WO2008061409A1

WO2008061409A1 - Enteric coated formulation comprising alkaline active agent and its preparation process

Info

Publication number: WO2008061409A1
Application number: PCT/CN2007/000486
Authority: WO
Inventors: Dapeng Li; Weidong Ren; Meili Ma
Original assignee: Dapeng Li; Meili Ma; Weidong Ren
Priority date: 2006-11-22
Filing date: 2007-02-12
Publication date: 2008-05-29
Also published as: CN101190185A

Abstract

An oral enteric coated formulation comprises alkaline pH regulator as active agent and its preparation process, said alkaline agent is selected from: sodium bicarbonate, potassium bicarbonate, sodium carbonate, citric acid, sodium citrate, potassium citrate, potassium hydrogen citrate, potassium-sodium hydrogen citrate, and mixtures thereof.

Description

Enteric preparation for alkaline medicine and preparation method thereof

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. Background technique

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. 45, it is weakly alkaline and the range is relatively narrow. At this time, the physiological functions are in the best state, but the body's own acid-base balance ability is limited, only about 10%. People can keep body fluids in the normal range; and mild body fluid imbalance (less than 7.35 or higher than 7.45) will cause the body's various functions to decline, such as in sub-health state, severe imbalance (less than 7 3 or higher than 7.5) will lead to a variety of diseases of unknown origin.

As the human body absorbs and metabolizes all the time, most of it is acidic waste. At present, the four factors of overnutrition, bad habits, excessive mental stress and environmental pollution will also cause more acidic substances in the body, which exceeds the human body. The ability to adjust, so that the body fluid pH is lower than the normal range, forming an acidic body. People who love to drink carbonated drinks, people who smoke, drink alcohol, insomnia, and irregular work are more likely to break the balance of the environment and form an acidic body.

In order to maintain the acid-base balance of body fluids, counteract the trend of acidification of body fluids, pay attention to the intake of alkaline substances (such as most vegetables and fruits) in daily diet, and reduce the intake of acidic substances (such as animal foods). However, only relying on dietary regulation is limited, especially for people with severe acidity and acidification of body fluids. The bicarbonate buffer system is an important means for the body to regulate the acid-base balance of body fluids. HC0 can neutralize excessive H+ and maintain the normal state of body fluids. In view of the direct relationship between body fluid pH and H ⁺ and HC0 plants, 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. These have been recognized by the medical community at home and abroad, and alkaline pH regulators have been clinically used for a long time.

Another important use of 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. Most of the acid-base imbalances of various renal tubular diseases and renal failure require alkalization of urine, and sodium bicarbonate is a commonly used therapeutic drug; in addition, diabetes, leukemia, etc. Kidney damage is often caused during the development of the disease or treatment. In symptomatic treatment, it is necessary to alkalinize the urine with sodium bicarbonate or the like.

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. In particular, 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.

At present, 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. When 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. 333g per day, but in practical applications, because the commercially available sodium bicarbonate tablets produce a large amount of CO ₂ gas in the stomach, causing side effects such as hiccups and bloating, the patient only Can take 4g for the first time, after every 4 hours l~2g, take up to 16g per day, can not take high dose according to the severity of the disease, had to change to intravenous drip, neither economic nor convenient.

Therefore, there is an urgent need in the art to develop new dosage forms of basic drugs to facilitate the use and reduce the side effects of existing drugs. Summary of the invention

SUMMARY OF THE INVENTION It is 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. In a first aspect of the invention, there is provided 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%. In another preferred embodiment, 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%.

In another preferred embodiment, 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%.

In another preferred embodiment, 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.

In another preferred embodiment, 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.

In another preferred embodiment, the formulation is selected from the group consisting of:

(a) an enteric tablet, the tablet comprising a core and an enteric coating, wherein the core comprises an alkaline pH adjuster and a pharmaceutically acceptable carrier;

(b) 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;

(c) enteric pellets, the pellet 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.

In another preferred embodiment, a barrier layer is also provided between the core and the enteric coating, or between the pellet core and the enteric coating.

In another preferred embodiment, 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.

In another preferred embodiment, 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.

In another preferred embodiment, the release layer is selected from the group consisting of a barrier coating material, a plasticizer, or a mixture thereof.

In another preferred embodiment, the release layer coating material is selected from the group consisting of hypromellose K4, hypromellose Κ100, 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.

In another preferred embodiment, the pharmaceutically acceptable carrier is conventional, sustained release or immediate release. In another preferred embodiment, the pharmaceutically acceptable carrier further comprises a binder, a sustained release agent, a lubricant, a glidant, a disintegrant, or a combination thereof. In another preferred embodiment, 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 Κ4, hypromellose Κ100, 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.

In a second aspect of the present invention, there is provided 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 ρ Η 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.

In a third aspect of the invention, there is provided the use of an oral enteric preparation of the above basic rhobar modifier for the preparation of a medicament for upregulating body fluids or urine.

In another preferred embodiment, the medicament is also used to treat metabolic acidosis, acid-base imbalance caused by impaired renal function, or gout.

In a fourth aspect of the invention, there is provided 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 ρΗ an oral enteric preparation as described above.

In another preferred embodiment, the subject's body fluid ρ Η is lower than 7.35.

In another preferred embodiment, 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 stomach reaction caused by the reaction and its reaction products, such as hiccups, gastrointestinal aeration, bloating and other adverse reactions; especially in large doses and long-term use, there are no such side effects, the patient compliance is good, and the current commercial preparations There is a significant difference in the ratio; the effect in the body is stable and long-lasting, and even if it is not a sustained-release preparation, there is no strong trough difference. The oral enteric preparation preparation method of the alkaline pH adjuster developed by the present invention is suitable for industrial application. DRAWINGS

Figure 1. Release curve of sodium bicarbonate enteric sustained-release tablets in artificial intestinal fluid.

Figure 2. Change in urine pH of the subject (n=7) In the figure: 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. detailed description

For a long time, 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. Experiments have shown that 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

The "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.

In a preferred embodiment, an oral enteric preparation of an alkaline pH adjusting agent is provided, 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. Typically, 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. One or a mixture thereof; 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 Κ 4, hypromellose Κ 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 Κ4, hypromellose Κ100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP, povidone K30 or In combination, the plasticizing layer 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 a combination thereof; enteric coating The acrylic resin polymer in the material is selected from the group consisting of polyacrylic resin II, poly Acrylic resin enamel, acrylic resin aqueous dispersion enteric coating premix, methacrylic resin polymer or a combination thereof; the plasticizer in the enteric coating layer is selected from polyethylene glycol 400, polyethylene glycol 1450, Polyethylene glycol 4000, polyethylene glycol 6000, diethyl phthalate or a combination thereof. Preparation

The oral enteric preparation of the present invention can be prepared by a conventional method in the art.

Generally, the preparation method includes the following steps:

1) mixing an alkaline rhodium modulating agent with an oral preparation auxiliary agent selected from conventional, sustained-release or immediate-release, into a core in the form of core, granule, powder or pellet; per 1000 tablets or tablets of oral enteric preparation In the core, the alkaline pH Η modifier is 10~2000 grams;

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.

3) The granules or pellets after the enteric coating of the package in the step 2) are filled into a common capsule.

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. Potassium acid, sodium potassium hydrogen citrate or a combination thereof; in every 1000 tablets or tablets of oral enteric preparation, 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 Preparing a core in the form of core, granule, powder or pellet containing an alkaline rhodium modulating agent according to a conventional method; 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 consisting of an acrylic resin, cellulose acetate and phthalate. Formate, hyprothenol 5〜3. 5%, granules or granules or granules or granules or granules or granules or granules or granules or granules or granules or granules or granules. 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 enteric preparation of the basic pH Η 剂 : : : : : : : 每每每每每每每每每每每每每每每每每每每每每每每每每每每每每每每每每每每The binder in the core is selected from the group consisting of starch, dextrin, povidone oxime 30, hypromellose Κ4, hypromellose Κ100, hypromellose 5CP, hypromellose 15CP, hypromellose a 50CP or hydroxypropyl cellulose or a combination thereof; the sustained release agent is selected from the group consisting of hypromellose K4, hypromellose Κ100, ethyl cellulose or sulis or a combination thereof; the lubricant is selected from magnesium stearate or talc Powder, the glidant is selected from the group consisting of micronized silica gel or polyethylene glycol, the disintegrant is selected from the group consisting of starch, microcrystalline cellulose or hydroxypropyl cellulose 15CP; the release layer coating material in the separator is selected from hypromellose Κ4, Hypromellose Κ100, hypromellose 5CP, hypromellose 15CP, hypromellose 50CP and povidone K30 or a combination thereof, the plasticizer in the separator is selected from polyethylene glycol 400, Polyethylene glycol 1450, polyethylene glycol 4000, polyethylene Alcohol 6000, diethyl phthalate or a combination thereof; coating the core with a separating layer to obtain a core coated with a separator, the amount of the separating layer being 2 to 5% by weight of the core; in the enteric coating material The acrylic resin polymer is selected from the group consisting of polyacrylic resin II, polyacrylic resin III, acrylic resin aqueous dispersion enteric coating premix, methacrylic resin polymer or a combination thereof, and the plasticizer in the enteric coating layer is selected from the group consisting of plasticizers Polyethylene glycol 400, polyethylene glycol 1450, polyethylene glycol 4000, polyethylene glycol 6000, diethyl phthalate or a combination thereof; enteric coating of the core coated with the barrier layer, to The tablet core weight gain is about 1.5 to 3. 5%, based on the weight of the core of the wrapped 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. 2 to 5%; mixed polyacrylic resin II, polyacrylic resin III, castor oil, diethyl phthalate, polysorbate 80 and ethanol, and then formulated into an enteric coating liquid; coated with enteric coating The liquid is applied to the core of the wrapped separator to a weight gain of about 1.5 to 3. 5%, based on the weight of the core of the wrapped separator, 1000 tablets of oral enteric preparation are prepared.

5克混合, 0份含肠溶。 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克的聚树脂树脂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. 1 5克和265〜465毫升。 3.7 grams, castor oil 4. 2~7. 4 grams, diethyl phthalate 2. 1~3. 7 grams, polysorbate 80 2. 1~3. 7 grams and 265~465 ml After the ethanol is mixed, it is formulated into an enteric coating liquid; the core of the coated layer is coated with an enteric coating liquid to a weight gain of 2 to 3. 5%, based on the weight of the core of the wrapped separator , 1000 tablets of oral enteric sustained release preparations were prepared.

The preferred preparation method of the oral pH-preserving agent for enteric preparation of the present invention further comprises: taking sodium hydrogencarbonate 100~

300克, with hypromellose 15CP 16~48g, polyethylene glycol 400 4~12g and 50% ethanol 400~1200 liters mixed, sprayed 0. 5mm blank pellet core 35~ 100g , the drug core in the form of pellets; with hypromellose 15CP 4. 9~ 21. 8 grams, polyethylene glycol 400 1. 3~5. 8 grams and aqueous ethanol (such as 40-60% ethanol, preferred 50% ethanol) mixed, formulated into a coating layer coating solution, coated with a coating layer in the form of a coating layer, to a core weight of 4 to 6% _; coated with an acrylic resin aqueous dispersion enteric coating After premixing 40. 5~ 146g and water 210~ 730ml, 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. Mixing, 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. In principle, 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:

(a) 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.

(b) 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.

(c) 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. In summary, the oral enteric preparation of the alkaline pH adjuster of the present invention has broad application prospects and good social benefits. Example

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples that do not specify the specific conditions are usually in accordance with conventional conditions, such as The theory and practice of Industrial pharmacy (Lachman L) or the third edition of Pharmacy (edited by Tu Xide et al., published by People's Health Publishing House). The conditions stated, or in accordance with the conditions recommended by the manufacturer. Raw material

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.), 枸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 ΙΠ (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 Fine Chemical Plant, chemically pure), diethyl phthalate (Beijing Zhonglian Chemical Reagent Factory, chemically pure). 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

Prescription: 1000 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. 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. After 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. 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 coating state. , to prevent adhesion, 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.

According to the Chinese Pharmacopoeia 2005 version of the enteric-coated sheet inspection method (slurry method), 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. (If there is drug release, sodium bicarbonate neutralizes acid to release C0 ₂ gas to form bubbles), and basically does not release the drug component (release <0.5%), but in 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

Prescription: 1000 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. 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 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. In the state of clothing, to prevent adhesion, 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

Prescription: 1000 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.

14 mesh sieve granulation, drying in a box, 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%.

According to the Chinese Pharmacopoeia 2005 version of the enteric-coated tablets inspection method (slurry method), 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

Prescription: 1000 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. According to the prescription, 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. First, 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%.

According to the Chinese Pharmacopoeia 2005 version of the enteric-coated test method (slurry method), 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

Prescription: 1000 capsules

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.

The test was carried out in the same manner as in Example 1, and the appearance was complete without deformation in 0. lmol/L hydrochloric acid solution for 2 hours, no bubble was generated, and substantially no drug component was released (release rate <0.5%), but Phosphate buffer (pH 6.8) The drug was completely released (released >90%) over the course of 20 minutes. Example 6: Sodium bicarbonate enteric capsule

Prescription: 1000 capsules

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.

The test was carried out in the same manner as in Example 1, and the appearance was complete without deformation in 0. lmol/L hydrochloric acid solution for 2 hours, no bubble was generated, and substantially no drug component was released (release rate < 1%), but in phosphate. Buffer (PH6.8) The drug was completely released (released >90%) over the course of 20 minutes. Example 7: Sodium bicarbonate enteric sustained release tablets

Prescription: 1000 tablets

Operation: Mix sodium bicarbonate, hypromellose, microcrystalline cellulose in a quick stirrer, add soft material made of ethanol, granulate in 16 mesh, dry in 40~50 °C oven, 14 mesh whole, Add micro-powder silica gel and magnesium stearate to mix; test the intermediate, according to the content of the tablet weight, use the special-shaped stamping into a sheet-like drug core. According to the prescription, 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. 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%.

According to the Chinese Pharmacopoeia 2005 version of the enteric-coated sheet inspection method (slurry method), 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

Prescription: 1000 capsules

Preparation Process:

1 Preparation of the drug core 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 Ό, 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.

2 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 40~50Ό, 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%.

3 Qualified enteric coated pellets are placed in a common gelatinous shell according to the dosage requirements to obtain sodium bicarbonate enteric pellets. Example 9: Sodium bicarbonate enteric pellets

Prescription: 1000 capsules

Preparation Process:

1 Preparation of the drug core 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.

2 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 30Ό, 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%.

3 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

According to the pharmacodynamic test guidelines promulgated by the State Food and Drug Administration, the pharmacodynamic test was designed to verify the effectiveness and safety of the drug alkalized urine of the present invention. 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. For example, 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.

1, healthy human body

(1) Preliminary efficacy test

Experimental design: Single dose, random, blank and positive control, self-crossover test.

Subject: Healthy adults

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. (Clinical for alkalized urine, 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. To verify the efficacy of the alkalized urine of the present invention 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.

Reference drug: Sodium bicarbonate tablets (commercially available) Specifications: 0. 5g Tianjin Lisheng Pharmaceutical Co., Ltd. Production Lot No.: 0511177

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. On the second day, 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. Table 2 Sodium bicarbonate preparation efficacy test _P H change (ΔρΗ> data statistics table (η=7)

Note - The values in the column of 7: 30 in the above table are the urine pH values of each subject. Based on this, the values of the time points thereafter are the pH changes obtained by comparing the pH value with the base point.

Table 3 Statistical data of the average change (ΔρΗ) of experimental data of subject pH (n=7)

Note: 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

From the test table, compared with the blank state, 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. Accompanying, and 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. There is no strong trough difference, so that the subject's urine pH has maintained a stable high level for a long period of time, and there is no discomfort after taking it, which better shows the design purpose of the test drug; The statistical results of the urine sample volume showed that the subjects had a more obvious decrease in urine output after taking the control drug than the blank state, which was consistent with the subjective feeling of the subject. In terms of adverse reactions, the test drugs were similar to the blanks, and there was no common stomach reaction in commercial ordinary tablets. The subjects had good compliance and significant differences compared with the control drugs; the control drugs (commercially available ordinary tablets) The adverse reactions are in line with the clinical practice, mainly concentrated in the stomach reaction, the frequency of occurrence is high, the duration is longer, and the subject's compliance is poor.

The experimental results show that the 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. Compared with the currently marketed preparations, the subjects were well tolerated and compliant.

(2) Tolerance and compliance test

Based on the above test, we added the following test to further investigate the tolerance and compliance of the drug of the present invention. Experimental design: multiple doses, self-intersection, controlled trials.

Subject: Healthy adults

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. Specific experimental data: The dosage is 1. 5g / time, 3 times / day (that is, the control drug takes 3 tablets each time, and the test drug takes 5 tablets at a time), which are taken half an hour before the meal. On the first day, take the reference drug according to the numbered number, take the test drug on the double, and take it for 3 consecutive days; the fourth day is the washing period, do not take any medicine; the fifth day, cross the self, cross the control, take the single The test drug, the dosage is the same as before, and then taken continuously for 3 days. During the trial, 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). At the end of the trial, 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.

Subject adverse reaction and tolerance compliance statistics

Other

Bloating, hiccup, blistering, tolerance, compliance, response

5 cases (71%): 5 cases 71%): 1 case (14%):

1, 2, 3, 5, 7 (3 males and 2 females) 1, 2, 3, 5, 7 No. 3 (male)

Day 1

Degree: 3 cases are mild, 2 cases are moderate: 2 cases are mild, 2 cases are moderate: slight

Good: 0

Equivalent, 1 case is more serious

General: 2 cases Willingness: 1 case Photo 6 cases (86%): 5 cases (86%): 2 cases (29%>:

(29%) (14%) Medicine 1, 2, 3, 5, 6, 7 (3 males and 3 females) 1, 2, 3, 5, 6, 7 No. 3, 6 (1 male and 1 female)

Day 2 Poor: 4 cases Unwilling: Degree: 3 cases are mild, 3 cases are moderate: 2 cases are mild, 2 cases are moderate: medium

(57%) 6 cases, etc., 2 cases are more serious

Very poor: 1 case (86%)

7 cases (100%): 1, 2, 3, 4, 5, 6, 7 7 cases (100%): 2 cases (29%):

(14%)

No. (4 males and 3 females) 1, 2, 3, 4, 5, 6, 7 No. 3, 6

Day 3

Degree: 3 cases were mild, 3 cases were moderate, 1 degree: 2 cases were mild, 3 cases were moderate: 1 case was medium,

No

The case is more serious, etc., 3 cases are more serious, 1 case is more serious

Good: 7 cases

Day 1 No No No No

Test (100%) Willingness: 7 cases will be tested on the 2nd day without or without general: 0 (100%) Poor medicine: 0 Unwilling: 0 Day 3 Nothing Nothing No difference: 0 As can be seen from the above statistics, when the drug is administered repeatedly and continuously, the drug of the present invention is significantly different from the currently marketed drug, and the adverse reaction does not substantially occur, especially the side effects of the stomach can be avoided, and the commercially available drug is avoided. The incidence of adverse reactions in the stomach is quite high, especially when side effects such as bloating and hiccups occur almost continuously, and the incidence of adverse reactions and the degree of reaction increase with the increase of the number of days taken. The drug tolerance and compliance of the drug of the present invention are significantly better than those of commercially available drugs, and can be taken long-term and well tolerated.

2, low-dose or super-dose sodium bicarbonate enteric-coated tablets to prevent gout, improve the body biochemical test indicators and tolerance test

Purpose of the test: To test the effect of oral low-dose or ultra-dose sodium bicarbonate enteric-coated tablets on prevention of gout, improvement of biochemical test indicators, and whether to significantly reduce side effects on the stomach.

Main efficacy indicators: The degree of alkalization of urine pH, the normal degree of biochemical test indicators, and the impact on gout.

1) Test dose: lOOmg / time, 2 times / day, take 1 month.

Test drug: The sodium bicarbonate enteric-coated tablet of Example 1, Specification: 100 mg.

Subject: Adult male with a history of gout and recent acute exacerbations. A number of biochemical test indicators have deviated from the normal range to varying degrees. In the treatment of gout, the commercially available sodium bicarbonate tablets were used to alkalinize urine. Before the start of the test, go to the regular hospital for blood biochemistry test, and then take the sodium bicarbonate enteric-coated tablet (100 mg/tablet) in Example 1, one tablet/time, twice/day, and take it for 1 month. During the test period, the urine pH was measured twice a day, and the adverse reactions and the degree of reaction (the degree of response were subjective, divided into mild, moderate, severe, and severe grades) were recorded. Blood biochemical tests were performed 1 month after the administration.

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. .

2) 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. There was no stomach bloating and reverse stomach side effects during the medication, indicating that the sodium bicarbonate of the present invention is enteric-coated. Patient resistance when taking large doses of the preparation Responsibility is still very good.

The above test shows that: 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. It can not only be used for treatment, but its prevention and regulation can not be ignored. , and can take long-term troubles without common stomach side effects, and it also has good application prospects in treatment and prevention. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entirety in the the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art after the above-described teachings of the present invention, which are also within the scope defined by the appended claims.

Claims

Rights request

An oral enteric preparation for an alkaline pH adjuster, wherein the enteric preparation is a tablet or a capsule, and the alkaline pH adjuster is 10~ per 1000 tablets or tablets of the enteric preparation. 2000 g; and the enteric preparation was placed in a 0.1 linol/L hydrochloric acid solution for 2 hours, and the release of the alkaline pH adjuster was less than 2%.

The oral enteric preparation according to claim 1, wherein the pH adjuster is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, citric acid, sodium citrate, and cesium. Potassium citrate, sodium hydrogen citrate or a combination thereof.

The oral enteric preparation according to claim 1, wherein the alkaline pH adjuster is from 100 to 1450 g per 1000 tablets or tablets of the enteric preparation.

The oral enteric preparation according to claim 1, wherein the preparation is selected from the group consisting of: (a) an enteric tablet, the tablet comprising a core and an enteric coating, wherein The drug core comprises an alkaline pH adjusting agent and a pharmaceutically acceptable carrier;

(c) enteric pellets, the pellet 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 An alkaline pH adjusting agent and a pharmaceutically acceptable carrier.

The oral enteric preparation according to claim 4, further comprising a barrier layer between the core and the enteric coating, or between the pellet core and the enteric coating.

The oral enteric preparation according to claim 4, wherein the enteric coating layer is composed of an enteric coating material and a plasticizer; wherein the enteric coating material is selected from an acrylic resin polymer. , one of cellulose acetate phthalate, hypromellose phthalate or a mixture thereof.

The oral enteric preparation according to claim 5, wherein the release layer is selected from the group consisting of a barrier coating material, a plasticizer, or a mixture thereof.

A method for preparing an oral enteric preparation according to claim 1, wherein the method comprises the steps of: An enteric coating will be coated on the exterior of the tablet core to form an enteric tablet, wherein the core comprises an alkaline pH adjusting agent and a pharmaceutically acceptable carrier;

The pharmaceutical powder or granules are filled in an enteric capsule to form an enteric capsule, wherein the pharmaceutical powder or granule contains an alkaline pH adjusting 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 adjuster and a pharmaceutically acceptable Acceptable carrier.

The use of an oral enteric preparation for an alkaline pH adjuster according to claim 1, which is for use in the preparation of a medicament for upregulating a body fluid pH or a urine pH.

A method for regulating a body fluid pH or a urine pH, comprising the steps of: administering the oral enteric preparation of claim 1 to a mammalian animal subject in need of an up-regulation of pH.