture under stirring at a slow speed with vacuum drying to 15 millibar.
B) preparation of final mixture
130 parts of (by weight) sorbitol and 540 parts of (by weight) mannitols and 50 parts of (by weight) fumet; the capsular beta-carotene of a kind of bag that can suspend in water and it are equivalent to 100% beta-carotene of 2 to 15 parts (by weight); if desired; add 50 to 250 parts of (by weight) vitamin Cs and/or a kind of solid alpha-tocopherol acetate that can in water, suspend (100% alpha-tocopherol acetate that is equivalent to 10 to 75 parts (by weight)); if desired; still can add other vitamin, with above-mentioned substance and 2415 parts (by weight) a) in the effervescent granule of preparation mix.The sheet that product has heavily is that 3.3g and its dissolution time are 60 to 90 seconds.
Embodiment 7: the ranitidine effervescent tablet
A) preparation of effervescent granule
With 840 parts of (by weight) crystallization citric acids, 210 parts of (by weight) citric acid powder, 45 parts of (by weight) sodium cyclamate and 4 parts of (by weight) saccharin sodium heat down in 60 ℃ in a kind of vacuum blending tank.Then with a kind of by 6 parts of (by weight) water, the solution suction that 1 part of (by weight) sodium citrate and 3 parts of (by weight) sorbitol are formed is also disperseed by stirring.Next add the sodium bicarbonate of 500 parts (by weight) and make their reactions, after this add 370 parts of (by weight) monosodium citrates, also make their reactions.At last, add the sodium carbonate of 100 parts (by weight) and under stirring at a slow speed, granule is carried out drying and reaching 15 millibars.
B) preparation of final mixture
In the effervescent granule of preparation, add 167 parts of (by weight) hydrochloric acid ranitidines, 125 parts of (by weight) mannitols add 100.4 parts of (by weight) granular antifoaming agent (being made up of 100 parts of (by weight) mannitols and 0.4 part of (by weight) simethicone) and fumet.This mixture mixing is used for homodisperse in 15 minutes, then it is pressed into the tablet of 2.5g.The dissolution time that this tablet has is 60 to 80 seconds, with sour degree of neutralization be about 2 milliequivalents, and content has (percent meter by weight) 6.8 hydrochloric acid ranitidines, 42.0 citric acids, 14.8 sodium citrates, 20.0 sodium bicarbonate, 4.0 sodium carbonate, 2.0 sweeteners, 5.0 mannitols, 0.1 sorbitol, 4.0 granular antifoaming agent (containing 0.016 dimethyl polysiloxane) and 1.2 fumet.
Embodiment 8:
When being heated to 60 ℃, 545 parts of (by weight) crystallization citric acids and 133 parts of (by weight) powdery citric acids or tartaric acid are mixed.Then, as the coating first time, by dispersed with stirring from the teeth outwards with a kind of solution of forming by 6 parts of (by weight) water and 4 parts of (by weight) sorbitol.Next, make the sodium bicarbonate of 222 parts (by weight) on the citric acid surface, react, and finally add the sodium bicarbonate of 80 parts (by weight).This product carries out drying with stirring at a slow speed.Granule is crossed the 1.5mm sieve, then the granule that sieves was mixed 10 minutes with 10rpm with following material, these materials have: 167 parts of (by weight) hydrochloric acid ranitidines, 100 parts (by weight) prevents foam granule (containing 0.4 part of (by weight) simethicone and 100 parts of (by weight) lactose), add 54 parts of (by weight) sweeteners and 40 parts of (by weight) fumet, said mixture is till obtaining dispersion uniformly.To plant mixture and be pressed into tablet, the heavy 1.43g of sheet, the dissolution time 65-70 second that has, hardness is 8, with sour degree of neutralization be about 1.5 milliequivalents.Do not contain monosodium citrate in this product.Up to the present also openly do not have so ranitidine effervescent tablet low and sour degree of neutralization.
Embodiment 9:
Citric acid with 38.2% and 0.26% saccharin sodium are heated to 60 ℃, use a kind of 2/3rds amounts of solution then, and with respect to final mixture, this solution is by 0.6% water, and 0.18% sorbitol and 0.12% sodium citrate are formed.Mixing by 10rpm disperses this solution 5 minutes.Add 16.2% sodium bicarbonate and 2.9% aspartame then, and they are combined on the surface of citric acid by the reaction on the neutral substance coatings.Get subsequently this solution in addition 1/3rd to carry out the second time moistening, add 12.9% monosodium citrate then, and finally add 5.2% sodium carbonate.When their are slowly mixed, by using vacuum, be 50 ℃ of dry effervescent granules to 15 millibar down at least in temperature.With alkaline effervescent granule product cross 1.5mm sieve and with 11.0% hydrochloric acid ranitidine, 6.5% mannitol, 6.5% anti-foam granule adds that 0.2% fumet mixes, this mixture is pressed into the tablet of 1.55g, the dissolution time that they have hardness be 7.3 o'clock be 50 seconds and have be lower than 2 milliequivalents with sour degree of neutralization.
Embodiment 10: only with the carrier crystalline particle of a kind of neutral substance parcel
Though cisapride is not so good as the ranitidine height to the sensitivity of acid, it still can reach antiacid protection by method as described below, because of pharmaceutical pack is embedded in the granule like this all the more especially.
A) with the preparation of the acidic crystallization of a kind of neutral substance parcel
593 parts of (by weight) crystallization citric acids and 70 parts of (by weight) citric acid powder are heated to 60 ℃.Use the solution that contains 4 parts of (by weight) sorbitol in a kind of 4 parts of (by weight) water then and this solution is distributed on the surface of citric acid by mixing.At last, the citric acid with parcel carries out vacuum drying under 50 to 60 ℃.
With regard to effervescent product form that occurs and the effervescent granule form that contains second alkali metal or alkaline earth metal carbonate integument,, may protect cisapride to resist the etch of citric acid in the drug particles here by adding sodium bicarbonate.
B) preparation of drug particles
With 160 parts of (by weight) mannitols, 10 parts of (by weight) cisaprides, 5 parts of (by weight) aerosil and 10 parts of (by weight) sodium bicarbonate are heated to 60 ℃ under mixing.A kind of solution is by 27 parts of (by weight) methyl ethyl ketones (or 45 parts of (by weight) acetone), 2 parts of (by weight) ethanol, 2 parts (by weight) gathers (vinylpyrrolidone) K30,1 part of (by weight) propylene glycol and 0.8 part of (by weight) docusate sodium are formed, and get half adding of this solution and it is disperseed 5 minutes to reach evenly moistening purpose.This mixture is dried to 0.8 crust,, and, finally carries out vacuum drying by stirring dispersion once more in 5-10 minute with the second portion suction of this solution.
Active agent particle is crossed the sieve of 0.3mm and they had the defencive function that increases and come to antacid etch, this only contains sodium bicarbonate owing to them.Then with they with use neutral substance, the acidic crystallization mixing of remaining carbonate and bicarbonate and other tablet ingredients coating also is pressed into tablet.
C) preparation of final mixture
To mix with following material according to a) citric acid dry and coating, these materials have: according to b) preparation drug particles, 50 parts of (by weight) sweeteners, 80 parts of (by weight) sodium carbonate, 430 parts of (by weight) sodium bicarbonate, 50 parts of (by weight) maltodextrins, 100 parts of (by weight) lactose, 150 parts of (by weight) mannitols, 50 parts (by weight) a kind of anti-foam granule and 20 parts of (by weight) fumet, then with the said mixture compacting tablet into about 1.6g, this tablet is that 7 o'clock dissolution time is 60 to 70 seconds in hardness.
Embodiment 11: the cisapride effervescent tablet
A) preparation of effervescent granule:
Citric acid is by 300 parts of (by weight) granules, 80 parts of (by weight) fine graineds and 40 parts of (by weight) powder constituents, in the time of 60 ℃, a kind of solution that it and 5 parts of (by weight) saccharin sodium one are reinstated 2.2 minutes (by weight) is moistening equably, this solution contains 0.4 part of (by weight) sorbitol, 0.15 part (by weight) sodium bicarbonate, 0.45 part of (by weight) citric acid and 1.2 parts of (by weight) water.Then 12 parts of (by weight) malic acid suction also are combined on the sorbitol layer that forms in the citric acid crystallization equably.At last, 205 parts of (by weight) sodium bicarbonate and 1.2 parts of (by weight) aspartame suction are also carried out homodisperse once more.This material is covered with 46 parts of (by weight) sodium carbonate, carry out vacuum drying and sieve by 1.2mm.
B) the particulate preparation of active component:
12 parts of (by weight) polyvinylpyrrolidones are dissolved in 12 parts of (by weight) ethanol; Then 6 parts of (by weight) propylene glycol and 6 parts of (by weight) docusate sodiums are added and this mixture is diluted with 165 parts of (by weight) methyl ethyl ketones.Half of getting this solution is dispersed on a kind of mixture, 960 parts of (by weight) mannitols arranged, 30 parts of (by weight) Aerosil in this mixture
(R), 60 parts of (by weight) sodium bicarbonate and 61 parts of (by weight) cisaprides are heated to 60 ℃.Carry out the part drying in a vacuum, and carry out further moisteningly with second half of above-mentioned solution, be bone dry immediately and sieve by 0.3mm.
The preparation of final mixture is similar to embodiment 5.
Claims (32)
1. one kind is suitable for by drinking oral administration, medication combined effervescent product with acid labile, it comprises the crystallization of at least a solid edible organic acid carrier, it is characterized by this carrier crystallization is covered by at least a ground floor coatings and at least a second coatings basically, wherein first coatings contains at least a water-soluble polymer that is selected from, sugar alcohol, the neutral substance of carbohydrate and hydrocolloid, the amount of neutral substance is from 0.05 to 1.0% weight with respect to the carrier crystallization, and second coatings contains at least a alkali carbonate that is selected from, alkali metal hydrogencarbonate, alkaline earth metal carbonate, alkali metal bicarbonates, material at least a solid edible organic acid alkali metal salt and at least a solid edible organic acid alkali salt.
2. according to the effervescent product of claim 1, it is characterized by it and covered by carbonate or bicarbonate at last.
3. according to the effervescent product of claim 1 or 2, it is granule or tablet form.
4. according to the effervescent product of claim 1 or 2, it is characterized by it and contain a kind of moisture bonding agent that is selected from natrium carbonicum calcinatum and sodium sulfate.
5. according to the effervescent product of claim 4, it is characterized by the content of moisture bonding agent, with respect to total mixture, is 4 to 10% weight.
6. according to the effervescent product of claim 1 or 2, it is characterized by it and contain at least one coatings, coatings contains the material that is selected from solid edible organic acid alkali metal salt and/or alkali salt, chooses wantonly also to comprise a kind of described neutral substance.
7. according to the effervescent product of claim 1 or 2, it is characterized by it and contain the part of at least a antifoaming agent, perhaps contain at least a antifoaming agent with the pelletized product form of separating as at least one described coatings.
8. according to the effervescent product of claim 3, it is characterized by the antifoaming agent that it also contains active medicinal matter and is selected from dimethyl polysiloxane and simethicone, and with respect to total mixture, the content of antifoaming agent is from 0.005 to 0.5% weight, or, be from 0.05 to 2.0% weight with respect to active medicinal matter.
9. according to the effervescent product of claim 3, it is characterized by comprise a kind of hydrophobic active medicinal matter and wherein hydrophobic substance be present in the isolating granule of effervescence component in, in these granules, hydrophobic substance is coated or is combined at least a material that is selected from suspending agent and neutral substance.
10. according to the effervescent product of claim 9, it is characterized by described neutral substance and be selected from mannitol and sorbitol.
11. according to the effervescent product of claim 9, it is characterized by granule and also contain at least a component, this component is selected from binding agent, surfactant and alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate and alkali metal bicarbonates.
12. according to the effervescent product of claim 11, it is characterized by described binding agent and be selected from polyvinylpyrrolidone, surfactant is selected from dioctyl sodium sulphosuccinate and sodium lauryl sulphate.
13. according to claim 3 effervescent product, it is characterized by with respect to total mixture, it contains the cimetidine of 2 to 30% weight, a kind of solid edible organic acid of 30 to 60% weight; At least a alkali metal of 12 to 40% weight or alkaline earth metal carbonate or bicarbonate, wherein 2 to 10% weight are the sodium carbonate as the moisture bonding agent; The sweetener of 1 to 4% weight; 0.01 to a kind of neutral substance of 30% weight, wherein 0.01 to 0.05% weight is used for the neutral substance coating; 0.005 to a kind of antifoaming agent of 0.5% weight and the fumet of 0.1 to 3% weight.
14., it is characterized by described neutral substance and contain the sorbitol of 3 to 20% weight and the mannitol of 2 to 10% weight according to the effervescent product of claim 13.
15. the effervescent product according to claim 3 is characterized by, with respect to total mixture, it contains following component: the cisapride of 0.4 to 4.5% weight; 0.4 suspending agent to 4.5% weight; 0.1 binding agent to 1% weight; 0.03 surfactant to 0.35% weight; A kind of solid edible organic acid of 30 to 55% weight; At least a alkali metal of 12 to 40% weight or alkaline earth metal carbonate or bicarbonate, wherein 2 to 10% weight are the sodium carbonate as the moisture bonding agent; 0.3 sweetener to 2.5% weight; 0.02 to the neutral substance of 55% weight, wherein 0.02 to 0.1% weight is used for the neutral substance coating; 0.005 antifoaming agent to 0.05% weight; Fumet with 0.2 to 5% weight.
16. effervescent product according to claim 15, it is characterized by binding agent is polyvinylpyrrolidone, surfactant is a dioctyl sodium sulphosuccinate, the edible organic acid is a citric acid, neutral substance is selected from maltodextrin, lactose and mannitol, and antifoaming agent is selected from dimethyl polysiloxane and simethicone.
17. the effervescent product according to claim 3 is characterized by, with respect to total mixture, it contains following component:
The beta-carotene of-0.1 to 0.5% weight, 100%;
The alpha-tocopherol acetate of-0 to 2% weight, 100%;
The solid edible organic acid of-35 to 70% weight;
At least a alkali metal of-11 to 38% weight or alkaline earth metal carbonate or bicarbonate;
The sweetener of-1 to 4% weight;
The neutral substance of-0.1 to 35.0% weight, wherein 0.1 to 0.5% weight is used for the neutral substance coating; With
The fumet of-0.3 to 3% weight.
18. according to the effervescent product of claim 17, it is characterized by the ascorbic acid that the solid edible organic acid comprises 0 to 10% weight, the malic acid of the citric acid of 35 to 55% weight and 0 to 5% weight.
19., it is characterized by described alkali metal or alkali metal bicarbonates and comprise the calcium carbonate of 5 to 15% weight and the sodium bicarbonate of 5 to 20% weight according to the effervescent product of claim 17.
20. the effervescent product according to claim 3 is characterized by, with respect to total mixture, it contains following component: the hydrochloric acid ranitidine of 3 to 14% weight is equivalent to each dosage 75-300mg; The citric acid of 30 to 50% weight; The monosodium citrate of 0 to 20% weight; The sodium bicarbonate of 10 to 30% weight; The sodium carbonate of 2 to 10% weight; The sweetener of 1 to 3% weight; 0.05 to the neutral substance that is used for first coating of 0.2% weight and the additional neutral substance of 0 to 15% weight; The anti-foam granule of 0 to 8% weight and the fumet of 0.1 to 4% weight.
21. effervescent tablet according to claim 1 or 2, it is characterized by except neutral substance, it also contains at least a solid edible organic acid or this organic acid alkali metal salt, and perhaps both all contain, and wherein the crystalline acid of organic acid and carrier is identical or different.
22., it is characterized by and contain the active medicinal matter that is selected from H2 blocker, cimetidine, ranitidine, cisapride and solatene according to the effervescent product of claim 3.
23. preparation method according to the effervescent product of claim 1, the crystallization of wherein at least a solid edible organic acid carrier provides in vacuum tank, under agitation with its be selected from water-soluble polymer, sugar alcohol, the aqueous solution of a kind of neutral substance of carbohydrate and hydrocolloid and moistening, the amount of neutral substance is from 0.05 to 1.0% weight with respect to the carrier crystallization, thereby form crystalline first coatings of carrier, a kind of alkali metal of powder type and/or alkaline earth metal carbonate and/or bicarbonate are disperseed equably and be combined on the surface layer of the first coatings humidity by mixing, thereby form crystalline second coatings of carrier, subsequently that the effervescent granule of preparation is dry and mixes with a kind of active medicinal matter and medicinal acceptable adjuvant, and choose wantonly it is pressed into tablet.
24. according to the method for claim 23, wherein said active medicinal matter is a kind of medicine of acid labile.
25. according to the method for claim 23, wherein said active medicinal matter is selected from H2 blocker, cimetidine, ranitidine, cisapride and solatene.
26. method according to claim 23, wherein said aqueous solution is except that containing neutral substance, also contain at least a solid edible organic acid and/or this organic acid alkali metal salt, wherein said solid edible organic acid is identical with the crystalline acid of carrier or be another kind of acid.
27. method according to claim 23 or 26, wherein by solution-wet with buffer substance, at least a additional coatings is added on the effervescent granule, and described buffer substance is selected from alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal carbonate, alkali metal bicarbonates, at least a solid edible organic acid alkali metal salt and at least a solid edible organic acid alkali salt.
28. according to the method for claim 26, wherein said aqueous solution further comprises a kind of neutral substance, this neutral substance is selected from a kind of water-soluble polymer, a kind of sugar alcohol, a kind of carbohydrate and a kind of hydrocolloid.
29. according to the method for claim 23, wherein except medicine, effervescent granule also mixes with a kind of pelletized product, this pelletized product is to make by a kind of antifoaming agent in appropriate solvent being added in also dry this solvent of neutral substance particle surface.
30. according to the method for claim 23, wherein that exsiccant effervescent granule is moistening with ethanol, this effervescent granule preferably contains a kind of dissolved antifoaming agent, and with this effervescent granule after drying, removes remaining moisture by ethanol evaporation.
31., wherein before active medicinal matter is sneaked into effervescent system, with a kind of binding agent and/or a kind of surfactant, use and be dispersed on a kind of suspending agent granule and drying it with the form of solution according to the method for claim 23.
32. method according to claim 23, wherein before active medicinal matter is sneaked into effervescent system, with it and at least a neutral substance, at least a suspending agent and at least a being selected from: alkali carbonate, alkali metal hydrogencarbonate, alkaline earth metal carbonate, alkali metal bicarbonates, at least a solid edible organic acid alkali metal salt, the material of at least a solid edible organic acid alkali salt mixes, after this, the solution of at least a binding agent and/or a kind of surfactant is coated and is dispersed on the compound particles at least once and drying.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4406641 | 1994-03-01 | ||
| DEP4406641.4 | 1994-03-01 | ||
| CH87394 | 1994-03-23 | ||
| CH873/946 | 1994-03-23 | ||
| CH873/94-6 | 1994-03-23 | ||
| EP94203112A EP0670160B1 (en) | 1994-03-01 | 1994-10-26 | Granular product or tablet containing an effervescent system and an active pharmaceutical substance, as well as a method for its preparation |
| EP94203112.1 | 1994-10-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1142182A CN1142182A (en) | 1997-02-05 |
| CN1213739C true CN1213739C (en) | 2005-08-10 |
Family
ID=27172490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95191882.6A Expired - Fee Related CN1213739C (en) | 1994-03-01 | 1995-02-23 | Granular product or tablet containing an effervescent system and an active pharmaceutical substance, as well as a method for its preparation |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPH09509669A (en) |
| CN (1) | CN1213739C (en) |
| AU (1) | AU681256B2 (en) |
| BR (1) | BR9506964A (en) |
| CA (1) | CA2183952C (en) |
| CZ (1) | CZ291710B6 (en) |
| DE (1) | DE670160T1 (en) |
| FI (1) | FI118033B (en) |
| HU (1) | HU228147B1 (en) |
| NO (1) | NO315308B1 (en) |
| NZ (1) | NZ281228A (en) |
| PL (1) | PL181714B1 (en) |
| RU (1) | RU2153331C2 (en) |
| TW (1) | TW403658B (en) |
| WO (1) | WO1995023594A1 (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US20030070584A1 (en) | 2001-05-15 | 2003-04-17 | Cynthia Gulian | Dip coating compositions containing cellulose ethers |
| US8309118B2 (en) | 2001-09-28 | 2012-11-13 | Mcneil-Ppc, Inc. | Film forming compositions containing sucralose |
| DE10224607B4 (en) * | 2002-06-04 | 2008-03-13 | Lts Lohmann Therapie-Systeme Ag | Film-form, disintegratable preparations for drug release and process for their preparation |
| AU2002350719A1 (en) * | 2002-11-29 | 2004-06-23 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US8906940B2 (en) | 2004-05-25 | 2014-12-09 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
| US20080031942A1 (en) * | 2004-12-03 | 2008-02-07 | Takeda Pharmaceutical Company Limited | Solid Preparation |
| SI2540298T1 (en) * | 2010-02-26 | 2016-02-29 | Toray Industries, Inc. | Coated solid preparation |
| MX2014006720A (en) * | 2011-12-09 | 2014-07-09 | Merck Patent Gmbh | Anhydrous sodium carbonate with few pores. |
| WO2014065890A1 (en) * | 2012-10-25 | 2014-05-01 | Otc Nutrition Llc | Fast dissolving solid calcium mineral supplement compositions and process of making |
| KR102253847B1 (en) | 2012-12-19 | 2021-05-21 | 바이엘 애니멀 헬스 게엠베하 | Tablets with improved acceptance and good storage stability |
| CN105670003A (en) * | 2014-11-21 | 2016-06-15 | 常州坤宇环保科技有限公司 | Anti-caking agent for super absorbent resin |
| EP3318135A1 (en) * | 2016-11-03 | 2018-05-09 | Perfetti Van Melle S.p.A. | Effervescent candy material, a process for its preparation and products made therefrom |
| KR20220084089A (en) * | 2019-10-17 | 2022-06-21 | 아이에스피 인베스트먼츠 엘엘씨 | Stable Effervescent Co-Treatment Excipient Compositions and Methods for Making the Same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1039170A (en) * | 1969-02-24 | 1971-07-22 | Abbott Laboratories | Tableting medium |
| US4704269A (en) * | 1985-06-11 | 1987-11-03 | Hudson Pharmaceutical Corporation | Effervescent antacid and analgesic compositions |
| CA2023493C (en) * | 1989-08-31 | 2000-01-04 | Masami Moroi | Composition for foaming preparation |
| CA2112663C (en) * | 1991-07-01 | 2002-04-23 | Thomas Gergely | Effervescent systems using reaction doping agents |
-
1994
- 1994-10-26 DE DE0670160T patent/DE670160T1/en active Pending
-
1995
- 1995-02-23 CN CN95191882.6A patent/CN1213739C/en not_active Expired - Fee Related
- 1995-02-23 CZ CZ19962519A patent/CZ291710B6/en not_active IP Right Cessation
- 1995-02-23 JP JP7522671A patent/JPH09509669A/en active Pending
- 1995-02-23 NZ NZ281228A patent/NZ281228A/en unknown
- 1995-02-23 HU HU9602380A patent/HU228147B1/en not_active IP Right Cessation
- 1995-02-23 CA CA002183952A patent/CA2183952C/en not_active Expired - Fee Related
- 1995-02-23 AU AU18114/95A patent/AU681256B2/en not_active Ceased
- 1995-02-23 RU RU96120083/14A patent/RU2153331C2/en not_active IP Right Cessation
- 1995-02-23 BR BR9506964A patent/BR9506964A/en not_active Application Discontinuation
- 1995-02-23 WO PCT/EP1995/000650 patent/WO1995023594A1/en active IP Right Grant
- 1995-03-01 TW TW084101871A patent/TW403658B/en not_active IP Right Cessation
-
1996
- 1996-08-22 PL PL95316113A patent/PL181714B1/en unknown
- 1996-08-28 NO NO19963588A patent/NO315308B1/en not_active IP Right Cessation
- 1996-08-30 FI FI963385A patent/FI118033B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO315308B1 (en) | 2003-08-18 |
| DE670160T1 (en) | 1996-03-14 |
| FI118033B (en) | 2007-06-15 |
| HUT75677A (en) | 1997-05-28 |
| FI963385A0 (en) | 1996-08-30 |
| PL181714B1 (en) | 2001-09-28 |
| AU1811495A (en) | 1995-09-18 |
| PL316113A1 (en) | 1996-12-23 |
| WO1995023594A1 (en) | 1995-09-08 |
| CA2183952A1 (en) | 1995-09-08 |
| CZ251996A3 (en) | 1997-01-15 |
| NZ281228A (en) | 1997-06-24 |
| CZ291710B6 (en) | 2003-05-14 |
| CN1142182A (en) | 1997-02-05 |
| CA2183952C (en) | 2007-01-16 |
| JPH09509669A (en) | 1997-09-30 |
| RU2153331C2 (en) | 2000-07-27 |
| TW403658B (en) | 2000-09-01 |
| HU228147B1 (en) | 2012-12-28 |
| NO963588D0 (en) | 1996-08-28 |
| BR9506964A (en) | 1997-09-09 |
| AU681256B2 (en) | 1997-08-21 |
| NO963588L (en) | 1996-10-31 |
| FI963385A (en) | 1996-10-30 |
| HU9602380D0 (en) | 1996-10-28 |
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