CN101190185A - Alkaline drug enteric preparation and preparation method thereof - Google Patents

Abstract

The invention discloses an oral enteric-coated preparation adopting alkalescence PH regulator as medicine active component and an industrial preparation method of the preparation. The alkalescence PH regulator is selected from one of baking soda, KHCO3, sodium carbonate, citric acid, sodium citrate, potassium citrate, potassium sodium hydrogen citrate or a mixture of the substances. The medicine compound of the invention is not released in stomach but in bowel, so as to avoid defects of the existing common oral preparation that is release in stomach and is counteracted with stomach acid to cause loss of the medicine component, hiccup and gastrectasia, etc. Then the medicine effect can be thoroughly performed, and bad reaction can be greatly alleviated and the toleration of the sufferers can be greatly enhanced. In the clinical application, the invention can be used for regulating acid-alkali balance of body, correcting acid body nature, basifying urine liquid, treating metabolic acidosis and gout, etc. diseases.

Description

Enteric coated preparation of a kind of alkalescent medicine and preparation method thereof

Technical field

The present invention relates to a kind of oral enteric preparation that contains alkalescent medicine and preparation method thereof, described alkalescent medicine refers to slant acidity body fluid or urine to be adjusted to the alkaline pH regulator of normal ph scope.

Background technology

The acid-base balance of human body fluid is one of human body three big basic balances (body temperature balance, nutritive equilibrium, body fluid acid-base balance).Body fluid claims extracellular fluid again, mainly refers to the tissue fluid between blood, lymph and organ, the tissue.People's organ, system are enclosed among the specific body fluid, and body fluid constitutes the interior environment of multicellular organism, and it is stable that body fluid often keeps, and just can make body that a stable internal medium is arranged.Human body fluid has certain acid-base value, often represents with the pH value of blood, urine, saliva etc., refers generally to pH value of blood.The acid-base balance of human body is meant H+ that metabolic process the is generated cushioning effect by buffer system, and the adjusting of lung kidney and Excretion, with the H of body fluid ⁺Concentration maintains the state in normal range.The normal blood pH value is 7.35～7.45, be alkalescence and scope is narrow, this moment, every physiological function was in optimum state, organism metabolism is the most vigorous, physical ability energy is the most abundant, immunologic function is the most powerful, but the acid-base balance ability of human body self is limited after all, and about 10% the people of only having an appointment can keep body fluid in normal range; And slight unbalance (be lower than 7.35 or be higher than 7.45) will cause the various functions of human body to descend as be in sub-health state, and unbalance (be lower than 7.3 or be higher than 7.5) of severe then can cause the disease of various unknown cause.Since human body all the time not the absorption of carrying out and metabolic process final produce mostly be acidic waste, at present excessive, this four big factor of environmental pollution of overnutrition, bad life habits, stress also can cause body inner acidic material on the high side, the regulating power that surpasses human body self, make the body fluid pH value be lower than normal range, form acidic physique.The people that love is drunk soda pop, the erratic people Geng Yi that smokes for a long time, drinks, has a sleepless night, works and rests breaks the balance of organismic internal environment, forms acidic physique.Acidic physique is usually said subhealth state, and promptly health is in the state between health and the disease, often have headache, forgetful, immunity is poor, the sense of fatigue, or phenomenons such as gastrointestinal upset, constipation, anxious state of mind are big, soreness of waist and ache in legs; And because of body immunity decline, lung, kidney etc. participate in the organ burden that acid-base balance is regulated in the body, the inside of human body environment begins to worsen, not only can influence children's intelligence, also easily cause allergy, flu, multiple calculi in vivo, arteriosclerosis, hypertension, carbohydrate metabolism disease, osteoporosis diseases, also cause kinds of tumors and cancer easily.Modern medicine study proves that 100% cancer patient is an acidic physique, cancerous cell the environment of suitable growth be exactly the body fluid pH value be about 6.8 acid environment.For keeping the acid-base balance of body fluid, the acidifying trend of the body fluid that contends with, in diet, note many picked-up alkaline matters (as most vegetable, fruit), the intake that reduces acidic materials (as animal food) is necessary, but only rely on the dietary adjustments effect limited after all, especially to acidic physique and an utterly inadequate amount especially of body fluid acidify severe patient.Bicarbonate buffer system is the important means that human body is regulated the body fluid acid-base balance, HCO ₃ ^-Too much H can neutralize ⁺, keep the normal condition of body fluid.(Li Wenshuo edits " liquid undergoing treatment " Beijing: Chinese Medicine science and technology publishing house, 1999.2) is in view of body fluid pH value and H ⁺, HCO ₃ ^-Direct relation is arranged, poison at therapic acid clinically and use alkalescent medicine often, as sodium bicarbonate (potassium), sodium carbonate, sodium citrate (potassium), citron potassium hydrogen phthalate sodium, sodium lactate, tromethane, basic amino acid etc., especially extensive use absorbs good sodium bicarbonate ordinary tablet, is that human body directly provides HCO with exogenous bicarbonate ₃ ^-, make HCO in the blood plasma ₃ ^-Concentration raises, in and the H in the body fluid ⁺Thereby correction acidosis, the metabolic acidosis diseases that reason caused (" clinical application notice " Beijing is compiled by Chinese Pharmacopoeia Commission: Chemical Industry Press, 2001.4) such as treatment heating, anoxia, blood circulation depletion, pathogenic microorganism or toxin, acute or chronic renal failure, some diuretic, acid enter in the body too much, the rising of blood potassium.Above-mentioned these have been that domestic and international medical circle generally acknowledges that the clinical practice of alkaline pH regulator for a long time.

Another important use that with the sodium bicarbonate is the alkaline pH regulator of representative clinically is an alkalized urine, make uric acid, sulfonamides and hemoglobin etc. should not in urine, form crystallization or gathering, thereby prevention uric acid renal calculus, reduce the nephrotoxicity of sulfa drugs, acute haemolysis prevents that hemoglobin is deposited on renal tubules, diseases such as Comprehensive Treatment gout (" clinical application notice ", " new pharmacology " 15 editions, Chen Xinqian chief editor, Beijing: People's Health Publisher, 2003).Though citric acid is an organic acid, final metabolism is HCO in human body ₃ ^-, make HCO in body fluid and the urine ₃ ^-Concentration increases, thereby raises its pH value, and is similar to the sodium bicarbonate effect, also is usually used in alkalized urine, corrects acidosis, also is a kind of alkaline pH regulator.

Alkaline pH regulators such as sodium bicarbonate ordinary tablet are obtained generally acknowledged good efficacy in long-term clinical application, but also existing problems always affect the treatment and use.1. gastric has gastric acid, during oral alkalescent medicine medicine at first with the reaction of gastric acid generation acid-base neutralization, consume the part medicine and cause drug wastage; 2. reduce the gastric acid amount, influence stomach normal stool absorption function; 3. since with the gastric acid effect, alkaline pH regulators such as low dose of sodium bicarbonate ordinary tablet can not reach the therapeutic purposes of effective alkalization body fluid or urine; 4. after the patient took alkaline pH regulator such as sodium bicarbonate ordinary tablet, pH produced strong trough difference in the body; 5. alkaline matter and gastric acid effect produce exothermic heat of reaction, and its product causes stomach discomfort, and especially sodium bicarbonate can discharge in patient's stomach in very fast dissolving, produce CO with the gastric acid direct reaction ₂Gas, cause untoward reaction such as singultus, gastrointestinal inflation, flatulence, even symptom such as stomach spasm takes place, serious gastric ulcer patient more has the danger (" clinical application notice ", " new pharmacology " 15 editions) that causes gastric perforation, and the patient needs to take every day for several times, treatment cycle is different in size, and the time, long slightly this untoward reaction just seemed especially outstanding, became the key factor that influences patient tolerability.When 6. the patient is badly in need of strengthening dose according to the degree that is in a bad way,, can't in time adjust dosage, can only take smaller dose, be difficult to reach desirable curative effect by tolerance degree because aforementioned all side effect patients are difficult to tolerance.7. the gastric acid that has among patient gastric acid many, that have are few, clinical be difficult to measure with the gastric acid effect after the amount of residue alkaline pH regulator, cause the clinician to be difficult to grasp the optimal dose of alkaline pH regulator such as sodium bicarbonate ordinary tablet.

When at present the alkaline pH regulator of sodium bicarbonate and so on is used for disease such as acidosis, alkalized urine, hyperchlorhydria as the acid-base balance regulator, oral tablet and injection are arranged, wherein tablet is common stomach dissolution type.When the sodium bicarbonate sheet is used for alkalized urine, day recommended dose is by the oral 1～10mmol/kg of body weight, every 1g sodium bicarbonate is equivalent to the 12mmol bicarbonate radical, by adult body weight for humans 70kg, the recommended dose of adult's alkalized urine need be taken 5.833～58.333g (referring to " clinical application notice ") every day, but in actual applications, because commercially available sodium bicarbonate ordinary tablet produces a large amount of CO at gastric ₂Gas causes side reactions such as singultus, flatulence, and the patient can only obey 4g first, per 4 hours 1～2g take 16g every day at most later on, can't be according to the oral high dose of the degree of being in a bad way, have to change intravenous drip into, both uneconomical also inconvenient (" clinical application notice ").

Summary of the invention

The technical problem to be solved in the present invention is oral enteric preparation of research and development alkalescent medicine and preparation method thereof.After alkaline pH regulator of the present invention is meant metabolism in vivo, thereby can make the body fluid of slant acidity or the material that the rising of urine pH value is adjusted to normal range.Some material such as citric acid, though belong to organic acid, final metabolism is HCO in human body ₃ ^-, similar to the sodium bicarbonate effect, also be usually used in the body fluid that alkalizes, correct acidosis, also belong to alkaline pH regulator of the present invention.

The oral enteric preparation of the alkaline pH regulator of the present invention's research and development should not react with gastric acid generation acid-base neutralization substantially; Do not reduce the gastric acid amount; Do not influence stomach normal stool absorption function; Can avoid the exothermic reaction of acid-base neutralization generation and the stomach discomfort that product causes thereof, as untoward reaction such as singultus, gastrointestinal inflation, flatulences; Especially big dose and when taking does not for a long time have aforementioned all side effect, and good patient compliance has been compared notable difference with present commercial preparation; Effect steadily lastingly, even be not slow releasing preparation, strong trough difference do not occur yet in the body.The oral enteric formulation preparation method of the alkaline pH regulator of the present invention's research and development should be fit to industrial applications.

For solving the problems of the technologies described above, the invention provides following technical proposals.

A kind of oral enteric preparation of alkaline pH regulator is characterized in that: described enteric coated preparation is made up of medicated core and enteric coatings (claiming enteric film coat or enteric coating again) or enteric coated capsule; Medicated core is label, granule, powder or the micropill that alkaline pH regulator and the oral formulations adjuvant that is selected from routine, slow release or rapid release are formed; Sealing coat is arranged between medicated core and the enteric coatings or do not have sealing coat; In per 1000 or the oral enteric preparation, the alkaline pH regulator is 10～2000 grams.

Described oral enteric preparation: the alkaline pH regulator in the medicated core is selected from a kind of or their mixture in sodium bicarbonate, potassium bicarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, the citron potassium hydrogen phthalate sodium; In per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～1450 grams; The oral formulations adjuvant is selected from a kind of in binding agent, slow releasing agent, lubricant, fluidizer, the disintegrating agent or their mixture in the medicated core; Sealing coat is selected from a kind of in sealing coat coating material, the plasticizer or their mixture; Enteric coatings is made up of enteric coatings material and plasticizer; The enteric coatings material is selected from a kind of in acrylic resin polymer, cellulose acetate phthalate, the Hydroxypropyl methyl cellulose phtalate or their mixture.

Oral enteric preparation of the present invention is preferred: in per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～500 grams, and preferred alkaline pH regulator agent is 100～300 grams; Binding agent is selected from a kind of or their mixture in starch, dextrin, 30 POVIDONE K 30 BP/USP 30, hypromellose or the hyprolose in the medicated core; Slow releasing agent is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, ethyl cellulose or the Sulisi (trade (brand) name), lubricant is selected from magnesium stearate or Pulvis Talci, fluidizer is selected from micropowder silica gel or Polyethylene Glycol, and disintegrating agent is selected from starch, microcrystalline Cellulose or hyprolose; The sealing coat coating material is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP, the 30 POVIDONE K 30 BP/USP 30 in the sealing coat, and plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the sealing coat; The acrylic resin polymer is selected from a kind of or their mixture in polyacrylic resin II, polyacrylic resin III, acrylic resin aqueous dispersion enteric coating pre-mixing agent, the methacrylic resin polymer in the enteric coatings material; Plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the enteric coatings.

The preparation method of the oral enteric preparation of aforementioned alkaline pH regulator of the present invention comprises the steps:

1) alkaline pH regulator and the oral formulations adjuvant that is selected from routine, slow release or rapid release are mixed, make the medicated core of label, granule, powder or micropill form; In the medicated core of per 1000 or an oral enteric preparation, the alkaline pH regulator is 10～2000 grams;

2) behind the medicated core parcel sealing coat with label, granule or micropill form in the step 1), wrap up enteric coating again; Perhaps the medicated core with label, granule or micropill form in the step 1) directly wraps up enteric coating; Perhaps with the medicated core of the granule in the step 1), powder or micropill form, the enteric coated capsule of directly packing into.

3) with step 2) in the parcel enteric coating after granule or micropill, the conventional capsule of packing into.

The preparation method of above-mentioned alkaline pH regulator oral enteric preparation comprises: the agent of step 1) medicated core neutral and alkali pH regulator is selected from a kind of or their mixture in sodium bicarbonate, potassium bicarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, the citron potassium hydrogen phthalate sodium; In per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～1450 grams; The oral formulations adjuvant is the conventional adjuvant of pharmaceutical field, conventional amount used in the medicated core, and method for making is made the medicated core of the label, granule, powder or the micropill form that contain the alkaline pH regulator routinely; The oral formulations adjuvant is selected from a kind of in binding agent, slow releasing agent, lubricant, fluidizer, the disintegrating agent or their mixture; Sealing coat is selected from a kind of in sealing coat coating material, the plasticizer or their mixture, to the medicated core coating, obtains wrapping up the medicated core of sealing coat with sealing coat, and the sealing coat consumption is 2～6% of medicated core weight by weight; Enteric coatings is made up of enteric coatings material and plasticizer; The enteric coatings material is selected from a kind of or their mixture in acrylic resin polymer, cellulose acetate phthalate, the Hydroxypropyl methyl cellulose phtalate; With enteric coatings liquid the medicated core that wraps up sealing coat is carried out coating, it is about 1.5～3.5% to increase weight to flaky medicated core, and the medicated core weightening finish of granule or micropill shape is to 25～30%, by the medicated core weight of wrapping up sealing coat.

The preferred for preparation method of alkaline pH regulator oral enteric preparation of the present invention: in per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～500 grams, and preferred alkaline pH regulator agent is 100～300 grams; Binding agent is selected from a kind of or their mixture in starch, dextrin, 30 POVIDONE K 30 BP/USP 30, hypromellose K4, hypromellose K100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP or the hyprolose in the medicated core; Slow releasing agent is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, ethyl cellulose or the Sulisi; Lubricant is selected from magnesium stearate or Pulvis Talci, and fluidizer is selected from micropowder silica gel or Polyethylene Glycol, and disintegrating agent is selected from starch, microcrystalline Cellulose or hyprolose 15CP; The sealing coat coating material is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP and the 30 POVIDONE K 30 BP/USP 30 in the sealing coat, and plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the sealing coat; To the medicated core coating, obtain wrapping up the medicated core of sealing coat with sealing coat, the sealing coat consumption is 2～5% of a medicated core weight; The acrylic resin polymer is selected from a kind of or their mixture in polyacrylic resin II, polyacrylic resin III, acrylic resin aqueous dispersion enteric coating pre-mixing agent, the methacrylic resin polymer in the enteric coatings material, and plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the enteric coatings; The medicated core that wraps up sealing coat is carried out enteric coatings, and it is about 1.5～3.5% to increase weight to flaky medicated core, by the medicated core weight of wrapping up sealing coat.

The preferred for preparation method of alkaline pH regulator oral enteric preparation of the present invention comprises: get sodium bicarbonate 100～500 grams, add starch, magnesium stearate, be pressed into label; Hypromellose 15CP, PEG400 and aquiferous ethanol (as 40-60% ethanol, preferred 50% ethanol) are mixed, be made into the sealing coat coating solution; To the label coating, the sealing coat consumption is 2～5% of label weight by weight with the sealing coat coating solution; After polyacrylic resin II, polyacrylic resin III, Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate and ethanol mixing, be made into enteric coatings liquid; With enteric coatings liquid the label that wraps up sealing coat is carried out coating, about 1.5～3.5% to increasing weight, by the label weight of wrapping up sealing coat, make 1000 oral enteric preparations.

The preferred for preparation method of alkaline pH regulator oral enteric preparation of the present invention comprises: get sodium bicarbonate 100～500 grams, starch 10～50 grams and micropowder silica gel 0.5～2.5 gram and mix, in 1000 enteric coated capsulees of packing into.

The preferred for preparation method of alkaline pH regulator oral enteric preparation of the present invention also comprises: get sodium bicarbonate 500 grams, mix with hypromellose K100300 gram, microcrystalline Cellulose 200 grams, micropowder silica gel 5 grams and magnesium stearate 5 grams, be pressed into label; With hypromellose 15CP 16～40 grams, PEG400 4.25～10.6 gram and 540～1350 milliliters of mixing of 50% ethanol, be made into the sealing coat coating solution; To the label coating, the sealing coat consumption is about 2～5% of label weight with the sealing coat coating solution; After polyacrylic resin II 10.5～18.5 gram, polyacrylic resin III 2.1～3.7 grams, Oleum Ricini 4.2～7.4 grams, diethyl phthalate 2.1～3.7 grams, polyoxyethylene sorbitan monoleate 2.1～3.7 grams and 265～465 milliliters of ethanol are mixed, be made into enteric coatings liquid; With enteric coatings liquid the label that wraps up sealing coat is carried out coating,,, make 1000 oral enteric soluble slowly-releasing preparations by the medicated core weight of wrapping up sealing coat to increasing weight 2～3.5%.

The preferred for preparation method of alkaline pH regulator oral enteric preparation of the present invention also comprises: get sodium bicarbonate 100～300 grams, after 400～1200 milliliters of hypromellose 15CP 16～48 gram, PEG400 4～12 grams and 50% ethanol mix, 0.5mm celphere 35～100 grams are sprayed, get the medicated core of micropill form; With hypromellose 15CP 4.9～21.8 gram, PEG400 1.3～5.8 grams and aquiferous ethanol (as 40-60% ethanol, preferred 50% ethanol) mix, be made into the sealing coat coating solution, wrap up, to medicated core weightening finish 4～6% with the medicated core of sealing coat coating solution to the micropill form; After acrylic resin aqueous dispersion enteric coating pre-mixing agent 40.5～146 grams and 210～730 milliliters of mixing of water, get enteric coatings liquid; With enteric coatings liquid the medicated core that wraps up sealing coat is wrapped up, to increasing weight 25～30%, enteric coated-pellet, enteric coated-pellet is packed in 1000 conventional capsule shells.

The present invention is preferably the preparation of the various oral enteric preparations of sodium bicarbonate for slant acidity body fluid or urine being adjusted to the oral enteric preparation of the alkaline pH regulator of normal ph scope.Said preparation is mixed with the adjuvant that suits by one or more alkaline pH regulators, make the medicated core of granule, label, powder, micropill form, coat the enteric coatings film then or be filled in the enteric capsule shells, make the oral common enteric coated preparation or the enteric-coated sustained-release preparation that contain alkalescent medicine (being the alkaline pH regulator).

The medicated core of said preparation contains active constituents of medicine alkaline pH regulator, alkaline pH regulator and suitable adjuvant such as filler, binding agent, disintegrating agent, slow releasing agent, fluidizer, lubricant etc. can be mixed, make the medicated core of required label, granule, powder, micropill form according to general commonly used preparation process, wrap up based on the coating membrane of enteric coatings material then or be filled in the enteric capsule shells.

The invention provides oral enteric preparation of a kind of alkalescent medicine and compositions thereof and preparation method thereof.In principle, the present invention can be by required enteric characteristic can be provided coating membrane or the capsule shells parcel medicated core that contains active constituents of medicine realize, therefore any promptly release or slow release contains pharmaceutically dosage form and all can be used as medicated core is with coating membrane with enteric characteristic or capsule shells parcel.

Alkalescent medicine among the present invention is preferably sodium bicarbonate, also can be a kind of in the alkalescent medicines such as citric acid, sodium citrate, potassium citrate, citron potassium hydrogen phthalate sodium, and two or more compositions in the above-mentioned alkalescent medicine.

To contain alkaline pH regulator and common oral preparation adjuvant and make common label (being medicated core) back bag enteric coatings film, can obtain common enteric coatel tablets; Make slow release label (being medicated core) back bag enteric coatings film as containing principal agent alkaline pH regulator and oral slow-releasing preparation adjuvant commonly used, or common label or matrix core are coated with the enteric solubility material is that the sustained release coating film of porogen then can obtain enteric-coated sustained-release tablet.

Principal agent alkaline pH regulator and common oral preparation adjuvant are mixed and made into ordinary powder, granule or micropill packs into and can obtain enteric coated capsule in the enteric capsule shells.

Principal agent alkaline pH regulator is made granule, micropill with enteric properties to be reinstalled in the conventional capsule shell and also can obtain enteric coated capsule.

For a long time, alkaline pH regulators such as sodium bicarbonate ordinary tablet are obtained generally acknowledged good efficacy in clinical practice, the wide range of prevention that is suitable for and treatment disease owing to have the described problem of this description background technology part always, has a strong impact on its curative effect and application.The inventor is being difficult to tolerate in all side effect of aforementioned sodium bicarbonate ordinary tablet, expects that accidentally pharmaceutical field is exclusively used in the alkaline pH regulator that slant acidity body fluid or urine are adjusted to normal ph makes the oral enteric preparation.Experimental results show that, compare with present commercial preparation, alkaline pH regulator oral enteric preparation of the present invention has that good effectiveness, safety and patient comply with, toleration: it does not discharge at gastric, do not absorb, thereby do not react with gastric acid generation acid-base neutralization, can not consume the part medicine and cause drug wastage; Do not reduce the gastric acid amount, thereby do not influence the normal digestive and absorptive functions of stomach; Avoided the untoward reaction such as singultus, flatulence, stomach spasm of common gastric solubility preparation; The gastric acid that has among patient gastric acid many, that have are few, clinical be difficult to measure with the gastric acid effect after the amount of residue alkaline pH regulator, enteric coated preparation of the present invention does not discharge at gastric, does not absorb, does not react with gastric acid generation acid-base neutralization, help regulating and control clinical using dosage, improve therapeutic quality, the medication specific aim is stronger, has avoided puzzlement patient's gastric side effects substantially.

The oral enteric preparation of alkaline pH regulator of the present invention discharges the absorption onset at intestinal, owing to avoided and the gastric acid effect, dose does not run off, but capacity performance drug effect, so can correspondingly reduce taking dose.The oral enteric preparation of alkaline pH regulator of the present invention because gastric side effects significantly reduces, during clinical the needs, can according to the state of an illness need be in prescribed limit large dose oral administration, also be suitable for taking for a long time, patient tolerability is still good.

The oral enteric preparation of alkaline pH regulator of the present invention can be widely used in regulating the acid-base balance of human body, corrects acidic physique, alkalized urine, symptoms such as treatment metabolic acidosis, gout are kept normal pH value of body, both can be used for treatment and also can be used for prevention.In sum, the oral enteric preparation of alkaline pH regulator of the present invention has wide application prospect and good social effect.

Description of drawings

Fig. 1, the release profiles of sodium bicarbonate enteric-coated sustained-release tablet in simulated intestinal fluid

Among Fig. 2, experimenter's urine pH value variation diagram (n=7) figure: the time of abscissa is hour, is meant the natural hour among 1 day, is meant 8 o'clock of the morning as 8.Vertical coordinate is the average change value of experimenter's urine pH value.PH value with test the 1st sample point on the same day (7:30 in morning) is a basic point, and the pH value of each sample point is kept to its changing value mutually with basic point later on, and it is in addition average to get all experimenters' changing value, represents the urine pH value situation of change of each sample point.

The specific embodiment

Used adjuvant all meets standard under the pharmacopeia continuous item: sodium bicarbonate (Hebei Huachen Pharmaceutical Co., Ltd.); potassium citrate (Hunan Hua Ri pharmaceutical Co. Ltd); citric acid (Anhui Huayuan Biological Pharmaceutical Industry Co., Ltd.); sodium citrate (Wuxi City No.2 Pharmaceutical Factory); magnesium stearate (Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong); hypromellose (Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong); Polyethylene Glycol (Gao Nan chemical plant, PVG); polyacrylic resin II (Lianyun Harbour ten thousand safe medical material company limiteies); polyacrylic resin III (Lianyun Harbour ten thousand safe medical material company limiteies); polyoxyethylene sorbitan monoleate (China Medicine (Group) Shanghai Chemical Reagent Co.); microcrystalline Cellulose (Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong).Oleum Ricini (Huai-Hai Fine Chemical Works, chemical pure), diethyl phthalate (connection chemical reagent factory in Beijing, chemical pure).Micropowder silica gel (Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong) meets industry standard.Acrylic resin aqueous dispersion enteric coating pre-mixing agent (Shanghai Colorcon Coating Technology Co., Ltd, company standard), celphere are (available from the high medicinal core pellet company limited of Shanghai China, standard numbering: Shanghai Q/WS-1-2274-2001).

Embodiment 1: the sodium bicarbonate enteric coatel tablets

Prescription: 1000

Preparation technology: sodium bicarbonate was pulverized 80 mesh sieves, add 10% starch slurry (being that starch is made with water mixing post-heating) and make soft material with rapid agitation, 14 mesh sieves are granulated, put oven drying, 40 ℃ of baking oven initial setting temperature are warming up to 50 ℃ after 1 hour, drying; Dried granule 12 mesh sieve granulate add dried starch, magnesium stearate mixing.Detect intermediate, according to content conversion sheet weight pharmacy core.Add immersion dissolving in the ethanol by the hypromellose and the Polyethylene Glycol of writing out a prescription with sealing coat; By prescription with polyacrylic resin II in the enteric coating liquid and polyacrylic resin III put soak dissolving in the alcoholic solution after, promptly carry out the coating operation after adding Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate mixing.Slice, thin piece is put in the coating pan, rotating coating pan is blown into hot blast and makes about kettle temperature to 40 ℃, at first spray into the sealing coat coating solution, adjust atomizing pressure, hydrojet speed, coating pan rotating speed, observe the coating state, prevent adhesion, sealing coat coating about 2% (by the actual label weight that is pressed into, volatile liquid adjuvant amounts such as ethanol do not count) of increasing weight; Proceed enteric coating operation after the sealing coat coating is finished and spray end, enteric coatings about 1.5% (by label weight that coats sealing coat) that increases weight until coating.

Press Chinese Pharmacopoeia version enteric coatel tablets in 2005 inspection technique (slurry method) and check sodium bicarbonate enteric coatel tablets of the present invention, in simulated gastric fluid through the time 2 hours, outward appearance is complete indeformable, (if drug release is arranged, sodium bicarbonate and sour neutralization can be emitted CO in no bubble generation ₂Gas forms bubble), do not discharge ingredient basically, but in the simulated intestinal fluid environment through the time 20 minutes the time, medicine discharges fully.

Embodiment 2: the sodium bicarbonate enteric coatel tablets

Prescription: 1000

Preparation technology: sodium bicarbonate was pulverized 80 mesh sieves, add 10% starch slurry and make soft material with rapid agitation, 14 mesh sieves are granulated, and put oven drying, and 40 ℃ of baking oven initial setting temperature are warming up to 50 ℃ after 1 hour, drying; Dried granule 12 mesh sieve granulate add dried starch, magnesium stearate mixing.Detect intermediate, according to content conversion sheet weight pharmacy core.Add immersion dissolving in the ethanol by the hypromellose and the Polyethylene Glycol of writing out a prescription with sealing coat; By prescription with polyacrylic resin II in the enteric coating liquid and polyacrylic resin III put soak dissolving in the alcoholic solution after, promptly carry out the coating operation after adding Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate mixing.Slice, thin piece is put in the coating pan, rotated coating pan and be blown into hot blast and make about kettle temperature to 40 ℃, at first spray into the sealing coat coating solution, adjust atomizing pressure, hydrojet speed, coating pan rotating speed, observe the coating state, prevent adhesion, the sealing coat coating increases weight about 3.5%; Proceed the enteric coating operation after the sealing coat coating is finished and spray end until coating, enteric coatings increases weight about 3.5%.

Press Chinese Pharmacopoeia version enteric coatel tablets in 2005 inspection technique (slurry method) and check sodium bicarbonate enteric coatel tablets of the present invention, in simulated gastric fluid through the time 2 hours, outward appearance is complete indeformable, no bubble produces, basically do not discharge ingredient, but in the simulated intestinal fluid environment through the time 20 minutes the time, medicine discharges fully.

Embodiment 3: the sodium bicarbonate enteric coatel tablets

Prescription: 1000

Preparation technology: sodium bicarbonate was pulverized 80 mesh sieves, add 10% starch slurry and make soft material with rapid agitation, 14 mesh sieves are granulated, and put oven drying, and 40 ℃ of baking oven initial setting temperature are warming up to 50 ℃ after 1 hour, drying; Dried granule 12 mesh sieve granulate add dried starch, magnesium stearate mixing.Detect intermediate, according to content conversion sheet weight pharmacy core.Add immersion dissolving in the ethanol by the hypromellose and the Polyethylene Glycol of writing out a prescription with sealing coat; By prescription with polyacrylic resin II in the enteric coating liquid and polyacrylic resin III put soak dissolving in the alcoholic solution after, promptly carry out the coating operation after adding Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate mixing.Slice, thin piece is put in the coating pan, rotated coating pan and be blown into hot blast and make about kettle temperature to 40 ℃, at first spray into the sealing coat coating solution, adjust atomizing pressure, hydrojet speed, coating pan rotating speed, observe the coating state, prevent adhesion, the sealing coat coating increases weight about 5%; Proceed the enteric coating operation after the sealing coat coating is finished and spray end until coating, enteric coatings increases weight about 3.5%.

Press Chinese Pharmacopoeia version enteric coatel tablets in 2005 inspection technique (slurry method) and check sodium bicarbonate enteric coatel tablets of the present invention, in simulated gastric fluid through the time 2 hours, outward appearance is complete indeformable, no bubble produces, basically do not discharge ingredient, but in the simulated intestinal fluid environment through the time 20 minutes the time, medicine discharges fully.

Embodiment 4: the potassium citrate enteric coatel tablets

Prescription: 1000

Preparation technology: potassium citrate was pulverized 80 mesh sieves, and the alcoholic solution that adds Polyethylene Glycol 6000 is made soft material with rapid agitation, and 12 mesh sieves are granulated, and put oven drying, and 40 ℃ of baking oven initial setting temperature are warming up to 50 ℃ after 1 hour, drying; Dried granule 10 mesh sieve granulate add the magnesium stearate mixing.Detect intermediate, according to content conversion sheet weight medicated core.By prescription hypromellose and Polyethylene Glycol are added immersion dissolving in the ethanol, preparation sealing coat coating solution; By prescription polyacrylic resin II, polyacrylic resin III are put immersion dissolving in the ethanol, add Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate mixing, be mixed with enteric coating liquid.Label is put in the coating pan, rotated coating pan and be blown into hot blast and make about kettle temperature to 40 ℃, at first spray into the sealing coat coating solution, adjust atomizing pressure, hydrojet speed, coating pan rotating speed, observe the coating state, prevent adhesion, the sealing coat coating increases weight about 5%; Proceed the enteric coating operation after the sealing coat coating is finished and spray end until coating, enteric coatings increases weight about 3.2%.

Press Chinese Pharmacopoeia version enteric coatel tablets in 2005 inspection technique (slurry method) and check potassium citrate enteric coatel tablets of the present invention, in simulated gastric fluid through the time 2 hours, outward appearance is complete indeformable, no bubble produces, basically do not discharge ingredient, but in the simulated intestinal fluid environment through the time 20 minutes the time, medicine discharges fully.

Embodiment 5: the sodium bicarbonate enteric coated capsule

Prescription: 1000

Sodium bicarbonate	100g
		Starch	10g
Micropowder silica gel	0.5g

Preparation technology: the raw material sodium bicarbonate was pulverized 80 mesh sieves, behind adding starch, the micropowder silica gel mixing, insert No. 2 enteric coated capsulees promptly.

Embodiment 6: the sodium bicarbonate enteric coated capsule

Prescription: 1000

Sodium bicarbonate	500g
		Starch	50g
Micropowder silica gel	2.5g

Preparation technology: the raw material sodium bicarbonate was pulverized 80 mesh sieves, behind adding starch, the micropowder silica gel mixing, insert No. 0 enteric coated capsule promptly.

Embodiment 7: the sodium bicarbonate enteric-coated sustained-release tablet

Prescription: 1000

Operation: sodium bicarbonate, hypromellose, microcrystalline Cellulose are put mix homogeneously in the flash mixer, add ethanol system soft material, 16 orders are granulated, and put 40～50 ℃ of dryings of baking oven, and 14 order granulate add micropowder silica gel, magnesium stearate mixing; Detect intermediate, heavy according to content conversion sheet, strike out flaky medicated core with abnormal shape.By prescription hypromellose and Polyethylene Glycol are added immersion dissolving in the ethanol, preparation sealing coat coating solution; By prescription polyacrylic resin II, polyacrylic resin III are put immersion dissolving in the ethanol, add Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate mixing, be mixed with enteric coating liquid, can carry out the coating operation respectively.Slice, thin piece is put in the coating pan, rotated coating pan and be blown into hot blast and make about kettle temperature to 40 ℃, at first spray into the sealing coat coating solution, adjust atomizing pressure, hydrojet speed, coating pan rotating speed, observe the coating state, prevent adhesion, the sealing coat coating increases weight about 5%; Proceed the enteric coating operation after the sealing coat coating is finished and spray end until coating, enteric coatings increases weight about 3.5%.

Pressing Chinese Pharmacopoeia version enteric coatel tablets in 2005 inspection technique (slurry method) detects, sodium bicarbonate enteric-coated sustained-release tablet of the present invention in simulated gastric fluid through the time 2 hours, outward appearance is complete indeformable, no bubble produces, basically do not discharge ingredient, but slowly discharge in the simulated intestinal fluid environment, data see Table 1, and curve as shown in Figure 1.

Table 1 sodium bicarbonate enteric-coated sustained-release tablet drug release determination data

Embodiment 8: the sodium bicarbonate enteric coated micropill

Prescription: 1000

Preparation technology:

1. prepare the medicated core hypromellose and in 50% alcoholic solution, soak dissolving, add PEG400 and sodium bicarbonate fine powder (200 order), make the pastille suspension under the stirring.Medicine-feeding is carried out in multi-functional fluidized coating machine, adopts side spray method, and coating machine operation data are as follows: nozzle diameter 1mm, air-introduced machine frequency 18～25Hz, 40～50 ℃ of inlet temperature, temperature is 45 ℃ in the bed, atomizing pressure 1.2～1.6Mpa, rotating disk frequency 8-10Hz, hydrojet speed 3～5g/min.Celphere is put in the fluidized coating machine, sprays the pastille suspension under fluidisation and rotation status.

2. coating bag sealing coat: will hypromellose add by prescription and to soak dissolving in the ethanol, prepare the sealing coat coating solution with Polyethylene Glycol; Take sealing coat on the end spray method, the coating amount increases weight about 4% for the pastille micropill.Coating machine operation data are as follows: nozzle diameter 1mm, and air-introduced machine frequency 15～20Hz, 40～50 ℃ of inlet temperature, temperature is 45 ℃ in the bed, atomizing pressure 1.2Mpa, hydrojet speed 2～4g/min.Bag enteric coatings: during the preparation coating solution, coating powder is added slowly in the water of stirring, stir standby after 45 minutes.The medicine carrying micropill put in the fluidized coating machine proceed coating with end spray method.Coating machine operation data are as follows: nozzle diameter 1mm, and air-introduced machine frequency 18～25Hz, 30 ℃ of inlet temperature, temperature is 28 ℃ in the bed, atomizing pressure 0.15Mpa, hydrojet speed 2～4g/min.The spray method is regulated the coating parameter at the bottom of the enteric coated employing, prevents adhesion between piller, can obtain the coated micropill of appearance, and the coating process needs the continuous stirring coating solution until end.The closing temperature gauge tap makes an interior temperature reduce to room temperature, and coating finishes.Coating increases weight about 25%.

3. qualified enteric coatings micropill is according to dosage required to pack in the conventional capsule shell, obtain the sodium bicarbonate enteric-coated pellet capsule.

Embodiment 9: the sodium bicarbonate enteric coated micropill

Prescription: 1000

Preparation technology:

1. prepare the medicated core hypromellose and in 50% alcoholic solution, soak dissolving, add PEG400 and sodium bicarbonate fine powder (200 order), make the pastille suspension under the stirring.Medicine-feeding is carried out in multi-functional fluidized coating machine, adopts side spray method, and coating machine operation data are as follows: nozzle diameter 1mm, air-introduced machine frequency 18～25Hz, 40～50 ℃ of inlet temperature, temperature is 45 ℃ in the bed, atomizing pressure 1.2～1.6Mpa, rotating disk frequency 8-10Hz, hydrojet speed 3～5g/min.Celphere is put in the fluidized coating machine, sprays the pastille suspension under fluidisation and rotation status.

2. coating bag sealing coat: will hypromellose add by prescription and to soak dissolving in the ethanol, prepare the sealing coat coating solution with Polyethylene Glycol; Take sealing coat on the end spray method, the coating amount increases weight about 6% for the pastille micropill.Coating machine operation data are as follows: nozzle diameter 1mm, and air-introduced machine frequency 15～20Hz, 40～50 ℃ of inlet temperature, temperature is 45 ℃ in the bed, atomizing pressure 1.2Mpa, hydrojet speed 2～4g/min.Bag enteric coatings: during the preparation coating solution, coating powder is added slowly in the water of stirring, stir standby after 45 minutes.The medicine carrying micropill put in the fluidized coating machine proceed coating with end spray method.Coating machine operation data are as follows: nozzle diameter 1mm, and air-introduced machine frequency 18～25Hz, 30 ℃ of inlet temperature, temperature is 28 ℃ in the bed, atomizing pressure 0.15Mpa, hydrojet speed 2～4g/min.The spray method is regulated the coating parameter at the bottom of the enteric coated employing, prevents adhesion between piller, can obtain the coated micropill of appearance, and the coating process needs the continuous stirring coating solution until end.The closing temperature gauge tap makes an interior temperature reduce to room temperature, and coating finishes.Coating increases weight about 30%.

3. qualified enteric coatings micropill is according to dosage required to pack in the conventional capsule shell, can obtain the sodium bicarbonate enteric-coated pellet capsule.

Experimental example 10, pharmacodynamics test

By the pharmacodynamics test guideline design pharmacodynamics test of national Bureau of Drugs Supervision promulgation, the effectiveness and the safety of preliminary identification medicine alkalized urine of the present invention.The acid-base value of human body fluid mainly refers to the pH value of blood, also can refer to urine, saliva etc.How to discharge because metabolite is final by urine, therefore the Acidity of Aikalinity of metabolite can influence the pH value of blood, urine equally, pH value of blood and urine pH value have just had certain dependency like this, and the urine pH value can reflect the situation and the variation tendency of pH value of blood to a certain extent.One of effect of commercially available sodium bicarbonate sheet is exactly an alkalized urine.This test replaces pH value of blood to come preliminary identification curative effect of the present invention with the urine pH value.The alkaline pH regulator is suitable for multiple different syndromes, and the dose that needs has a scope, and gap is bigger, and concrete dose must be with reference to respective specified.For example, the taking dose of sodium bicarbonate enteric coatel tablets can be by the dose of sodium bicarbonate ordinary tablet, but but because of enteric coatel tablets capacity performance drug effect of the present invention and there is not the stomach side reaction, so can strengthen or reduce dosage according to the state of an illness.

1, healthy human body

(1) the preliminary test of pesticide effectiveness

EXPERIMENTAL DESIGN: single dose, at random, blank and positive control, self cross matching.

Experimenter: normal adults

Main curative effect index: the alkalization degree of experimenter's urine pH value.

Safety indexes: side effect such as flatulence, singultus and experimenter's toleration.

Test dose: single dose, 1 3g.(when being used for alkalized urine clinically, the patient can oral sodium bicarbonate sheet, and recommended dose is 4g for first dose, and notes detecting the urine pH value to determine drug effect.Sodium bicarbonate enteric coatel tablets in the embodiment of the invention 1 are the change dosage form product of commercially available sodium bicarbonate sheet, still are oral, do not change the route of administration of sodium bicarbonate, so taking dose can be according to the usage and dosages of commercially available prod.Be the drug effect of checking alkalized urine of the present invention, the present invention carries out according to the usage and dosage of commercially available prod, considers that the experimenter is healthy human body but not patient, and we take the circumstances into consideration decrement with taking dose is 3g.)

Sodium bicarbonate enteric coatel tablets among investigational agent: the embodiment 2, specification: 300mg.

Contrast medicine: sodium bicarbonate sheet (commercially available) specification: 0.5g Tianjin Lisheng Pharmaceutical Co., Ltd. product batch number: 0511177

EXPERIMENTAL DESIGN and enforcement: select the normal adults marshalling to experimentize.Be one group of concrete experimental data below: 7 of experimenters, 4 male 3 woman, volume is 1～No. 7, adopts self cross-reference method, carries out the contrast test of this product and sodium bicarbonate ordinary tablet.Dosage is 3g/l time/day (promptly contrast the medicine clothes and once obey 6, investigational agent is once obeyed 10), and early (medicine) being taken before meal is used before the meal, the 1st day is blank, and even numbers was taken investigational agent according to List of Documents livery contrast medicine in the 2nd day, carried out self on the 3rd day and intersect, even numbers is taken the contrast medicine, and odd numbers is taken investigational agent.Duration of test is unified diet, unified amount of drinking water, and 7:30～17:30 writes down and adds up test data every 1 hour fixed point determination test person's urine sample volume and pH value; The record experimenter's untoward reaction and the extent of reaction (extent of reaction is experimenter's subjective feeling, divides slight, medium, more serious, serious 4 grades).

Result of the test: the statistical result of experimenter's urine pH value sees that result of the test sees Table 2, table 3 and Fig. 2.Do not have the experimenter during process of the test empty and sense of discomfort occurs.There are 5 routine experimenters untoward reaction to occur after taking the contrast medicine, mainly contain stomach reactions such as flatulence, singultus, full abdomen.After taking investigational agent, no experimenter main suit has sense of discomfort, and concrete condition sees Table 4.

Table 2 sodium bicarbonate preparation test of pesticide effectiveness pH changes (Δ pH) data statistic (n=7)

Annotate: the numerical value of going up 7:30 column in the table is each experimenter's urine pH value, and as basic point, after this numerical value of each time point is the pH changing value that this pH value and basic point compare gained.

Table 3 experimenter pH value experimental data mean change (Δ pH) statistical table (n=7)

	7:30 (basic point)	8:30	9:30	10:30	11:30	12:30	13:30	14:30	15:30	16:30	17:30
												Blank	5.8829	0.2593	0.4114	0.6707	0.3879	-0.2071	-0.1500	0.3007	0.4714	0.4343	-0.0357
Investigational agent	5.7521	0.3150	1.0293	1.4464	1.5286	1.1743	0.9600	1.2514	1.2193	0.9714	0.6614
												The contrast medicine	5.4907	1.0136	1.2943	1.6364	1.5329	0.7671	0.4443	0.9443	1.0679	0.8957	0.6400

Annotate: the numerical value of going up 7:30 column in the table is experimenter's urine pH meansigma methods, and as basic point, after this numerical value of each time point is the pH variation meansigma methods that this pH value and basic point compare gained.

Table 4 experimenter untoward reaction and compliance situation statistics

	Untoward reaction example number	Untoward reaction percentage ratio	The untoward reaction content	Compliance
					Blank	0	0	Stomach reaction: other reaction of reaction such as no flatulence, singultus: do not have	Well
The contrast medicine	5 examples	71.43%	Stomach reaction: 1. flatulence (5 example): occur this reaction very soon after 1,2,3,5, No. 7 experimenters (3 male 2 woman) take medicine, faded away in 1～2 hour.The extent of reaction: 1 example is slight, and 4 examples are medium.2. singultus (5 example): very fast appearance after 1,2,3,5, No. 7 experimenters take medicine, singultus is frequent, is difficult to eliminate in long-time.	The experimenter all finishes Total Test.Occur that untoward reaction person is subjective to be reluctant

			The extent of reaction: 2 examples are slight, and 3 examples are medium.3. satiety (1 example): very fast appearance during No. 3 experimenter's lunches.The extent of reaction: medium.Other reaction: do not have	Meaning is taken the contrast medicine again, and compliance is relatively poor.
					Investigational agent	0	0	Stomach reaction: other reaction of reaction such as no flatulence, singultus: do not have	Well

From result of the test, with respect to space state, contrast medicine and the investigational agent urine sample pH value that all can effectively raise, alkalized urine, it is rapid to take the effect of back 1 hour internal reference medicine, but flatulence, reaction such as singultus takes place immediately together, and investigational agent compares according to medicine effect delay, takes onset hardly in back 1 hour, suitable with blank, just begin onset afterwards, similar to the maximum alkalization degree of urine to the contrast medicine, but effect is steadily lasting, there is not intensive trough difference, make experimenter's urine pH value in considerable time, keep stable high level, and take the back, demonstrated the purpose of design of investigational agent preferably without any sense of discomfort; In addition, to the statistical result showed of urine sample volume, with respect to space state, take the contrast medicine after the experimenter more obvious hypourocrinia trend is arranged, more consistent with experimenter's subjective feeling.Aspect untoward reaction, take investigational agent to blank similar, the common stomach reaction of commercially available conventional tablet does not take place, experimenter's compliance is good, has compared significant difference with the contrast medicine; The untoward reaction of contrast medicine (commercially available conventional tablet) meets clinical practice, mainly concentrates on the stomach reaction, the occurrence frequency height, and duration is longer, and experimenter's compliance is relatively poor.

Experimental result shows, the investigational agent " sodium bicarbonate enteric coatel tablets " of the present invention's preparation is alkalized urine effectively, identical with contrast medicine " sodium bicarbonate sheet " alkalized urine action intensity, but action time is more steady lasting, and do not contrast the stomach untoward reaction such as singultus, flatulence of medicine, also do not have other side effect, comparing present commercial preparation has significant difference, and experimenter's toleration and compliance are good.

(2) toleration and compliance test

On above-mentioned experimental basis, we have appended following test, further investigate the toleration and the compliance of medicine of the present invention.

EXPERIMENTAL DESIGN: multiple dose, self intersect, controlled trial.

Experimenter: normal adults

Safety indexes: side effect such as flatulence, singultus and experimenter's toleration.

Sodium bicarbonate enteric coatel tablets among investigational agent: the embodiment 2, specification: 300mg.

Contrast medicine: sodium bicarbonate sheet (commercially available) specification: 0.5g Tianjin Lisheng Pharmaceutical Co., Ltd. product batch number: 0511177

EXPERIMENTAL DESIGN and enforcement: select the healthy adult people for experimenter's marshalling experimentizes, adopt self cross-reference method, carry out the contrast test of this product and sodium bicarbonate ordinary tablet.Concrete experimental data: dosage is 1.5g/ time, and 3 times/day (promptly contrast 3 of the each clothes of medicine, investigational agent is once obeyed 5) is before the meal and takes half an hour.Even numbers was taken investigational agent, took continuously 3 days according to List of Documents livery contrast medicine in the 1st day; Be the cleaning phase, and do not take any medicine in the 4th day; Carried out self on the 5th day and intersect, even numbers is taken the contrast medicine, and odd numbers is taken investigational agent, and the dosage usage is the same, takes continuously 3 days again.Duration of test is unified diet, unified amount of drinking water, (extent of reaction is experimenter's subjective feeling for the record experimenter's untoward reaction and the extent of reaction, divide slight, medium, more serious, serious 4 grades), the record experimenter is to the tolerance degree and the compliance (whether being ready to continue to take medicine) of test during off-test.

Result of the test: the experimenter successively untoward reaction all occurs after taking the contrast medicine in the process of the test, mainly contains reactions such as flatulence, singultus, satiety; After taking investigational agent, no experimenter main suit has untoward reaction, and concrete condition sees Table 5.

Table 5 experimenter untoward reaction and tolerance compliance statistical table

From above statistical conditions as a result as can be seen, when repeatedly and continuously taking, medicine of the present invention compares with present marketed drugs that there were significant differences, untoward reaction can not take place substantially, especially gastric side effects can be avoided, and the stomach adverse reaction rate of marketed drugs is quite high, and side effect such as flatulence, singultus nearly all can take place when taking especially continuously, and is all rising with the increase adverse reaction rate of taking natural law and the extent of reaction.Experimenter's tolerance degree of medicine of the present invention and compliance all significantly are better than marketed drugs, can take for a long time and toleration is good.

2, low dose or super large dosage sodium bicarbonate enteric coatel tablets are to preventing gout, improving body biochemical investigation index effect and tolerance experiment

Test objective: test oral low dose or super large dosage sodium bicarbonate enteric coatel tablets to the prevention gout, improve body biochemical investigation index effect, and whether significantly minimizing to the stomach side effect

Main curative effect index: the alkalization degree of urine pH value, the normal degree of biochemical investigation index, to the influence of gout.

Safety indexes: side effect such as flatulence, singultus and experimenter's toleration.

1) test dose: 100mg/ time, 2 times/day, took 1 month.

Sodium bicarbonate enteric coatel tablets among investigational agent: the embodiment 1, specification: 100mg.

Experimenter: the adult male that gout history and acute attack are in the recent period arranged.Multinomial biochemical investigation index once departed from normal range to some extent, once united during the treatment gout and took commercially available sodium bicarbonate sheet alkalized urine.Went to regular hospital to carry out the blood biochemical investigation before on-test, take the sodium bicarbonate enteric coatel tablets (100mg/ sheet) among the embodiment 1 then, 1 slice/time, 2 times/day, adhered to having taken 1 month.Duration of test fixed point every day is measured urine pH value 2 times, and the record untoward reaction and the extent of reaction (extent of reaction is a subjective feeling, divides slight, medium, more serious, serious 4 grades) are taken laggard promoting the circulation of blood biochemical investigation in 1 month.

Result of the test: from the statistical conditions of urine pH value, its numerical value has notable difference before and after the test, is rising situation, shows that investigational agent truly has alkalinization to urine; Blood biochemical investigation before and after the contrast test is single as can be seen, its many index such as uric acid, triglyceride, T-CHOL, low-density lipoprotein cholesterol, glucose etc. have had tangible improvement after the off-test, substantially return to normal range, experimenter's subjective feeling shows that also physical condition take a favorable turn, tired out sense disappears substantially, and duration of work energy is concentrated; Duration of test finds no the common gastric side effects of commercially available sodium bicarbonate sheet such as flatulence, singultus, does not also have other sense of discomfort, and toleration and compliance are good.The test data statistical conditions show: experimenter's biochemical indicator has clear improvement, especially the uric acid index that characterizes gout returns to normal range, physical condition has well broken away from sub-health state, does not have tangible gastric side effects or other discomforts after taking medicine for a long time.

2) test dose: the 500mg/ sheet, first clothes 5g (10) after this every 4 hours clothes 3g (6), serve on 3 days, after be kept to 2g (4), took altogether 7 days.

Sodium bicarbonate enteric coatel tablets among investigational agent: the embodiment 3 (specification: the 500mg/ sheet), first clothes 5g (10) after this every 4 hours clothes 3g (6), serve on 3 days, after be kept to 2g (4), took altogether 7 days, gout is not shown effect.Dosage the highest every day is 23g, be significantly higher than the generally the highest dosis tolerata (16g) of commercially available sodium bicarbonate sheet, period in a medicine is not seen gastric side effects such as flatulence, singultus always, and patient tolerability is still very good when showing sodium bicarbonate enteric coated preparation large dose oral administration of the present invention.

More than test shows: sodium bicarbonate oral enteric preparation of the present invention, not only have and the same therapeutical effect of commercially available sodium bicarbonate sheet, and there are not ordinary tablet patients such as flatulence, singultus to be difficult to the gastric side effects of avoiding and tolerating, but the dose capacity plays a role, safety increases, toleration greatly increases, can in prescribed limit, strengthen dose and improve the treatment dynamics, also be suitable for taking for a long time and still compliance is good, compare with present commercially available sodium bicarbonate sheet and have very significantly characteristics and advantage; Low dose also has the alkalized urine effect, show and to produce wholesome effect the acid-base balance of human body especially acidic physique, not only can be used for treatment, its prevention and regulating action also can not be ignored, and can take the puzzlement that does not have common gastric side effects for a long time, can have a good application prospect equally aspect treatment and the prevention.

Claims (10)

1. the oral enteric preparation of an alkaline pH regulator is characterized in that: described enteric coated preparation is made up of medicated core and enteric coatings or enteric coated capsule; Medicated core is label, granule, powder or the micropill that alkaline pH regulator and the oral formulations adjuvant that is selected from routine, slow release or rapid release are formed; Sealing coat is arranged between medicated core and the enteric coatings or do not have sealing coat; In per 1000 or the oral enteric preparation, the alkaline pH regulator is 10～2000 grams.

2. the described oral enteric preparation of claim 1 is characterized in that: the alkaline pH regulator in the medicated core is selected from a kind of or their mixture in sodium bicarbonate, potassium bicarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, the citron potassium hydrogen phthalate sodium; In per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～1450 grams; The oral formulations adjuvant is selected from a kind of in binding agent, slow releasing agent, lubricant, fluidizer, the disintegrating agent or their mixture in the medicated core; Sealing coat is selected from a kind of in sealing coat coating material, the plasticizer or their mixture; Enteric coatings is made up of enteric coatings material and plasticizer; The enteric coatings material is selected from a kind of in acrylic resin polymer, cellulose acetate phthalate, the Hydroxypropyl methyl cellulose phtalate or their mixture.

3. the described oral enteric preparation of claim 2 is characterized in that: in per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～500 grams, and preferred alkaline pH regulator agent is 100～300 grams; Binding agent is selected from a kind of or their mixture in starch, dextrin, 30 POVIDONE K 30 BP/USP 30, hypromellose or the hyprolose in the medicated core; Slow releasing agent is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, ethyl cellulose or the Sulisi, lubricant is selected from magnesium stearate or Pulvis Talci, fluidizer is selected from micropowder silica gel or Polyethylene Glycol, and disintegrating agent is selected from starch, microcrystalline Cellulose or hyprolose; The sealing coat coating material is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP, the 30 POVIDONE K 30 BP/USP 30 in the sealing coat, and plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the sealing coat; The acrylic resin polymer is selected from a kind of or their mixture in polyacrylic resin II, polyacrylic resin III, acrylic resin aqueous dispersion enteric coating pre-mixing agent, the methacrylic resin polymer in the enteric coatings material; Plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the enteric coatings.

4. the preparation method of one of claim 1～3 oral enteric preparation comprises the steps:

1) alkaline pH regulator and the oral formulations adjuvant that is selected from routine, slow release or rapid release are mixed, make the medicated core of label, granule, powder or micropill form; In the medicated core of per 1000 or an oral enteric preparation, the alkaline pH regulator is 10～2000 grams;

2) behind the medicated core parcel sealing coat with label, granule or micropill form in the step 1), wrap up enteric coating again; Perhaps the medicated core with label, granule or micropill form in the step 1) directly wraps up enteric coating; Perhaps with the medicated core of the granule in the step 1), powder or micropill form, the enteric coated capsule of directly packing into.

3) with step 2) in the parcel enteric coating after granule or micropill, the conventional capsule of packing into.

5. the preparation method of claim 4 oral enteric preparation is characterized in that:

The agent of step 1) medicated core neutral and alkali pH regulator is selected from a kind of or their mixture in sodium bicarbonate, potassium bicarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, the citron potassium hydrogen phthalate sodium; In per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～1450 grams; The oral formulations adjuvant is selected from a kind of in binding agent, slow releasing agent, lubricant, fluidizer, the disintegrating agent or their mixture; Sealing coat is selected from a kind of in sealing coat coating material, the plasticizer or their mixture, to the medicated core coating, obtains wrapping up the medicated core of sealing coat with sealing coat, and the sealing coat consumption is 2～6% of medicated core weight by weight; Enteric coatings is made up of enteric coatings material and plasticizer; The enteric coatings material is selected from a kind of or their mixture in acrylic resin polymer, cellulose acetate phthalate, the Hydroxypropyl methyl cellulose phtalate; With enteric coatings liquid the medicated core that wraps up sealing coat is carried out coating, it is about 1.5～3.5% to increase weight to flaky medicated core, and the medicated core weightening finish of granule or micropill shape is to 25～30%, by the medicated core weight of wrapping up sealing coat.

6. the preparation method of claim 5 oral enteric preparation is characterized in that: in per 1000 or the oral enteric preparation, the alkaline pH regulator is 100～500 grams, and preferred alkaline pH regulator agent is 100～300 grams; Binding agent is selected from a kind of or their mixture in starch, dextrin, 30 POVIDONE K 30 BP/USP 30, hypromellose K4, hypromellose K100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP or the hyprolose in the medicated core; Slow releasing agent is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, ethyl cellulose or the Sulisi; Lubricant is selected from magnesium stearate or Pulvis Talci, and fluidizer is selected from micropowder silica gel or Polyethylene Glycol, and disintegrating agent is selected from starch, microcrystalline Cellulose or hyprolose 15CP; The sealing coat coating material is selected from a kind of or their mixture in hypromellose K4, hypromellose K100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP and the 30 POVIDONE K 30 BP/USP 30 in the sealing coat, and plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the sealing coat; To the medicated core coating, obtain wrapping up the medicated core of sealing coat with sealing coat, the sealing coat consumption is 2～5% of a medicated core weight; The acrylic resin polymer is selected from a kind of or their mixture in polyacrylic resin II, polyacrylic resin III, acrylic resin aqueous dispersion enteric coating pre-mixing agent, the methacrylic resin polymer in the enteric coatings material, and plasticizer is selected from a kind of or their mixture in PEG400, Polyethylene Glycol 1450, Macrogol 4000, polyethylene glycol 6000, the diethyl phthalate in the enteric coatings; The medicated core that wraps up sealing coat is carried out enteric coatings, and it is about 1.5～3.5% to increase weight to flaky medicated core, by the medicated core weight of wrapping up sealing coat.

7. the preparation method of claim 6 oral enteric preparation is characterized in that: get sodium bicarbonate 100～500 grams, add starch, magnesium stearate, be pressed into label; Hypromellose 15CP, PEG400 and aquiferous ethanol are mixed, be made into the sealing coat coating solution; To the label coating, the sealing coat consumption is 2～5% of label weight by weight with the sealing coat coating solution; After polyacrylic resin II, polyacrylic resin III, Oleum Ricini, diethyl phthalate, polyoxyethylene sorbitan monoleate and ethanol mixing, be made into enteric coatings liquid; With enteric coatings liquid the label that wraps up sealing coat is carried out coating, about 1.5～3.5% to increasing weight, by the label weight of wrapping up sealing coat, make 1000 oral enteric preparations.

8. the preparation method of claim 6 oral enteric preparation is characterized in that: get sodium bicarbonate 100～500 grams, starch 10～50 grams and micropowder silica gel 0.5～2.5 gram and mix, in 1000 enteric coated capsulees of packing into.

9. the preparation method of claim 6 oral enteric preparation is characterized in that: get sodium bicarbonate 500 grams, mix with hypromellose K100 300 grams, microcrystalline Cellulose 200 grams, micropowder silica gel 5 grams and magnesium stearate 5 grams, be pressed into label; With hypromellose 15CP 16～40 grams, PEG400 4.25～10.6 gram and 540～1350 milliliters of mixing of 50% ethanol, be made into the sealing coat coating solution; To the label coating, the sealing coat consumption is about 2～5% of label weight with the sealing coat coating solution; After polyacrylic resin II 10.5～18.5 gram, polyacrylic resin III 2.1～3.7 grams, Oleum Ricini 4.2～7.4 grams, diethyl phthalate 2.1～3.7 grams, polyoxyethylene sorbitan monoleate 2.1～3.7 grams and 265～465 milliliters of ethanol are mixed, be made into enteric coatings liquid; With enteric coatings liquid the label that wraps up sealing coat is carried out coating,,, make 1000 oral enteric soluble slowly-releasing preparations by the medicated core weight of wrapping up sealing coat to increasing weight 2～3.5%.

10. the preparation method of claim 5 oral enteric preparation, it is characterized in that: get sodium bicarbonate 100～300 grams, after 400～1200 milliliters of hypromellose 15CP 16～48 gram, PEG400 4～12 grams and 50% ethanol mix, 0.5mm celphere 35～100 grams are sprayed, get the medicated core of micropill form; Mix with hypromellose 15CP 4.9～21.8 grams, PEG400 1.3～5.8 grams and aquiferous ethanol, be made into the sealing coat coating solution, wrap up with the medicated core of sealing coat coating solution, to medicated core weightening finish 4～6% to the micropill form; After acrylic resin aqueous dispersion enteric coating pre-mixing agent 40.5～146 grams and 210～730 milliliters of mixing of water, get enteric coatings liquid; With enteric coatings liquid the medicated core that wraps up sealing coat is wrapped up, to increasing weight 25～30%, enteric coated-pellet, enteric coated-pellet is packed in 1000 conventional capsule shells.

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