WO2008061409A1 - Formulation entérique revêtue comprenant un agent alcalin actif et son procédé d'élaboration - Google Patents

Formulation entérique revêtue comprenant un agent alcalin actif et son procédé d'élaboration Download PDF

Info

Publication number
WO2008061409A1
WO2008061409A1 PCT/CN2007/000486 CN2007000486W WO2008061409A1 WO 2008061409 A1 WO2008061409 A1 WO 2008061409A1 CN 2007000486 W CN2007000486 W CN 2007000486W WO 2008061409 A1 WO2008061409 A1 WO 2008061409A1
Authority
WO
WIPO (PCT)
Prior art keywords
enteric
alkaline
coating
preparation
core
Prior art date
Application number
PCT/CN2007/000486
Other languages
English (en)
Chinese (zh)
Inventor
Dapeng Li
Weidong Ren
Meili Ma
Original Assignee
Dapeng Li
Meili Ma
Weidong Ren
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dapeng Li, Meili Ma, Weidong Ren filed Critical Dapeng Li
Publication of WO2008061409A1 publication Critical patent/WO2008061409A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to an oral enteric preparation containing a basic drug, which is an alkaline pH adjuster capable of regulating a mild acid body fluid or urine to a normal pH range, and a preparation method thereof.
  • the acid-base balance of human body fluids is the three basic balances of the human body (temperature balance, nutritional balance, body fluid acid-base balance).
  • Body fluids also known as extracellular fluids, mainly refer to blood, lymph, and tissue fluid between organs and tissues. Human organs and systems are surrounded by specific body fluids, which constitute the internal environment of multicellular organisms. Human body fluids have a certain pH, often expressed in terms of blood, urine, saliva, etc., generally referred to as blood pH.
  • the acid-base balance of the human body refers to the buffering effect of H + generated by the metabolic process through the buffer system, and the regulation and excretion of the lung and kidney, maintaining the H+ concentration of the body fluid within the normal range.
  • the normal blood pH is 7. 35 ⁇ 7.
  • alkaline drugs such as sodium bicarbonate (potassium), sodium carbonate, sodium citrate (potassium), potassium hydrogen citrate are often used in the treatment of acidosis.
  • sodium, sodium lactate, tromethamine, basic amino acids, etc. especially widely used in the absorption of good sodium bicarbonate tablets, exogenous bicarbonate directly provides HC0 to the human body, so that the concentration of HC0 in the plasma is increased, neutralizing body fluids H + , thereby correcting acidosis, treating fever, hypoxia, blood circulation failure, pathogenic microorganisms or toxins, acute or chronic renal failure, certain diuretics, excessive acid entry into the body, elevated blood potassium, etc.
  • Metabolic acidosis disease have been recognized by the medical community at home and abroad, and alkaline pH regulators have been clinically used for a long time.
  • alkaline pH adjusters represented by sodium bicarbonate in the clinic is to alkalinize urine, so that uric acid, sulfonamides and hemoglobin are not suitable for crystallization or aggregation in the urine, thereby preventing uric acid kidney stones. cut back Nephrotoxicity of sulfa drugs, acute hemolysis prevents hemoglobin deposition in the renal tubules, comprehensive treatment of gout and other diseases.
  • the kidney plays an important role in regulating the acid-base balance of the human body. When various primary or secondary kidney diseases damage the kidneys, causing renal insufficiency, it will affect the kidney's regulation of acid and alkali, leading to the body's acid-base balance. Disorders make the original symptoms more complicated and more serious.
  • Alkaline pH adjusters such as sodium bicarbonate tablets have achieved good results in long-term clinical applications, but there have been problems that affect efficacy and application. These problems include: 1 stomach acid in the stomach, oral administration of alkaline drugs first acid-base neutralization reaction; 2 neutralizing gastric acid has a certain effect on the normal digestion and absorption of the stomach; 3 due to the first action with gastric acid, small
  • the alkaline pH adjusting agent such as a dose of sodium bicarbonate ordinary tablet cannot fully and effectively achieve the therapeutic purpose of alkalized body fluid or urine; 4 the patient adopts an alkaline pH adjusting agent such as a sodium hydrogencarbonate ordinary tablet, and the pH in the body produces a strong valley difference; 5 alkaline substances react with gastric acid to produce exothermic reaction, and the reaction product causes stomach discomfort.
  • sodium bicarbonate can be dissolved and released quickly in the stomach of the patient, and directly reacts with gastric acid to produce C0 2 gas, causing it to be reversed and stomach. Intestinal aeration, bloating and other adverse reactions, and even symptoms such as stomach cramps, patients with severe gastric ulcers are more likely to cause gastric perforation.
  • the patient needs to take it several times a day, the treatment period varies, and the time is a little longer. This adverse reaction is particularly prominent and becomes a key factor affecting patient tolerance. 6 patients need to increase the dose according to the severity of the disease, because the above-mentioned various side effects are difficult to tolerate, can not adjust the dose in time, can only take a smaller dose according to the degree of tolerance, it is difficult to achieve the desired effect.
  • an alkaline pH adjuster such as sodium hydrogencarbonate is used as an acid-base balance regulator for acidosis, alkalization of urine, hyperacidity and the like, and has an oral tablet and an injection, wherein the tablet is a common stomach solution. type.
  • sodium bicarbonate tablets are used to alkalinize urine, the recommended daily dose is 1 ⁇ 10mmol/kg by weight, and each lg of sodium bicarbonate is equivalent to 12 leg ol bicarbonate. According to the adult weight of 70kg, adult alkalized urine The recommended dosage of the liquid is 5.833 ⁇ 58.
  • an object of the present invention to provide an alkaline pharmaceutical preparation which is convenient to take and a process for preparing the same, which is effective for reducing or substantially eliminating the side effects of existing drugs.
  • an oral enteric preparation of a basic drug which is a tablet or a capsule, and an alkaline P- pertusnal agent per 1000 tablets or tablets of an enteric preparation 10 to 2000 grams; and And the enteric preparation was placed in a 0.1 mol/L hydrochloric acid solution for 2 hours, and the release rate of the alkaline pH adjuster was less than 2%.
  • the enteric preparation is placed in a 0.1 mol/L hydrochloric acid solution for 2 hours, and the release of the alkaline pH adjuster is less than 1 °/. , more preferably less than 0.5%.
  • the oral enteric preparation is placed in a phosphate buffer (pH 6.8) for 45 minutes (more preferably for 20 minutes), and the release of the alkaline pH adjuster is greater than 80%, more preferably The ground is greater than 90%.
  • the pH adjusting agent is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, sodium hydrogen citrate or Their combination.
  • the alkaline P H modifier is from 100 to 1450 g, preferably from 100 to 500 g, per 1000 tablets or tablets of the enteric preparation.
  • the formulation is selected from the group consisting of:
  • an enteric tablet comprising a core and an enteric coating, wherein the core comprises an alkaline pH adjuster and a pharmaceutically acceptable carrier;
  • an enteric capsule comprising an enteric capsule and a pharmaceutical powder or granules in an enteric capsule, wherein the pharmaceutical powder or granule comprises an alkaline pH adjusting agent and a pharmaceutically acceptable carrier;
  • enteric pellets comprising a capsule and an enteric pellet located in the capsule, wherein the enteric pellet comprises a pellet core and an enteric coating, wherein the pellet core comprises Alkaline P circulatory agent and a pharmaceutically acceptable carrier.
  • a barrier layer is also provided between the core and the enteric coating, or between the pellet core and the enteric coating.
  • the enteric coating layer is composed of an enteric coating material and a plasticizer; wherein the enteric coating material is selected from the group consisting of an acrylic resin, cellulose acetate phthalate, One of hypromellose phthalate or a mixture thereof.
  • the acrylic resin polymer in the enteric coating material is selected from the group consisting of polyacrylic resin II, polyacrylic resin III, acrylic resin aqueous dispersion enteric coating premix, methacrylic resin polymer or
  • the plasticizer in the enteric coating layer is selected from the group consisting of polyethylene glycol 400, polyethylene glycol 1450, polyethylene glycol 4000, polyethylene glycol 6000, diethyl phthalate or a combination thereof.
  • the release layer is selected from the group consisting of a barrier coating material, a plasticizer, or a mixture thereof.
  • the release layer coating material is selected from the group consisting of hypromellose K4, hypromellose ⁇ 100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP, povidone K30 or a combination thereof
  • the plasticizer in the separator is selected from the group consisting of polyethylene glycol 400, polyethylene glycol 1450, polyethylene glycol 4000, polyethylene glycol 6000, diethyl phthalate or Its combination.
  • the pharmaceutically acceptable carrier is conventional, sustained release or immediate release.
  • the pharmaceutically acceptable carrier further comprises a binder, a sustained release agent, a lubricant, a glidant, a disintegrant, or a combination thereof.
  • the binder in the core is selected from the group consisting of starch, dextrin, povidone K30, hypromellose or hydroxypropyl cellulose or a combination thereof;
  • the sustained release agent is selected from the group consisting of hyprothenol Cellulose ⁇ 4, hypromellose ⁇ 100, ethylcellulose or sulis or a combination thereof;
  • the lubricant is selected from magnesium stearate or talc;
  • the glidant is selected from micronized silica gel or polyethylene glycol; From starch, microcrystalline cellulose or hydroxypropyl cellulose.
  • a method for preparing an oral enteric preparation of the above basic rhodium modulating agent comprising the steps of: encapsulating an enteric coating on the outside of a tablet core to form an enteric tablet, Wherein the drug core comprises an alkaline pH modulation agent and a pharmaceutically acceptable carrier;
  • the drug powder or granules are filled in an enteric capsule to form an enteric capsule, wherein the medicinal powder or granule contains a basic ⁇ ⁇ modulating agent and a pharmaceutically acceptable carrier;
  • the enteric pellets are filled in a capsule to form an enteric pellet, wherein the enteric pellet comprises a pellet core and an enteric coating, and the pellet core contains an alkaline pH regulator and a pharmaceutically acceptable Acceptable carrier.
  • an oral enteric preparation of the above basic rhobar modifier for the preparation of a medicament for upregulating body fluids or urine.
  • the medicament is also used to treat metabolic acidosis, acid-base imbalance caused by impaired renal function, or gout.
  • a method of modulating body fluids or urine comprising the step of: administering to said mammalian subject (e.g., a human) in need of upregulation of ⁇ an oral enteric preparation as described above.
  • said mammalian subject e.g., a human
  • the subject's body fluid ⁇ ⁇ is lower than 7.35.
  • the application amount is 0.2 to 50 g/day per person, preferably 1 to 30 g/day per person.
  • the oral enteric preparation of the alkaline pH adjusting agent developed by the invention basically does not undergo acid-base neutralization reaction with gastric acid; does not neutralize gastric acid, does not affect the normal digestion and absorption function of the stomach; can avoid the exothermic heat generated by acid-base neutralization
  • the oral enteric preparation preparation method of the alkaline pH adjuster developed by the present invention is suitable for industrial application.
  • the time on the abscissa is hour, which refers to the natural time of day, such as 8 at 8 o'clock in the morning.
  • the ordinate is the average change in the urine pH of the subject.
  • the pH value of the first sampling point (7:30 in the morning) on the test day is the base point, and the pH value of each sampling point is subtracted from the base point to its change value, and the variation values of all subjects are averaged, indicating Changes in urine pH at the sampling point.
  • alkaline pH adjusters such as sodium bicarbonate ordinary tablets have achieved well-recognized therapeutic effects in clinical applications, and a wide range of suitable diseases for prevention and treatment are available, since the problems described in the background section of the present specification have been severely affected.
  • Efficacy and application The inventors have made extensive and intensive research into the oral enteric preparations for the first time when it is difficult to tolerate the various side effects of the above-mentioned ordinary sodium bicarbonate tablets.
  • the alkaline pH-adjusting oral enteric preparation of the present invention has good efficacy, safety, and patient compliance and tolerance as compared with the currently marketed preparations.
  • the present invention has been completed on this basis. the term
  • alkaline pH adjusting agent and the "alkaline drug” as used in the present invention are used interchangeably, and both refer to an increase in the pH value of a body fluid or urine which is acidic in the body and then adjusted to a normal range after metabolism in the body. substance.
  • Some substances, such as citric acid are organic acids, but are eventually metabolized to HC0 in the human body, so that the concentration of HC0 3 in body fluids and urine increases the pH, which is similar to that of sodium bicarbonate. It is commonly used to alkalinize body fluids, correct acidosis, and is also an alkaline pH adjuster of the present invention.
  • Representative basic pH adjusting agents include, but are not limited to: sodium bicarbonate, potassium bicarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, sodium hydrogen citrate or their combination.
  • an oral enteric preparation of an alkaline pH adjusting agent which comprises a core and an enteric coating layer (also known as an enteric film coating or an enteric coating) or an intestine.
  • the composition of the capsule; the core is an alkaline pH adjuster and a core, granule, powder or pellet composed of a conventional, sustained-release or immediate-release oral preparation; there is isolation between the core and the enteric coating layer
  • the layer has no barrier layer; in every 1000 tablets or tablets of oral enteric preparation, the alkaline pH adjuster is 10 to 2000 grams.
  • the oral preparation adjuvant in the core is selected from the group consisting of a binder, a sustained release agent, a lubricant, a flow aid, a disintegrant, or a mixture thereof;
  • the release layer is selected from the group consisting of a barrier coating material and a plasticizer.
  • the enteric coating layer is composed of an enteric coating material and a plasticizer;
  • the enteric coating material is selected from the group consisting of an acrylic resin, cellulose acetate phthalate, and hydroxypropyl One of or a mixture of methyl cellulose phthalates.
  • the oral enteric preparation of the present invention is preferably: in an oral enteric preparation of 1000 tablets or tablets, the alkaline pH adjusting agent is 100 to 500 g, preferably the alkaline pH adjusting agent is 100 to 300 g; and the binder in the core is selected from the group consisting of Starch, dextrin, poly' ketone K30, hypromellose or hydroxypropyl cellulose or a combination thereof; sustained release agent selected from hypromellose ⁇ 4, hypromellose ⁇ 100, ethyl cellulose or Sulis (trade name) or a combination thereof, the lubricant is selected from magnesium stearate or talc, the glidant is selected from micro-powder silica gel or polyethylene glycol, and the disintegrant is selected from the group consisting of starch, microcrystalline cellulose or hydroxypropyl cellulose;
  • the barrier coating material in the barrier layer is selected from the group consisting of hypromellose ⁇ 4, hypromellose ⁇ 100
  • the oral enteric preparation of the present invention can be prepared by a conventional method in the art.
  • the preparation method includes the following steps:
  • the alkaline pH ⁇ modifier is 10 ⁇ 2000 grams;
  • step 2) wrapping the core in the form of core, granule or pellet in step 1) with the coating layer, and then wrapping the enteric coating; or directly wrapping the core in the form of core, granule or pellet in step 1) Solubilizing the coating; or directly loading the granules in the form of granules, powder or pellets in step 1) into enteric capsules.
  • the preparation method of the above-mentioned alkaline rhodium modulating agent oral enteric preparation comprises the following steps: Step 1)
  • the alkaline rhodium modulating agent in the medicine core is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, citric acid, sodium citrate, strontium.
  • the alkaline pH modulation agent is 100 to 1450 grams
  • the oral preparation auxiliary materials in the medicine core are conventional auxiliary materials in the pharmaceutical field, and the conventional dosage
  • the oral preparation auxiliary is selected from the group consisting of a binder, a sustained release agent, a lubricant, a glidant, and disintegration One of the agents or a mixture thereof
  • the release layer is selected from the group consisting of a barrier coating material, a plasticizer, or a mixture thereof, and the core is coated with a separator to obtain a core coated with the separator, isolated
  • the amount of the layer is 2 to 6% by weight of the core
  • the enteric coating layer is composed of an enteric coating material and a plasticizer
  • the enteric coating material is selected from the group
  • the pellet-shaped core is weighted to 25 to 30%, based on the weight of the core of the barrier-coated barrier.
  • the preferred preparation method of the oral pH-preserving agent of the present invention comprises: taking sodium carbonate 100-500 g, adding starch, magnesium stearate, and pressing into a tablet core; and treating hypromellose 15CP, polyethylene glycol Alcohol 400 is mixed with aqueous ethanol (such as 40-60% ethanol, preferably 50% ethanol) to form a release layer coating liquid; the core layer is coated with a release layer coating liquid, and the amount of the separation layer is the core weight by weight.
  • aqueous ethanol such as 40-60% ethanol, preferably 50% ethanol
  • the basic preparation method of the alkaline pH adjuster oral enteric preparation comprises: taking sodium bicarbonate 100 ⁇ 500 grams, starch 10 ⁇ 50 grams and micronized silica gel 0. 5 ⁇ 2. 5 grams of mixed, 1000 capsules of enteric solution In the capsule.
  • the preferred preparation method of the oral pH adjusting agent oral enteric preparation of the invention further comprises: taking 500 g of sodium hydrogencarbonate, 300 g of hypromellose K100, 200 g of microcrystalline cellulose, 5 g of microsilica gel and stearic acid. 5 grams of magnesium mixed, pressed into a core; hydroxypropyl methylcellulose 15CP 16 ⁇ 40 grams, polyethylene glycol 400 4. 25 ⁇ 10. 6 grams and 50% ethanol 540 ⁇ 1350 ml mixed, formulated into a separator package 5 ⁇ 111 2. 1 The coating layer is coated with a coating layer of the core layer, the amount of the separator is about 2 to 5% by weight of the core; the polyacrylic resin 11 10. 5 ⁇ 18. 5 grams, polyacrylic resin 111 2.
  • the preferred preparation method of the oral pH-preserving agent for enteric preparation of the present invention further comprises: taking sodium hydrogencarbonate 100 ⁇
  • the enteric coating liquid is obtained; the core of the wrapped layer is wrapped with an enteric coating liquid to a weight gain of 25 ⁇ 30%, The enteric coated pellets were obtained, and the enteric coated pellets were placed in 1000 ordinary capsule shells.
  • the present invention is an oral enteric preparation which can adjust an acidic pH liquid or urine to a normal pH range, and is preferably a variety of oral enteric preparations of sodium hydrogencarbonate.
  • the preparation is prepared by mixing one or more alkaline pH adjusters with suitable excipients, and forming a core in the form of granules, cores, powders, pellets, and then coating the enteric solution.
  • the sexual coating film is filled or filled in an enteric capsule shell to prepare an oral common enteric preparation or an enteric sustained-release preparation containing a basic drug (i.e., an alkaline pH adjuster).
  • the drug core of the preparation contains a pharmaceutically active ingredient alkaline P H modifier, and the alkaline pH adjuster and suitable auxiliary materials such as a filler, a binder, a disintegrant, a sustained release agent, a glidant, a lubricant, etc.
  • suitable auxiliary materials such as a filler, a binder, a disintegrant, a sustained release agent, a glidant, a lubricant, etc.
  • the cores in the form of cores, granules, powders, and pellets are prepared according to a commonly used formulation process, and then coated with an enteric coating material or filled in an enteric capsule shell.
  • the present invention provides an oral enteric preparation of a basic medicine and a composition thereof, and a preparation method thereof.
  • the present invention can be achieved by coating a drug core containing a pharmaceutically active ingredient with a coating film or a capsule shell capable of providing desired enteric properties, and thus any immediate release or sustained release dosage form can be used as a core.
  • the enteric coated coating film or capsule shell is wrapped.
  • the alkaline-containing pH adjusting agent and the common oral preparation auxiliary material are made into a common core (ie, a drug core) and then coated with an enteric coating film to obtain an ordinary enteric coated tablet; for example, a basic pH adjusting agent containing a main drug and a commonly used oral solution are used.
  • the sustained-release preparation auxiliary material is made into a sustained-release tablet core (ie, a drug core) and then coated with an enteric coating film, or a conventional core or matrix core coated with an enteric material as a porogen as a sustained-release coating film.
  • An enteric sustained release tablet is obtained.
  • the enteric capsule can be obtained by mixing the main drug alkaline pH adjuster with a common oral preparation auxiliary to prepare a common powder, granule or pellet into the enteric capsule shell.
  • the enteric capsule can also be obtained by preparing the main drug alkaline pH adjusting agent into granules having enteric properties and pellets and then filling them into a common capsule shell.
  • the main advantages of the invention include:
  • the oral enteric preparation of the alkaline pH adjuster of the present invention is not released in the stomach, does not absorb, and thus does not first undergo acid-base neutralization reaction with gastric acid; does not react with gastric acid, and does not affect normal digestion of the stomach. Absorption function; avoids adverse reactions such as hiccups, bloating, stomach cramps of common stomach-soluble preparations; the enteric preparation of the present invention does not release, absorb, or acid-base neutralization reaction with gastric acid in the stomach, and is beneficial for regulating clinical use.
  • the dose, the quality of the treatment is improved, the medication is more targeted, and the stomach side effects that plague the patient are substantially avoided.
  • the oral enteric preparation of the alkaline pH adjuster of the present invention is effective in intestinal absorption and absorption, and since the action with gastric acid is avoided, the effect can be fully exerted, so that the dosage can be reduced accordingly.
  • the oral enteric preparation of the alkaline pH adjuster of the present invention has a significant reduction in side effects due to the stomach, and can be taken in large doses within a prescribed range according to the condition of the patient, and is also suitable for long-term use, and the patient is still well tolerated.
  • the oral enteric preparation of the basic pH adjusting agent of the invention can be widely used for regulating the acid-base balance of the human body, correcting the acidic body, alkalizing the urine, treating metabolic acidosis, acid-base imbalance caused by renal damage , gout and other symptoms, maintain normal body fluid pH, both for treatment and prevention.
  • the oral enteric preparation of the alkaline pH adjuster of the present invention has broad application prospects and good social benefits.
  • the excipients used are in line with the relevant standards of the Pharmacopoeia: sodium bicarbonate (Hebei Huachen Pharmaceutical Co., Ltd.), potassium citrate (Hunan Huari Pharmaceutical Co., Ltd.), tannic acid (Anhui Huayuan Biological Pharmaceutical Co., Ltd.), ⁇ Sodium citrate (Wuxi Second Pharmaceutical Factory), Magnesium Stearate (Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.), Hypromellose (Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.), Polyethylene Glycol (Shanghai Pudong Gaonan) Chemical Plant), Polyacrylic Resin II (Lianyungang Wantai Pharmaceutical Materials Co., Ltd.), Polyacrylic Resin ⁇ (Lianyungang Wantai Pharmaceutical Materials Co., Ltd.), Polysorbate 80 (China Pharmaceutical (Group) Shanghai Chemical Reagent Company), Microcrystalline Cellulose (Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.) Castor oil (Huaihai
  • Micro-silica gel (Shandong Liaocheng Ahua Pharmaceutical Co., Ltd.) in line with industry standards.
  • Acrylic resin water dispersion enteric coating premix (Shanghai Kalekang Coating Technology Co., Ltd. Enterprise standard), pareil (purchased from Shanghai Hua pharmaceutical pellets by high Limited, standard number: Hu Q / WS- 1-2274- 2001)
  • Example 1 sodium bicarbonate enteric-coated tablets
  • Preparation process Sodium bicarbonate is crushed through 80 mesh sieve, 10% starch slurry (that is, starch is mixed with water and heated) to make soft material by rapid stirring method, 14 mesh sieve granules, oven drying, oven initial Set the temperature 4 (TC, 1 hour later, heat up to 50 ° C, dry; dry granules 12 mesh sieve granules, add 1000 starch, magnesium stearate to mix. Detect the intermediate, press the drug core according to the content of the tablet.
  • 10% starch slurry that is, starch is mixed with water and heated
  • the hypromellose of the isolation layer and the polyethylene glycol are added to the ethanol to be soaked and dissolved; the polyacrylic resin II and the polyacrylic resin III in the enteric coating solution are soaked and dissolved in the ethanol solution according to the prescription, and then added to the solution.
  • sesame oil, diethyl phthalate, and polysorbate 80 mix and feed Line coating operation. Place the film in the coating pan, rotate the coating pan and blow into the hot air to make the temperature in the pan to about 4CTC.
  • spray the coating liquid on the separator to adjust the atomization pressure, the spray speed, the rotation speed of the coating pan, and observe the coating state.
  • the weight of the coating of the barrier layer is about 2% (according to the weight of the core made by actual pressing, the amount of volatile liquid auxiliary such as ethanol is not counted); the coating of the barrier layer is continued after the coating is completed. The 5% (based on the weight of the core of the coated insulation layer) is added to the weight of the enteric coating layer.
  • the sodium bicarbonate enteric-coated tablet of the present invention was examined, and the appearance was completed without deformation in a 0.1 mol/L hydrochloric acid solution (simulated gastric juice) for 2 hours, and no bubble was generated.
  • a 0.1 mol/L hydrochloric acid solution simulated gastric juice
  • sodium bicarbonate neutralizes acid to release C0 2 gas to form bubbles
  • phosphate buffer pH 6.8
  • Simulated intestinal fluid The drug was completely released (released > 90%) over the course of 20 minutes.
  • Example 2 Sodium bicarbonate enteric coated tablets
  • Preparation process Sodium bicarbonate is crushed through 80 mesh sieve, 10% starch slurry is added into soft material by rapid stirring method, and sieved by 14 mesh sieve, dried in an oven, the initial set temperature of the oven is 40 ° C, and the temperature is raised after 1 hour. Dry to 50 ° C; dry granules of 12 mesh sieve, add dry starch, magnesium stearate and mix. The intermediate was tested and the drug core was weighed according to the content of the tablet.
  • the hypromellose of the isolation layer and the polyethylene glycol are added to the ethanol to be soaked and dissolved; the polyacrylic resin II and the polyacrylic resin in the enteric coating solution are soaked and dissolved in the ethanol solution, and then added to the solution.
  • the sesame oil, diethyl phthalate, and polysorbate 80 are mixed and then subjected to a coating operation. Place the film in the coating pan, rotate the coating pan and blow into the hot air to make the temperature in the pan to about 40 °C. First, spray the coating liquid on the separator to adjust the atomization pressure, the spray speed, the rotation speed of the coating pan, and observe the package.
  • the weight of the barrier layer is about 3.5%; after the coating of the barrier layer is completed, the enteric coating operation is continued until the coating is sprayed off, and the weight of the enteric coating layer is increased according to the Chinese Pharmacopoeia 2005.
  • the annual version of the enteric-coated tablet inspection method (slurry method) examines the sodium bicarbonate enteric-coated tablet of the present invention, and the appearance is intact without deformation in a 0, lmol/L hydrochloric acid solution for 2 hours, and no bubble is generated, and substantially no drug component is released ( The release rate was ⁇ 0.5%, but the drug was completely released (release rate > 90%) over 20 minutes in a phosphate buffer (pH 6.8) environment.
  • Example 3 Sodium bicarbonate enteric coated tablets
  • Preparation process Sodium bicarbonate is crushed through a som sieve, and the mo% starch slurry is made into a soft material by a quick stirring method.
  • the initial set temperature of the oven is 40 ° C, and after 1 hour, the temperature is raised to 50 ° C, and dried; the dry granules are sieved into 12 mesh sieves, and dried starch and magnesium stearate are added to mix.
  • the intermediate was tested and the drug core was weighed according to the content of the tablet. According to the prescription, the hypromellose of the isolation layer and the polyethylene glycol are added to the ethanol to be soaked and dissolved; the polyacrylic resin II and the polyacrylic resin III in the enteric coating solution are soaked and dissolved in the ethanol solution according to the prescription, and then added to the solution.
  • the sesame oil, diethyl phthalate, and polysorbate 80 are mixed and then subjected to a coating operation. Place the film in the coating pan, rotate the coating pan and blow into the hot air to make the temperature in the pan to about 40 ,. First, spray the coating liquid on the separator to adjust the atomization pressure, the spray speed, the speed of the coating pan, and observe the coating state. The 5%. The weight of the enteric coating layer is about 3.5%. The lining of the coating layer is about 5%.
  • the sodium bicarbonate enteric-coated tablets of the present invention were examined, and the appearance was intact and not deformed in 0. lmol/L hydrochloric acid solution for 2 hours, and no bubbles were generated, basically The drug component was not released (release ⁇ 0.5%), but the drug was completely released (released >90%) over 20 minutes in a phosphate buffer (pH 6.8) environment.
  • Example 4 Potassium citrate enteric coated tablets
  • Preparation process Potassium citrate is crushed through 80 mesh sieve, and ethanol solution of polyethylene glycol 6000 is added for rapid stirring. The method is made into soft material, 12 mesh sieve granules, oven drying, oven initial set temperature 40 ° C, 1 hour later, the temperature is raised to 50 ° C, dry; dry granules 10 mesh sieve granules, add magnesium stearate to mix . The intermediate was tested and the drug core was compressed according to the content of the tablet.
  • hypromellose and polyethylene glycol are added to ethanol to dissolve and dissolve, and the coating liquid of the separation layer is prepared; the polyacrylic resin II and the polyacrylic resin III are dissolved in ethanol and dissolved in the prescription, and castor oil and o-benzene are added. Diethyl dicarboxylate and polysorbate 80 were mixed to prepare an enteric coating solution.
  • the core is placed in a coating pan, and the rotating coating pan is blown into the hot air to make the temperature in the pot to about 40 ° C.
  • the coating liquid is sprayed into the separator to adjust the atomization pressure, the spray speed, and the speed of the coating pan. 2% ⁇
  • the weight of the enteric coating layer is about 3.2%.
  • the potassium citrate enteric-coated tablet of the present invention was examined, and in the lniol/L hydrochloric acid solution for 2 hours, the appearance was intact without deformation, and no bubble was generated, basically The drug component was not released (release ⁇ 0.5%), but in the phosphate buffer (pH 6.8) environment for 20 minutes, the drug was completely released (release degree > 90 ° / 0 ).
  • Example 5 Sodium bicarbonate enteric capsule
  • Preparation process The raw material sodium hydrogencarbonate is crushed through an 80 mesh sieve, and the starch and the micro-silica gel are mixed and mixed, and then the No. 2 enteric-coated capsule is obtained.
  • Example 6 Sodium bicarbonate enteric capsule
  • Preparation process The raw material sodium hydrogencarbonate is crushed through an 80 mesh sieve, and the starch and the micro-silica gel are mixed and hooked, and then the enteric capsule No. 0 is obtained.
  • Example 7 Sodium bicarbonate enteric sustained release tablets
  • the diethyl diformate and the polysorbate 80 are mixed and formulated into an enteric coating liquid, and the coating operation can be carried out separately. Place the film in the coating pan, rotate the coating pan and blow into the hot air to make the temperature in the pan to about 40 °C. First, spray the coating liquid on the separator to adjust the atomization pressure, the spray speed, the speed of the coating pan, and observe the package. The 5%.
  • the weight of the enteric coating layer is about 3.5%.
  • the coating of the enteric coating layer is about 5%.
  • the sodium bicarbonate enteric sustained-release tablet of the present invention was subjected to 0. lmol/L hydrochloric acid solution for 2 hours, and the appearance was intact without deformation, and no bubble was generated.
  • the drug component was not released, but slowly released in the phosphate buffer (pH 6.8) environment.
  • the data is shown in Table 1, and the curve is shown in Figure 1.
  • Example 8 Sodium bicarbonate enteric pellets
  • Hypromellose was soaked and dissolved in a 50% ethanol solution, and polyethylene glycol 400 and sodium hydrogencarbonate fine powder (200 mesh) were added, and a drug-containing suspension was prepared under stirring.
  • the medicine is carried out in the multi-functional fluidized coating machine.
  • the side spray method is adopted.
  • the operating data of the coating machine is as follows: nozzle diameter 1 leg, induced draft fan frequency 18 ⁇ 25Hz, inlet air temperature 40 ⁇ 50 ⁇ , bed temperature 45° C, atomization pressure 1. 2 ⁇ 1. 6Mpa, turntable frequency 8-10Hz, spray rate 3 ⁇ 5g/min.
  • the blank pellet core is placed in a fluidized coating machine to spray the medicated suspension in a fluidized and rotated state.
  • Coating bag isolation layer According to the prescription, hypromellose and polyethylene glycol are added to ethanol to dissolve and dissolve, and the separation layer coating liquid is prepared. The bottom spray method is used to isolate the layer, and the coating amount is the weight of the drug-containing pellets. About 4%.
  • the operating data of the coating machine is as follows: nozzle diameter 1 let, the fan frequency 15 ⁇ 20Hz, inlet air temperature 40 ⁇ 50 ⁇ , bed temperature 45 °C, atomization pressure 1. 2Mpa, spray rate 2 ⁇ 4g/min.
  • Intestinal coating layer When preparing the coating liquid, the coating powder is slowly added to the stirred water, stirred for 45 minutes and then used. The drug-loaded pellets were placed in a fluidized coating machine and the coating was continued by a bottom spray method.
  • the operating data of the coating machine is as follows: Nozzle diameter 1 Let the induced draft fan frequency 18 ⁇ 25Hz, inlet air temperature 30°C, bed temperature 28 °C, atomization pressure 0. 15Mpa, spray rate 2 ⁇ 4g/min.
  • the enteric coating adopts the bottom spray method, adjusts the coating parameters, prevents the adhesion between the pellets, and obtains the coated pellets with ideal appearance.
  • the coating process needs to continuously stir the coating liquid until the end. Turn off the temperature control switch to bring the temperature inside the bed to room temperature and the coating is finished. The coating gained about 25%.
  • Hypromellose was soaked and dissolved in a 50% ethanol solution, and polyethylene glycol 400 and sodium hydrogencarbonate fine powder (200 mesh) were added, and a drug-containing suspension was prepared under stirring.
  • the medicine is carried out in a multi-functional fluidized coating machine.
  • the side spray method is adopted.
  • the operating data of the coating machine is as follows: nozzle diameter lmm, induced draft fan frequency 18 ⁇ 25Hz, inlet air temperature 40 ⁇ 50, bed temperature 45°C,
  • the atomization pressure is 1. 2 ⁇ 1 6Mpa, the turntable frequency is 8-10Hz, and the spray rate is 3 ⁇ 5g/min.
  • the blank pellet core is placed in a fluidized coating machine to spray the medicated suspension in a fluidized and rotated state.
  • Coating bag isolation layer According to the prescription, hypromellose and polyethylene glycol are added to ethanol to dissolve and dissolve, and the separation layer coating liquid is prepared. The bottom spray method is used to isolate the layer, and the coating amount is the weight of the drug-containing pellets. About 6%.
  • the operating data of the coating machine is as follows: Nozzle diameter 1 should be, the frequency of the induced draft fan is 15 ⁇ 20Hz, the inlet air temperature is 40 ⁇ 50°C, the temperature in the bed is 45°C, the atomization pressure is 1. 2Mpa, and the spraying rate is 2 ⁇ 4g/min. .
  • Intestinal coating layer When preparing the coating liquid, the coating powder is slowly added to the stirred water, stirred for 45 minutes and then used.
  • the drug-loaded pellets were placed in a fluidized coating machine and the coating was continued by a bottom spray method.
  • the operating data of the coating machine is as follows: Nozzle diameter 1 wake up, induced draft fan frequency 18 ⁇ 25Hz, inlet air temperature 30 ⁇ , bed temperature 28 °C, atomization pressure 0. 15Mpa, spray rate 2 ⁇ 4g/min.
  • the enteric coating adopts the bottom spray method, adjusts the coating parameters, prevents the adhesion between the pellets, and obtains the coated pellets with ideal appearance.
  • the coating process needs to continuously stir the coating liquid until the end. Turn off the temperature control switch to bring the temperature inside the bed to room temperature and the coating is finished.
  • the weight gain of the coating is about 30%.
  • the qualified enteric coated pellets can be filled into the ordinary capsule shell according to the dosage requirement to obtain the sodium bicarbonate enteric pellet capsule.
  • Experimental Example 10 pharmacodynamic test
  • the pH of human body fluid mainly refers to the pH of blood, and can also refer to urine, saliva, and the like. Since the metabolites are eventually excreted in the urine, the acidity and alkalinity of the metabolites will also affect the pH of the blood and urine, so that the pH of the blood has a certain correlation with the pH of the urine. It can reflect the blood pH value and the trend of change to some extent.
  • One of the functions of commercially available sodium bicarbonate tablets is to alkalinize urine.
  • This test initially validates the efficacy of the present invention by replacing the pH of the blood with the pH of the urine. Alkaline pH adjustment
  • the dosage regimen is applicable to a variety of different conditions, and there is a range of dosages required, and the difference is large. The specific dosage should still refer to the corresponding regulations.
  • the dosage of sodium bicarbonate enteric-coated tablets can be measured according to the dosage of ordinary sodium bicarbonate tablets. Because the enteric-coated tablets of the present invention can fully exert the effects of the drug and have no side effects of the stomach, the condition can be increased or decreased depending on the condition. small dose.
  • Main efficacy indicators The degree of alkalization of the subject's urine pH.
  • Safety indicators side effects such as bloating, hiccups and tolerance of subjects.
  • Test dose single dose, 1 time 3g.
  • the patient can take oral sodium bicarbonate tablets, the recommended dose of the first dose is 4g, and pay attention to the detection of urine pH to determine the efficacy.
  • the sodium bicarbonate enteric solution in the first embodiment of the present invention The tablet is a modified dosage form of commercially available sodium bicarbonate tablets, which is still orally administered, and does not change the administration route of sodium bicarbonate, so the dosage can be used according to the usage amount of the commercially available product.
  • the present invention is carried out according to the usage and dosage of the commercially available product. Considering that the subject is a healthy human body rather than a patient, we will reduce the dosage by 3g as appropriate.
  • Test drug The sodium bicarbonate enteric-coated tablet of Example 2, specification: 300 mg.
  • Experimental design and implementation Select healthy adults to group experiments.
  • the following is a set of specific experimental data - 7 subjects, 4 males and 3 females, compiled as No. 1 ⁇ 7, using their own cross-control method, a comparison test of this product and ordinary sodium bicarbonate tablets.
  • the dosage is 3g/l times/day (that is, the control drug is taken once for 6 tablets, and the test drug is taken for 10 tablets at a time). It is taken on an empty stomach before breakfast, and the first day is blank.
  • the reference drug is taken according to the numbered number. Take the test drug on the double, take the self-intersection on the third day, take the control drug on the double, and take the test drug on the single.
  • Uniform diet during the test period uniform drinking water, 7: 30 ⁇ 17: 30 every hour to determine the urine sample volume and pH value, record and statistics the test data; record the adverse reactions and reaction levels of the subjects (reaction The degree is subjective, subjective, mild, moderate, severe, and severe.
  • Test results The statistical results of the urine pH of the subjects are shown in Table 2, Table 3 and Figure 2. No subjects experienced discomfort during the blank period of the test. Five subjects developed adverse reactions after taking the control drug, mainly including gastric bloating, hiccups, and satiety. After taking the test drug, no subject complained of discomfort, as shown in Table 4.
  • the values in the column of 7:30 in the above table are the average values of the urine pH of the subjects. Based on this, the values at each time point are the average of the pH changes obtained by comparing the pH value with the base point. Subject adverse reaction and compliance statistics
  • the reference drug and the test drug can effectively increase the pH value of the urine sample, alkalinize the urine, and the reference drug acts rapidly within 1 hour after taking the drug, and the reaction such as bloating and hiccup is immediately followed.
  • the test drug is delayed compared to the control drug, it is almost ineffective within 1 hour after taking it, and it is equivalent to the blank, and then it starts to work.
  • the maximum alkalization degree of urine is similar to that of the control drug, but the effect is stable and lasting.
  • test drug "sodium bicarbonate enteric-coated tablet” prepared by the invention can effectively alkalinize the urine, and the alkalized urine has the same strength as the control drug "sodium bicarbonate tablet", but the action time is more stable and long-lasting, and There were no adverse reactions in the stomach such as hiccups and bloating of the control drugs, and there were no other side effects.
  • the subjects were well tolerated and compliant.
  • Safety indicators side effects such as bloating, hiccups and tolerance of subjects.
  • Test drug The sodium bicarbonate enteric-coated tablet of Example 2, specification: 300 mg.
  • Trial design and implementation Select healthy adults to conduct experiments on subjects, and use their own cross-control method to compare the product with ordinary sodium bicarbonate tablets.
  • the diet was unified, the amount of drinking water was unified, and the adverse reactions and the degree of response of the subjects were recorded (the degree of response was subjective, subjective, mild, moderate, severe, severe).
  • the subjects were recorded. Tolerance and compliance of the test (whether or not you are willing to continue taking the drug).
  • Test results During the test, the subjects took adverse reactions after taking the control drugs, mainly including bloating, hiccups, satiety and other reactions; after taking the test drugs, no subjects complained of adverse reactions, as shown in the table. 5.
  • Main efficacy indicators The degree of alkalization of urine pH, the normal degree of biochemical test indicators, and the impact on gout.
  • Safety indicators side effects such as bloating, hiccups and tolerance of subjects.
  • Test dose lOOmg / time, 2 times / day, take 1 month.
  • Test drug The sodium bicarbonate enteric-coated tablet of Example 1, Specification: 100 mg.
  • Test results From the statistics of urine pH value, the values before and after the test are significantly different, showing an upward trend, indicating that the test drug has alkalization effect on the urine; the blood biochemical test sheet before and after the comparison test can be seen, the test After the end, many indicators such as uric acid, triglyceride, total cholesterol, low-density lipoprotein cholesterol, glucose, etc. have been significantly improved, the basic sputum returned to the normal range, subjective feelings also indicate that the health of the subject has improved, The feeling of fatigue basically disappeared, and the concentration during work was concentrated. During the test, no common stomach side effects such as bloating, hiccup and other commercially available sodium bicarbonate tablets were found, and there was no other discomfort, and the tolerance and compliance were good.
  • the statistics of the test data showed that: the biochemical indicators of the subjects were significantly improved, especially the uric acid index indicating the gout returned to the normal range, the physical condition was good and the sub-health state was removed, and there was no obvious stomach side effect or other discomfort after taking the drug for a long time. .
  • Test dose 500mg/tablet, first serving 5g (10 pieces), then take 3g (6 pieces) every 4 hours, even for 3 days, then reduce to 2g (4 pieces), take 7 days.
  • Test drug The sodium bicarbonate enteric-coated tablet of Example 3 (specification: 500m g / piece), the first service 5g (10 pieces), after which 3g (6 pieces) were taken every 4 hours, even for 3 days, then reduced For 2g (4 tablets), take 7 days, gout did not occur.
  • the maximum dose was 23g per day, which was significantly higher than the average tolerated dose (16g) of commercially available sodium bicarbonate tablets.
  • the sodium bicarbonate oral enteric preparation of the present invention not only has the same therapeutic effect as the commercially available sodium hydrogencarbonate tablets, but also has no stomach side effects which are difficult to avoid and tolerate in ordinary tablets such as bloating and hiccups. It can fully play its role, and the safety is improved. If the sexuality is greatly increased, the dosage can be increased within the prescribed range to improve the treatment. It is also suitable for long-term use and still has good compliance, and the currently commercially available sodium bicarbonate tablets. Compared with very obvious characteristics and advantages; low dose also has the effect of alkalizing urine, which shows that it has a beneficial effect on the acid-base balance of the human body, especially acidic body.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)

Abstract

Formulation entérique orale revêtue comprenant un régulateur de pH alcalin en tant qu'agent actif et son procédé d'élaboration, ledit agent alcalin étant choisi dans le groupe suivant: bicarbonate de sodium, bicarbonate de potassium, carbonate de sodium, acide citrique, citrate de sodium, citrate de potassium, citrate d'hydrogène de potassium, citrate d'hydrogène de potassium-sodium, et leurs mélanges
PCT/CN2007/000486 2006-11-22 2007-02-12 Formulation entérique revêtue comprenant un agent alcalin actif et son procédé d'élaboration WO2008061409A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2006100979351A CN101190185A (zh) 2006-11-22 2006-11-22 一种碱性药物的肠溶制剂及其制备方法
CN200610097935.1 2006-11-22

Publications (1)

Publication Number Publication Date
WO2008061409A1 true WO2008061409A1 (fr) 2008-05-29

Family

ID=39429371

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/000486 WO2008061409A1 (fr) 2006-11-22 2007-02-12 Formulation entérique revêtue comprenant un agent alcalin actif et son procédé d'élaboration

Country Status (2)

Country Link
CN (1) CN101190185A (fr)
WO (1) WO2008061409A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102406656A (zh) * 2011-11-21 2012-04-11 南开大学 碳酸氢钠肠溶片及制备方法
CN102429887B (zh) * 2011-12-21 2013-01-02 西南大学 枸橼酸钾钠咀嚼片及其制备方法
CN102552164B (zh) * 2012-01-05 2014-07-16 金陵药业股份有限公司 一种枸橼酸钾缓释微丸及其制备方法
CN106035992A (zh) * 2016-05-31 2016-10-26 四川达邦生物科技有限公司 一种能耐高温并能定点释放的乳酸球菌微丸配方及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54138128A (en) * 1978-04-19 1979-10-26 Akiyama Jiyouzai Kk Double contrast medium for intestine
CN1717252A (zh) * 2003-09-30 2006-01-04 共和药品工业株式会社 含有碱性药物的制剂
WO2006001799A1 (fr) * 2004-06-14 2006-01-05 Sang Youn Whang Revetement sensible a la position pour une pilule de bicarbonate a teneur principale en potassium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54138128A (en) * 1978-04-19 1979-10-26 Akiyama Jiyouzai Kk Double contrast medium for intestine
CN1717252A (zh) * 2003-09-30 2006-01-04 共和药品工业株式会社 含有碱性药物的制剂
WO2006001799A1 (fr) * 2004-06-14 2006-01-05 Sang Youn Whang Revetement sensible a la position pour une pilule de bicarbonate a teneur principale en potassium

Also Published As

Publication number Publication date
CN101190185A (zh) 2008-06-04

Similar Documents

Publication Publication Date Title
CN104906064B (zh) 一种普瑞巴林胃漂浮缓释片剂及其制备方法
US20080171085A1 (en) Novel biphasic delivery system for a pharmaceutical or nutraceutical composition and method of administration
WO2015003479A2 (fr) Pastille solide administrée par voie orale pour nourrissons et enfants et procédé de préparation
AU2005309297A1 (en) Novel formulation of pyridoxal 5'-phosphate and method of preparation
CN101416947A (zh) 复方α-酮酸咀嚼片及制备方法
WO2008061409A1 (fr) Formulation entérique revêtue comprenant un agent alcalin actif et son procédé d'élaboration
CN101461788B (zh) 一种间苯三酚口腔崩解片及其制备方法
CN109044988A (zh) 一种盐酸二甲双胍药物组合物及其制备方法和应用
JP2013542975A (ja) クエン酸及び重炭酸塩を含んでなる医薬組成物、並びにシスチン尿症を治療するためのこれらの使用
CN102755310B (zh) 一种含有左旋多巴的组合物药物制剂
CN106456611A (zh) 用于治疗恶心、呕吐或腹泻症状的恩丹西酮缓释固体制剂
CN100404025C (zh) 含有盐酸曲马多和对乙酰氨基酚的口崩片及其制备方法
CN101411702B (zh) 盐酸奈福泮萘普生钠复方缓释制剂及其制备方法
CN100448431C (zh) 一种用于治疗儿童感冒的氨酚麻美口腔崩解片及制备方法
CN113274365B (zh) 雷美替胺速释缓释双释放制剂及其制备方法
CN100569232C (zh) 复方醋酸棉酚缓释药剂
CN109568281B (zh) 一种柳氮磺胺吡啶片及其制备方法
CN106109432A (zh) 一种含有盐酸舍曲林掩味口崩片及其制备方法
CN105726503A (zh) 一种盐酸左氧氟沙星片
CN101756981A (zh) 一种布洛氯雷伪麻缓释制剂及其制备方法
CN106466302B (zh) 口服氯化钾缓释片及其制备方法
CN109045034A (zh) 一种盐酸莫西沙星药物组合物及其制备方法和应用
CN101756987A (zh) 一种愈创木酚甘油醚、伪麻黄碱和右美沙芬的复方缓释制剂
CN102406739B (zh) 一种治疗小儿疝气的中药及其制备方法
CN110711184B (zh) 一种盐酸坦洛新缓释微粒及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07710912

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07710912

Country of ref document: EP

Kind code of ref document: A1