TWI309168B - A solid pharmaceutical composition of proton pump inhibitor - Google Patents

Description

1309168 V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) Field of the Invention The present invention relates to a pharmaceutical preparation containing a substituted benzimidazole proton inhibitor. The invention recites omeprazole (ome pra ζ ο 1 e ) as a substituted benzopyrene which inhibits gastric acid secretion: 5-methoxy-2- [ [4-methoxy-3-, 5-dimethyl Benzyl-2-pyridinyl) methyl]sulfinyl]-1 Η-benzimidazole. Omeprezazole belongs to the class of antisecretory compounds as a proton pump inhibitor ("ΡΡI s,") and does not exhibit anticholinergic or H2 histamine antagonist properties. The secretory surface specifically inhibits the H+, K+-ATPase enzyme system and suppresses gastric acid secretion. Usually, omeprazole, lansoprazole and other proton pump inhibitors are formulated as enteric coated solid dosage forms (delayed release) Capsules or lozenges) or injection solutions (recovery products), and active duodenal ulcer, gastric ulcer, stomach and esophageal reflux disease (GERD), severely corrosive esophagitis, underreactive symptomatic GERD, and morbidity Excessive secretory conditions such as short-term prescription drugs for Zollinger Ellison syndrome. These conditions result from the production of acid and pepsin (as an aggressive factor), as well as mucus, bicarbonate and prostate. Unbalanced between manufacturing (considered as a defensive factor). The conditions listed above often occur in healthy or severe patients and may be accompanied by significant upper gastrointestinal tract H2 - histamine antagonists, antacids, and sucralfate are usually administered to reduce pain and the associated complications of these conditions. These 1309168 V. Inventions (2) The drug has its own specific disadvantages. Some of these drugs are not completely effective in treating the aforementioned conditions and/or producing undesirable side effects such as mental confusion, constipation, diarrhea, and thrombocytopenia. H2-histamine antagonists such as rani tidine and race Cime ti dine is a relatively expensive treatment method. Especially in patients with NPO, it is often necessary to use an automated input fluid pump to continuously enter the drug intravenously. Patients with significant physiological stress are under pressure-related gastric mucosal damage. And subsequent risk of upper gastrointestinal bleeding (Marrone and Silen, pathogenesis, diagnosis and treatment of acute gastric mucosal injury, CLIN GASTROENTEROL 13 : 635 - 650 (1 984 )). Clearly associated with pressure-related mucosal damage Risk factors for mechanical oxygenation, coagulation, massive burns, head injuries, and organ transplants (Zinner et al., intensive care unit patients) Prevention of intestinal bleeding, 31) 1 ^. 0 ¥ 仙 (: 01. (^3 £1'., 153: 214-220 (1981); Larson et al, stomach reaction to severe head injury, am. J. SURG., 147:97 - 1 05 (1 984); Czaja et al. Acute gastroduodenal disease after heat injury: endoscopic evaluation of incidence and natural history, N ENGL . J_ MED., 29 1: 925-929 (1974); Skillman et al, respiratory failure, hypotension, sepsis, and jaundice: clinical symptoms associated with fatal bleeding from acute pressure ulcers, AM. SURG., 1 1 7:523 - 530 (1 969); And Cook et al., risk factors for gastrointestinal bleeding in patients with severe III, n ENGL. MED., 330:377 - 38 1 (1 994 )). One or more of these factors are often found in intensive care unit patients with serious illnesses. Recent generations have investigated other risk factors previously identified, such as acid-base disorders, multiple invasive 1309168

V. Description of invention (3) Injury, significant hypertension, major surgery, multiple procedures, acute renal failure, sepsis, and coma (Cook et al., risk factors for gastrointestinal bleeding in patients with severe III, N ENGL. J. MED. , 330:377 - 38 1 (1 994 )). Regardless of these dangerous forms, pressure-related mucosal damage causes significant morbidity and mortality. Significantly severe bleeding occurs in at least 20% of patients with one or more of these, risk factors and untreated (Martin et al., continuous intravenous cisplatin reduces stress-related upper gastrointestinal bleeding in undeveloped pneumonia, CRIT. CARE MED., 21:1 9-39 (1 993 )). About 10% of patients with bleeding require surgery (often for gastrectomy) and 30% to 50% of reported mortality (Czaja et al., Acute gastroduodenal disease after heat injury: endoscopic evaluation of incidence and natural history, N ENGL. J. MED., 29 1:925 - 929 (1 974); Peura and Johnson, Prevention and Treatment of Gastric Duodenal Mucosal Injury in Patients in Intensive Care Unit, ANN INTERN MED.,1 03 :1 73 -177 (1985)). Those who do not need surgery often need multiple blood transfusions and extended hospitalization. Prevention of pressure-related upper gastrointestinal bleeding is an important clinical goal. Prilosec®, Prev.acid® and other PPIs reduce gastric acid production by inhibiting H+, K+-ATPase (the common last path of gastric acid secretion) in the gastric parietal cells ( Fellenius et al., Substituted benzimidazoles inhibit gastric acid secretion by blocking H+, K+-ATPase, NATURE, 290: 159-161 (1981); Wallmark et al., Correlation between gastric acid secretion and gastric H+, K+-ATPase activity Sex,: T. BIOL. CHEM., 260:1368, 13684 (1985); Frykloud et al., Function and structure of gastric epithelial cells after H+ and K+-ATPase blockade, AM. J. PHYSIOL 1309168

1309168 V. INSTRUCTIONS (5) At neutral pH, omeprazole, lansoprazole and other PPIs are chemically stable, fat-soluble, and weakly alkaline and lack inhibitory activity. These neutral weak bases reach the cells of the gastric mucosa from the blood and spread to the secretory tubule where the agent becomes protonated and thereby captured. The protonating reagent is recombined to form a sulfenic acid and a sulfonamide. The sulfonamide reacts covalently with the thiol group at a key position in the extracellular (luminal) region of the H+, K+-ATPase (Hardman et al., Goodman & Gilman's The Pharmacological Basis of Therapeutics, p. 9 0 7 (9) 'h ed . 1 996 )). Therefore, omeprazole and moxaprazole are effective for prodrugs to be activated. The specific efficacy of PP Is also depends on: (a) the selective distribution of H+, K+-ATPase; (b) the need for acidic conditions to catalyze the production of reactive inhibitors; and (c) the capture of protonated agents and acidic lumens. A cationic sulfonamide adjacent to the target enzyme (Hardman et al., 1 9 9 6). Omeprexazole and lansoprazole can be used for oral administration of intestinal coated fine granules in gelatin capsules. Other proton pump inhibitors, such as rabeprazole and pantoprazole, are supplied in an enteric coating dosage form. Intestinal dosage forms of the prior art have been used, but are acid unstable, so it is very important that these agents are not exposed to low P Η gastric acid prior to absorption. Although these agents are stable in the test p Η, they are rapidly destroyed when p Η is lowered (for example, via gastric acid). Thus, if the microencapsulation or intestinal coating is disrupted (e.g., the compound is chopped into fat, or the chewable capsule), the dosage form of the prior art is exposed to the stomach for degradation via gastric acid. In the United States due to the lack of intravenous or oral liquid dosage forms, limit Omega 1309168 5, invention instructions (6) retinazole, morseprazole and riboprilazole test or for patients with acute care. Ba rie et al: Therapeutic use of omeprazole in refractory stress-induced gastric mucosal hemorrhage, CRIT. CARE MED., 20: 899-901 (1992) J describes the use of omeprazole enteric drug ninth through Nasal tube is administered to patients with acute care in multiple organ failure to control gastrointestinal bleeding. However, these drugs are not ideal because they will gather and block the tubes, and they are not suitable for patients who cannot swallow medicines. AMJ · HEALTH-SYST PHATM 56 : 2327 - 30 ( 1 999 ). Proton pump inhibitors such as omeprazole represent another advantageous option for the treatment of stress-related mucosal damage associated with H2-histamine antagonists, antacids, and sucralfate. However, in their current dosage form (capsules containing enteric coated granules or enteric coated tablets), proton pump inhibitors are difficult or impossible to administer to patients who are barely able or unable to swallow tablets or capsules (eg acute acute Patients with diseases, children, seniors, and patients with dysphagia) Therefore, it is hoped that a proton pump inhibitor solution or suspension can be delivered to the patient intestine to provide the advantages of a proton pump inhibitor. There are no disadvantages of current intestine coated solid dosage forms. Omeprezazole is the first proton pump inhibitor to be formulated and has been formulated for many different applications, such as U.S. Patent No. 5,219,870 to Kim, teaches: polyethylene glycol, animal fat (adeps solidu S) And a mixture of sodium lauryl sulfate in a soluble basic amino acid, so that the designed formula can be administered in the rectum. Berglund's U.S. Patent No. 5,3 9 5,3 2 3 discloses the mixing of solid-8-body supplies.

1309168 V. INSTRUCTION DESCRIPTION (7) The medicine is a non-enteral acceptable liquid dosage form for parenteral administration to a patient. 0 Patent No. 5, 39 5, 3 23 teaches the use of omeprazole lozenges The omeprazole tablet is placed in the device to be neutralized by a physiological saline solution and can be injected parenterally into the patient. The device and the parenteral injection method of omeprazole do not provide the omeprezazole solution as an enteric product nor provide the omeprezazole solution directly to the disease or affected area (ie, the stomach and upper gastrointestinal tract). And this omeprazole formulation does not provide this formulation - 1 ^. That is, the anti-acidic effect 〇Lovg re η et al., U.S. Patent No. 4,786,505, the disclosure of which incorporates omeprazole and a basic reaction compound, or omepruri The azole basic salt is combined with the test compound as a core substance in a pharmaceutical formulation of a tablet formulation. The core is then enterally coated. The alkaline substance used, optionally white as the sodium carbonate salt, is used to form a "micro-pH" surround each of the omeprazole fine particles to protect the iiitr acid pH highly sensitive omeprazole. The powder mixture is then coated with intestine-coated beads, medicinal herbs, lozenges and can be loaded into the capsules in a conventional medical procedure. This omeprexazole formulation does not teach a non-intestinal coated omeprazole dosage formulation, which can be administered to patients who cannot and/or reluctantly swallow 11 Yanjiao infusion tablets or medicines, nor teaches convenient dosage forms. Used in the manufacture of omegaprien or other proton pump inhibitor solutions or suspensions. Several buffered omeprazole oral solutions/suspensions have been disclosed, for example, Pi lbrant et al.: Development of Ormepril Oral Formula SCAND. J · GASTR0ENT .20 (Suppl. 108): 113-120 ( 1985) Instructed to micronize 60 mg of omeprazole in 50 ml of water and suspension containing 8 mmoles -9 - sodium bicarbonate 1309168 V. Inventive Note (8) Float. This suspension was administered as follows: After fasting for at least 0 hours, a solution of 8 mmoles of sodium bicarbonate in 50 ml of water was administered to the patient. After the patient took the omeprazole suspension for 5 minutes, it was rinsed with another 50 ral sodium bicarbonate solution. After 10, 20, and 30 minutes, another 50 ml of sodium bicarbonate solution was administered. Anders son et al.: Pharmacokinetics of various single intravenous and oral doses of omeprazole, EUR J. CLIN· PHARMACOL. 39: 195-1 97 (1 990) revealed 10 rag, 40 mg, and 90 rag oral omeprazole dissolved in PEG 400, sodium bicarbonate, and water. The concentration of omeprazole could not be determined because the diluent volume was not revealed. In spite of this, it is apparent from this reference that multiple doses of sodium bicarbonate are administered after the omeprazole suspension. Anders son et al.: Pharmacokinetics and bioavailability of single and repeated oral administration of omeprazole in healthy subjects, BR.丨.CLIN. PHARMAC. 29:557 -63 (1 990) teaches oral use of 20 Mg omeprazole, which is dissolved in 20 g of PEG 400 (gravity velocity = 1.14) and diluted with 50 rol of water containing 8 mmoles of sodium bicarbonate. To protect omeprazole from gastric acid, a buffer of 48 mmoles sodium bicarbonate in 300 ml of water is given. Regardh et al.: The pharmacokinetics of omeprazole in humans - single intravenous and oral doses, THER. DRUG M0N. 1 2:163 -72 (1990) shows that oral doses of 0.4 mg/ml are dissolved After PEG 400, water and sodium bicarbonate (8 mmoles). A solution containing 16 mmoles of sodium bicarbonate in 100 ml of water was continuously administered with the omeprexazole solution. The tube was then rinsed with -1 0 - 1309168 5. Inventive Note (9) 50 ral 0.16 mo 1/L sodium bicarbonate solution. In the IV and oral experiments, 50 ml of 0.16 mo 1/L sodium bicarbonate was administered 5 minutes before the administration, and after 10, 20, and 30 minutes.

Landahl et al.: Pharmacokinetics of omeprazole in elderly healthy volunteers' CLIN. PHARMACOKINETICS 23(6): 469-476 (1992) teaches the use of 40 mg of oral dose of omeprazole in PEG 400 , sodium bicarbonate and water. This reference does not disclose the final concentration used. Again, this reference teaches the administration of sodium bicarbonate (8 mmol/L and 16 mmol/L) multiple times after the omeprazole solution.

Andersson et al.: [MC] pharmacodynamics of omeprazole in patients with cirrhosis, CLIN. PHARMACOKINETICS 24(1): 71-78 (1993) reveals oral administration of 40 mg of omeprazole, which is dissolved in PEG 400, water, and sodium bicarbonate. This reference does not teach the final concentration of the omeprazole solution administered, although the document emphasizes the need to take all 48 mmoles of sodium bicarbonate before, during and after administration to protect the agent from acid degradation.

Nakagawa et al.: Stage of anti-ulcer agent of Blue Sopren (AG-1749) I. Research, J.  CLIN.  THERAPEUTICS & MED. (1991) teaches oral administration of 30 mg of lansoprazole in 100 ml of sodium bicarbonate, which is administered to the patient through the nasogastric tube. All of the buffered omeprazole solutions described in these references were administered orally and administered to healthy subjects capable of ingesting oral doses. In all of these studies, omeprazole was suspended in a solution containing sodium bicarbonate (as a pH buffer, which protects the acid-sensitive omeprazole) during administration. All of this -11- _ 1309168 V. Description of the invention (1〇) In some studies, it is necessary to repeatedly administer sodium bicarbonate before, during, and after administration of omeprazole via the oral route to prevent omepruri Acid degradation of azoles. In the above cited studies, up to 48 mmoles of sodium bicarbonate in 300 ml of water must be taken in a single dose orally with omeprazole. The buffered omeprazole solution of the above cited literature requires the ingestion of large amounts of sodium bicarbonate and a large volume of water via repeated administration. This is considered necessary to prevent degradation of omeprazole. In the above cited studies, the fundamentally healthy volunteers, rather than the sick patients, were given diluted omegaprexazole and a large volume of sodium bicarbonate by using the pre-dose and the post-dose. A large amount of sodium bicarbonate can produce at least six significant adverse effects, while significantly reducing the efficacy of omeprazole in patients and reducing overall patient health. First, the liquid volume of these dose formulations is not suitable for patients with ill or acute illness, they must receive multiple doses of omegapurine. Large volumes will cause dilatation of the stomach and increase possible complications of acute illness, such as lung inhalation of the stomach contents. Second, because sodium bicarbonate is often neutralized or absorbed in the stomach and causes snoring, patients with stomach and esophageal reflux may aggravate or worsen reflux, because snoring can cause stomach acid to move upwards (Br un t on, control stomach acid) And reagents for treating peptic ulcers IN, Goodman AG et al; The Pharmacologic Basis of Therapeutics. (New York, p.  907 (1990)) ° Third, patients with conditions such as high blood pressure or heart failure are generally advised to avoid excessive sodium intake, which may cause deterioration or aggravation of hypertension (Brunton, supra). A large intake of sodium bicarbonate contradicts this recommendation. -12- 1309168 V. INSTRUCTIONS (11) 〇 Fourth, patients with various conditions, such as patients with acute acute diseases, should avoid excessive intake of sodium bicarbonate, which may cause metabolism. Alkalineemia causes severe deterioration of the patient's condition. Fifth, excessive intake of antacids (such as sodium bicarbonate) can cause serious adverse effects from drug interactions. For example, by altering the pH of the stomach and urine, the antacid changes the rate of dissolution and absorption of the agent, bioavailability and renal excretion (B r u n t ο η, supra). Sixth, due to the need for prolonged administration of sodium bicarbonate to buffered omegaprezazole solutions, it is difficult for patients to meet the prescribed course of treatment. For example, Pilbrant et al. disclose that oral administration requires the administration of a solution of 8 mmoles of sodium bicarbonate in 50 ml of water to a subject fasted for at least 1 hour. After 5 minutes, the subject ingested a suspension of 60 mg of omeprazole in 50 ml of water and containing 8 ramoles of sodium bicarbonate. This was additionally rinsed with 50 ml of 8 mmoles sodium bicarbonate solution. After 10 minutes of ingestion of omeprazole, the subjects took 50 ml of sodium bicarbonate solution (8 mmoles). This was repeated for 20 minutes and 30 minutes after taking omeprazole, and all 48 mmoles of sodium bicarbonate and 300 ml of water were obtained from the subject taking a single dose of omeprazole. This treatment not only requires the intake of excessive amounts of sodium bicarbonate and water, it may harm some patients, and even a healthy patient may not be eligible for this treatment. It has been demonstrated that patients who require a pharmacy administration schedule are non-compliant, so the efficacy of the conventional technique buffered by omeprazole solution is expected to be reduced due to non--13-1309168 V. Illustration (12) compliance. . It was found that compliance was significantly reduced when the patient was asked to leave one or two (usually morning and evening) dose schedules for each medication. The use of a buffered omeprazole solution of the prior art [which requires a number of steps, different agents (sodium bicarbonate + omegapren + PEG 400 versus sodium bicarbonate alone) and the entire Omega for effective results The rule of administration of specific time distribution at each stage of the treatment of ribazole] is quite awkward compared to the current theory of drug compliance and human nature. The prior art (Pilbrant et al. 1985) teaches that the buffered omegaprisane suspension can be stored in the refrigerator for one week, and the initial freeze is stored at 99% for one year. Therefore, it is hoped that the omeprazole or other proton pump inhibitor solution or suspension can be stored at room temperature or in the refrigerator for a period of time longer than the conventional technique still retaining 99% of the initial efficacy. In addition, dosage forms useful as omeprazole and sodium bicarbonate can be used to immediately produce the omeprexazole solution/suspension of the present invention supplied in solid form, which helps to improve shelf life at room temperature and reduce product cost. Reduce expensive shipping costs and less expensive storage. Therefore, it is hoped that a proton pump inhibitor formulation will provide a cost-effective method to treat the above conditions without the adverse side effects of H2 receptor antagonists, antacids and sucralfate. Furthermore, it is hoped that a proton pump inhibitor formulation will facilitate the preparation and administration of patients who are unable to take in solid dosage forms (such as tablets or capsules) to provide a cost-effective means of treating the aforementioned conditions without H2 receptor antagonists, The adverse side effects of antacids and sucralfate can be quickly absorbed and delivered orally or enterally in liquid or solid form. It is hoped that the liquid formula will not be -14- 1309168. 5. Description of the invention (13) It will block inside the tube (for example, a nasogastric tube or other smaller tube) and act as an antacid for immediate delivery. A further advantage is a potential agent or enhancer having pharmacological activity of PPIs. Applicant reasoned that PPIS can only exert efficacy on H+ 'K+-ATPa s e when gastric cell wall cells are activated. Therefore, Applicants have confirmed that synergistic enhancement of PPI s activity can be achieved when administered to the gastric mucosal cell activator. In addition, conventionally administered PPIs in intravenous dosage forms are often administered in larger doses than oral dosage forms. For example, a typical adult IV dose of omeprazole is greater than 100 mg/day, resulting in an oral dose of 20 to 40 mg/day. A larger IV dose is necessary to achieve the desired pharmacological effect, as many gastric mucosal cells are at rest (almost inactive) during the IV dose given to patients who have taken oral substance without oral (ηρο), so only a small amount Activity (inserted into the secretory tubular membrane) H+, K+-ATPase can be inhibited. Since the amount of IV required for the IV dose is significantly different, it will be very beneficial for compositions and methods for IV administration (where the required agent is significantly less). SUMMARY OF THE INVENTION The above advantages and objects are attained by the present invention. The present invention provides an oral solution/suspension containing a proton pump inhibitor and at least one buffer. The PPI may be any substituted benzimidazole compound having H+, K+ - ATP a s e inhibitory activity and being unstable to acid. The composition of the present invention may be further formulated into a powder, a tablet, a suspension tablet, a chewable tablet, a capsule, a bi-sized tablet or a capsule, a foamed powder 'foamed lozenge, a drug 9 and a fine particle. Such dosage forms facilitate delivery mechanisms that lack any intestinal coating or delayed release, as well as contain pPI and -15- 1309168. V. INSTRUCTION DESCRIPTION (14) At least one buffer protects the PPI against acid degradation. Liquid and dry dosage forms may further comprise an anti-foaming agent, a gastric wall cell activator and a flavoring agent. In another embodiment, it is disclosed that the oral dosage form comprises a combination of an enteric coated or delayed release PPI and an antacid. These dosage forms may optionally contain a non-intestinal coated PPI. Kits utilizing the dry dosage forms of the present invention are also shown herein to provide for easy preparation of liquid compositions from dry dosage forms. According to the present invention, there is further provided a method of treating a gastric acid disorder by orally administering to a patient a pharmaceutical composition and/or dosage form disclosed herein. Furthermore, the present invention relates to a method for enhancing the medicinal activity of a proton pump inhibitor administered intravenously, wherein at least one of the gastric wall cell activators is before, during, and/or after intravenous administration of a proton pump inhibitor Oral administration to the patient. Finally, the present invention is directed to a method for most effectively performing the types and amounts of buffers suitable for individual PPIs. BRIEF DESCRIPTION OF THE DRAWINGS Other advantages of the present invention can be readily appreciated as would be appreciated by reference to the following detailed description. Wherein: Figure 1 shows the effect of the omeprazole solution of the present invention on gastric pH in patients with gastrointestinal bleeding in the risk of pressure-related mucosal damage; Figure 2 is a flow chart illustrating the number of patients participating; Figure 3 is a bar graph illustrating the administration of omeprazole to the stomach pH before and after the omeprazole solution according to the invention of the invention - 16 - 1309168 5. The invention is illustrated by a graph Oral administration of the same as the stomach pH after the administration of the cocoa base (ChocoBase) plus the blue botoprex, and the blue spiropazole alone; Figure 5 is a graph illustrating the pH probe for confirming GERD; Figure 6 is an illustration of the graph GERD's endoscopy confirmation; Figure 7 is a graph illustrating the percentage of patients who have received any type of reflux therapy in the past; Figure 8 is a graph illustrating the efficacy of theobromine formula 1; and Figure 9 is a chart illustrating the administration of ρρι / The pH around the buffer formulation is 値. Detailed design of the invention I. In general, the present invention relates to a pharmaceutical composition comprising a proton pump inhibitor and a buffer with or without one or more gastric cell wall activators and is non-intestinal coated, sustained or delayed release. . However, the present invention is to be construed as being limited to the specific embodiments of the invention. . For the purposes of this application, the term "proton pump inhibitor" (or "PPI") means any substituted benzimidazole having pharmacological activity as an inhibitor of H+, K+_ATPase, including but not limited to omegapril.唑mepraz〇le, lanS〇praZQle, pantoprazole, rabeprazole, Isomitol 1309168 V. Description of invention (16) Esomeprazole, pariprazole, and leminoprazole. The definition of "ρρι" also means that the active agent of the present invention can be used in the form of salts, esters, guanamines, mirror images, isomers, tautomers, prodrugs, derivatives, etc., if necessary. Administration, but the salts 'esters, guanamines, mirrors, isomers, tautomers, prodrugs, or derivatives are pharmacologically applicable, i.e., effective in the methods, compositions, and compositions of the present invention. Salts, esters, guanamines, mirror images, isomers, tautomers, prodrugs and other derivatives of active agents can be synthesized by synthetic organic chemistry and J.  March, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. The skilled artisan (New York: Wiley-Interscience, 1992) was prepared using known standard procedures. The therapeutic agent of the present invention can be formulated as a single dose pharmaceutical composition or as a separate pharmaceutical dosage form. Although the most suitable route in any case will depend on the nature and severity of the condition being treated and the nature of the particular compound employed, the pharmaceutical compositions according to the invention include those suitable for oral, rectal, buccal (eg sublingual), or parenteral. (eg intravenous) for administration. As further explained in the text, PPIs typically inhibit ATPase in the same manner. Due to the difference in acid instability of the patented compounds, there is a large difference in the initial and relative efficacy. The composition of the invention contains a dry formulation 'solution and/or suspension of a proton pump inhibitor. The terms "suspension" and "solution" as used herein are interchangeable and mean a solution and/or suspension of substituted benzimidazoles. -18- 1309168 V. INSTRUCTIONS (17) After absorption of PPI (or intravenous administration), the drug is transported through the blood to various tissues and cells, including gastric parietal cells. Without wishing to be bound by any theory, it is proposed that when the PPI is a weakly alkaline dosage form and is non-ionized, it is free to pass through the physiological membrane, including the cell membrane of the gastric parietal cells. The non-ionized PPI of Xianxin is transferred into the acid-secreting part of the gastric parietal cells: secretory tubules. Once in the acidic environment of the secretory tubules, the PPI is significantly protonated (ionized) and converted to an acidic dosage form of the agent. Typically, the ionized proton pump inhibitor is membrane impermeable and forms a disulfide covalent bond with the cysteine residue in the alpha-subunit of the proton pump. Such activated dosage forms include "ΡΡΙ" as defined herein. The pharmaceutical composition of the present invention contains a proton pump inhibitor, such as omeprazole, moxapril or other proton pump inhibitors and derivatives thereof, which can be used to treat or prevent gastrointestinal conditions including but not limited to activity Duodenal ulcer, gastric ulcer, dyspepsia, gastric and esophageal reflux disease (GERD), severely corrosive esophagitis, underreactive GERD, and hypersecretory conditions such as Linger's Ellison syndrome (Ζ ο 1 1 inger Ε 1 1 is ο η s ynd r ome ). Treatment of these conditions can be achieved by administering to the patient an effective amount of the pharmaceutical composition of the present invention. Proton pump inhibitors are administered and administered according to good medical behavior, taking into account the patient's individual clinical condition, location and method of administration, schedule of administration, and other factors known to the practitioner. The term "effective amount" is in accordance with the prior art and refers to an amount of PPI or other agent that is effective to achieve pharmacological or therapeutic improvement without undue adverse side effects, including but not limited to increasing gastric pH, reducing gastrointestinal bleeding, and reducing blood transfusion. Need, improve survival rate, faster -19- 1309168 V. Description of invention (18) Rehabilitation, activation of gastric parietal cells and inhibition of H+, K + - ATPase or improvement or elimination of symptoms 'and familiarity with the skill of the artist Other indications of the measurement. The dosage of omeprazole or other proton pump inhibitors can range from less than about 2 mg/day to about 300 mg/day. For example, the standard estimated adult daily oral dose is typically 20 mg of omeprazole, 30 mg of lansopril, 40 rag of topirazole '20 mg of riboprazole, 20 mg of escarpone 'And pharmacologically equivalent doses of Pelipprex and Limeopril. The proton pump inhibitor pharmaceutical formulation for use in the present invention can be administered orally or parenterally to a patient. For example, it can be achieved by a nasogastric tube or other tube placed in the gastrointestinal tract. In order to avoid the acute acute deficiency associated with the administration of large amounts of sodium bicarbonate, the PPI solution of the present invention is administered in a single dose without further administration of any sodium hydrogencarbonate, or a large amount of sodium bicarbonate or a buffer is not required as a whole. That is, unlike the conventional PPI solution and the administration rules outlined above, the formulation of the present invention is administered in a single dose which does not require administration of sodium bicarbonate before or after administration of the PPI. The present invention excludes the need for additional volume of water and sodium bicarbonate prior to or after administration. The amount of sodium bicarbonate administered by a single dose of the present invention is less than the amount of sodium bicarbonate administered by the prior art teachings described above. II.  Preparation of Oral Liquids U.S. Patent No. 5,840,737 to Phi 1 1 ips: The oral liquid pharmaceutical composition of the present invention is prepared from mixed omeprazole intestine coated fine granules (Prilosec® AstraZeneca) or omepruri A azole base or other proton pump inhibitor or derivative thereof, and a solution comprising at least one buffer (including -20 - 1309168 V, invention instructions (19) or no gastric wall cell activator, as described below). In a specific embodiment, > can obtain white powder. , capsules, and lozenges, or omeprazole or other proton pump inhibitors obtained from parenteral solutions are mixed with sodium bicarbonate solution to achieve the desired omeprazole (or other PPI) concentration. For example, the concentration of the solution of the medium omeprazole in the solution may range from about 0. 4 mg/ml to about 10 . 0 mg / ml. The preferred concentration of omeprazole in the solution ranges from about 1 .  0 rag / m 1 to about 4. 0 mg/ml to 2. 0 mg/ml is the standard concentration 0 for Prevacid® TAP Pharmaceuticals.  In C . The concentration range can be from about 0. 3 mg/ml to about 10 mg/ml, with a preferred concentration of 3 rag/1 ill. ο Although sodium bicarbonate is a preferred buffer for protecting PPI s against acid degradation> many other weak and strong bases can also be used. (eg its mixture). The “buffering agent” or “buffering agent” in the case of this series of m refers to the weak or strong base (and its mixture) suitable for any medical use, and when combined with the PPI formula or delivery (.   For example, before and/or after, the amount of bioavailability of the buffer administered to the PPI is substantially sufficient to substantially prevent or inhibit the PPI from being degraded by gastric acid. Therefore, in the presence of gastric acid, the buffer of the present invention preferably has to increase the pH of the stomach to the extent that it satisfies the bioavailability of the drug to affect the therapeutic effect. Thus examples of buffers include, but are not limited to, sodium bicarbonate, potassium bicarbonate magnesium hydroxide, magnesium lactate, magnesium gluconate, other magnesium salts, aluminum hydroxide> aluminum hydroxide/sodium bicarbonate coprecipitate, amine Mixture of base acid and buffering agent> Mixture of aluminum glycinate and buffer, alkamic acid salt and buffer-2 1 - 1309168 5. Mixture of invention (2〇). And a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium phosphate, dipotassium phosphate, trisodium phosphate, tripotassium phosphate, Sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium citrate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium hydrogencarbonate, and other calcium strontium The pharmaceutically acceptable carrier of the oral liquid may contain a hydrogen carbonate of a Group IA metal as a buffer, and may be prepared by mixing a hydrogen carbonate of a Group IA metal (with sodium hydrogencarbonate as a hydrazine) with water. The concentration of the IA group metal bicarbonate in the composition is usually from about 5. 0 percentage to about 6. 0 percentage. In one embodiment, the Group IA metal bicarbonate content ranges from about 3 mEq to about 45 mEq per oral administration. In another embodiment, the sodium bicarbonate used in the solution of the invention is 8. 4% is about 2 mg of omeprazole, ≥14 (or mmole) of sodium bicarbonate, and every 2 mg of omegapril. 2 mEq (mmole) to 5 mEq (mmole) range. In one embodiment, the enterocoated omeprexazole particles are obtained from a delayed release capsule (Prilosec® AstraZeneca). Alternatively, use Omega Purui test powder. The enteric-coated omeprazole granules are mixed with a solution of sodium bicarbonate (NaHC〇3) dissolved in the intestine and formed into a solution of omeprazole (8. 4%) 溶液 The solution of the invention and other dosage forms of the invention have pharmacokinetic advantages over standard intestinal coating -22 - 1309168 V, invention description (21) and timed release PPI dosage forms, including: (a) a faster agent absorption time (about 10 to 60 minutes) after the PPI solution or the dry dosage form; about 1 to 3 hours after the administration of the enteric coating drug; (b) the buffer protects the PPI from acid degradation before absorption; When the antacid is released and the PPI is being absorbed, the buffer acts as an antacid; and (d) the solution is permeable to the inner tube (eg nasogastric tube or other feeding tube (jejunum or duodenum), including small pinhole catheters) The feeding tube is administered without coagulation. Solutions, suspensions and powders for reconstitutable delivery systems include excipients such as suspending agents (eg gum, xanthan gum, cellulosic and sucrose), humectants (eg Yamanashi) Sugar alcohols), cosolvents (eg ethanol, water, PEG and polyethyl alcohol), surfactants (eg sodium lauryl sulfate, Spans, Tweens, and whale base pyridine), preservatives and antioxidants (eg Peila) And (p Arabens), vitamins E and C, and ascorbic acid), anticoagulants, coating agents, and chelating agents (eg EDTA). In addition, various addition agents can be incorporated into the solutions of the invention to enhance their stability, sterility and isoperosity. Antimicrobial preservatives (such as ambic η), antioxidants, chelating agents, and additional buffers may be added, and microbiological evidence indicates that the formulation has antimicrobial and antifungal activity. Agents and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc., may enhance the prophylactic action of microorganisms. In many cases it will be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. In addition, it is desirable to use a thickening agent such as methylcellulose to reduce the precipitation of omeprazole or other PPI or its derivatives from the suspension. -23 - 1309168 V. INSTRUCTIONS (22) The liquid oral solution may further contain a flavoring agent ( Such as chocolate, thalmantin, aspartame, SARS or watermelon) or other flavoring agents stable at pH 7 to 9, anti-foaming agents (eg dimethyl eucalyptus (sime) Thicone) 80 mg, Mylicon®) and gastric wall cell activators (discussed below). The invention further comprises containing omeprezazole or other proton pump inhibitors and derivatives thereof and at least one buffering agent in a dosage form for preservation a pharmaceutical composition whereby the composition is dissolved and/or dispersed to produce a suspension suitable for enteral administration to a subject when the composition is placed in an aqueous solution. The pharmaceutical composition is in a solid prior to dissolution or suspension in the aqueous solution. Dosage Forms, Omeprezazole or other PPIs and buffers can be formed into tablets, capsules, medicinal or fine granules by methods known to those skilled in the art. The resulting omeprazole solution was stable at room temperature for several weeks and inhibited the growth of bacteria or fungi as shown in Example X below. Indeed, as demonstrated in Example XIII, this solution maintained an efficacy of over 90% for 12 months. By providing a pharmaceutical composition comprising omeprazole or other PPI and a buffer in a solid dosage form, which is later dissolved or suspended in the amount of the aforementioned aqueous solution to produce the desired concentration of omeprazole and buffer 'because no liquid is required to be transported Significantly reduce product, shipping and storage costs (reduced weight and cost) without the need to refrigerate solid dosage forms of omeprazole or solution. Once the resulting solution is mixed, it can be used to provide a dose to a single patient for a period of time or to a patient. III. Lozenges and other solid dosing agents are described in the above-mentioned U.S. Patent No. 5,840,737 to Phillips, U.S. Patent No. 5,840,737, the disclosure of which is incorporated herein by reference. The suspension tablet and the foamed lozenge or powder may be swallowed or dissolved first so as to subsequently react with water, gastric secretions or other diluents to produce an aqueous dosage form of the invention. The pharmaceutical lozenges or other solid dosage forms of the present invention can be rapidly disintegrated in an aqueous medium with minimal shaking or shaking and form an aqueous solution of PPI and buffer. These lozenges use these commonly available materials to achieve these and other purposes. The lozenges or other solid dosage forms of the present invention provide a precise dosage of PPI which may be less water soluble. They are especially useful for medications for children and the elderly, and others that are somewhat more acceptable than swallowing or chewing a tablet. When the manufactured tablets have low friability, they are easy to handle. As used herein, the term "suspended tablet" means that the compressed tablet can be rapidly broken after being placed in water and rapidly dispersed to form a suspension containing a precise PPI dose. The suspension tablet of the present invention contains a therapeutic amount of a PPI, a combination of a buffer and a disintegrating agent. More specifically, the suspension tablet contains about 20 mg of omeprazole and about 4 to 30 mEq of sodium bicarbonate. Croscarmelose sodium is a disintegrating agent known for use in lozenge formulations and is available from FMC Corporation, Philadelphia, Pa. Ac-Di-Sol® is a trademark. Often mixed separately in compressed tablet formulations or combined with microcrystalline cellulose to rapidly break up the tablet. Microcrystalline cellulose, which is treated alone or in combination with other ingredients, is also a commonly used additive for compressed tablets and which promotes the ability to compress the compressibility of the tablet material. -25 - 1309168 V. Description of the Invention (24) Forces are well known. Available from Avicel®. Two Avicel® products are available, Avicel®PH is microcrystalline cellulose; and Avicel® AC-815 is a spray-dried residue co-processed with microcrystalline cellulose and calcium-sodium alginate complexes, with calcium to sodium ratio The range is about 0. 40 : 1 to about 2. 5: 1. Although AC-81 5 consists of 85% microcrystalline cellulose (MCC) and 15% sodium-sodium alginate complex, this ratio can be changed to about 75% MCC versus 25% alginate for the purposes of the present invention. Up to about 95% MCC versus 5% alginate. Depending on the particular formulation and active ingredient, the two components may be present in about equal or unequal amounts, and may be comprised of from about 1% to about 50% by weight of the tablet. In addition to the above ingredients, the suspension tablet composition may contain other ingredients commonly used in pharmaceutical lozenges, including flavoring agents, sweeteners, glidants, lubricants, or other common lozenge adjuvants, to familiarize themselves with the art. It is obvious and easy to understand. Although sodium carboxymethylether cellulose is preferred, other disintegrating agents such as crospovidone and sodium starch glycolate may also be used. In addition to the suspension tablet, the solid formulation of the present invention may be in the form of a powder, a lozenge, a capsule, or other dosage form suitable for a solid dosage form (e.g., a pharmaceutical dosage form or a foaming lozenge, tablet or powder). The inventive solution is present in the diluent or ingestion. For example, water used in gastric exudates or water used in swallowing solid dosage forms can be used as an aqueous diluent solution. The compressed tablet is a solid dosage form' which can be prepared by compacting an excipient formulation containing the active ingredient and selected to aid in handling and improving the properties of the product. The term "suspended lozenge" is often used to refer to a non-noisy, uncoated lozenge for oral ingestion, either by single compression or by pre-clamping and subsequent compression. -26- 1309168 V. INSTRUCTIONS (25) The dry oral formulation may contain excipients such as binding agents (eg, hydroxypropyl methylcellulose, polyvinylpyridone, other cellulosic and starch) diluents (eg, lactose and other sugars, starch, dicalcium phosphate, and fiber). Quality) > M-4 powders (such as starch polymers and cellulosics), as well as lubricants (such as stearates and talc). Such solid dosage forms can be made as is well known in the art. Tablet formulations include J such as one or more lactose, mannitol, corn starch, potato starch 9 microcrystalline cellulose 'arabin gum, gelatin, colloidal cerium oxide, sodium cross-carboxymethyl ether, talc, magnesium stearate, Stearic acid, and other excipients> Colorants, diluents, buffers, humectants, preservatives, flavoring agents, and pharmaceutically compatible carriers. The manufacturing method can employ four known methods - or a combination: (1) dry mixing; (2) direct compression; (3) milling; and (4) water-free fine particle action. Lachman et al., The Theory and Prac t i c e 0 f I ndustrial Pharmacv M996). The tfch and other agents are also included in the film coating, preferably after oral ingestion or in contact with a diluent. Non-limiting examples of buffers which can be used in such tablets include sodium bicarbonate, soil metal salts such as calcium carbonate, calcium hydroxide, calcium lactate, calcium glycerophosphate, calcium acetate, magnesium carbonate, magnesium hydroxide, magnesium citrate. , magnesium aluminum oxide, aluminum hydroxide or magnesium aluminum hydroxide. A particularly alkaline earth metal salt which can be used in the manufacture of an acid-resistant tablet is calcium carbonate. 0 An example of a low-density alkaline earth metal salt which can be used in the production of fine particles of the present invention is ultra-light carbon acid, available from Specialty Minerals Inc. , Adams, Me 〇 -27- 1309168 V. Description of the invention (26) The density of ultra-light calcium carbonate is about 0 before treatment as in the present invention. 37 g/ml. Other acceptable buffers are also provided in the present invention. The fine particles used for the manufacture of a tablet according to a specific example of the present invention can be prepared by spray drying or pre-compression of the raw material. The alkaline earth metal salt used in the present invention has a density range of about 〇 before being processed into fine particles by any treatment.  3 g / m 1 to about 0. 55 g/ml, preferably about 0. 35 g/ml to about 0. 45 g/ml, more preferably about 0. 37 g/ml to about 0. 42 g/ml. Further, the present invention can be produced by using a micronized compound in a fine particle or a powder. Microcrystallization is a treatment that reduces the size of solid drug particles. Since the dissolution rate is directly proportional to the solid surface area and reducing the particle size will increase the solid surface area, reducing the particle size will increase the dissolution rate. Although the increase in surface area caused by micronization may cause particle coagulation to negate the benefit of micronization and is an expensive manufacturing step, it is significant for increasing the dissolution rate for relatively water-insoluble drugs such as omeprazole and other proton pumps. interest. The invention also relates to administering a kit to alleviate mixing and administration. For example, a powder or lozenge that is supplied for one month may be packaged by separating one month of thinner and reusing the plastic dose cup. More specifically, the package may contain 30 days of suspended tablets (each containing 20 mg of omegapril) ' 1 L sodium bicarbonate 8 .  4% solution, and a 30 m 1 dose cup. The user places the tablet in an empty dose cup, fills it with sodium bicarbonate to a value of 30 m 1 , waits for dissolution (can be gently stirred or shaken), and then ingests the suspension. Those skilled in the art will appreciate that such kits can contain many variations of the above components. For example, -28 - 1309168 V. Inventive Note (27), if the tablet or powder is compounded to contain PPI and a buffer, the diluent may be water, sodium bicarbonate, or other compatible diluent' and the dose cup size. May be greater or less than 30 ral. These kits can also be packaged in unit dose formulations, or in weekly, monthly, or annual kits. While the tablet of the present invention is intended to be in the form of a suspension dosage form, the tablet formed using the fine granules can also be used to form fast-cracking chewable tablets, buccal tablets, tablets, or swallowable tablets. Thus, the intermediate formulation and its method of manufacture provide another novel aspect of the invention. Foamed tablets and powders can also be prepared in accordance with the present invention. Foamed salts have been used to disperse drugs in water for oral administration. The foaming salt is a fine or coarse powder containing a pharmaceutical agent in a dry mixture, usually composed of sodium hydrogencarbonate, citric acid and tartaric acid. When this salt is added to water, the acid reacts with the base to evolve carbon dioxide gas, which is called "foaming". The composition of the foamed fine particles is selected depending on the requirements of the manufacturing process and the production of products which can be quickly dissolved in water. The two essential ingredients are at least one acid and at least one base. The base reacts with the acid to release carbon dioxide. Examples of such acids include, but are not limited to, tartaric acid and citric acid. Preferably, the acid is a composition of tartaric acid and citric acid. Examples of bases include, but are not limited to, sodium carbonate, potassium hydrogencarbonate, and sodium hydrogencarbonate. Preferably, the base is sodium hydrogencarbonate' and the foaming composition has a pH of about 6. 0 or more. The foaming salt preferably includes the following ingredients, which are capable of producing bubbles: sodium hydrogencarbonate, citric acid, and tartaric acid. When added to water, acids and alkali react to release carbon dioxide to produce bubbles. It should be noted that any acid-base composition which can cause carbon dioxide release -29- 1309168 V. invention description (28) can be used to replace sodium hydrogencarbonate as long as the ingredient is suitable for medical use and the obtained pH is about 6.00 or higher. And a combination of citric acid and tartaric acid. It should be noted that 3 molecules of NaHC03 are required to neutralize one molecule of citric acid, and two molecules of NaHC03 are required to neutralize one molecule of tartaric acid. The proportion of the desired ingredients is as follows: Citric acid: tartaric acid: sodium bicarbonate = 1: 2:3.  44 (weight). This ratio can change and continue to produce an effective release of carbon dioxide. For example, the ratio of 1: 0 : 3 or 0: 1: 2 is also valid. The method for preparing the expanded fine particles of the present invention uses three basic methods: wet and dry fine granulation, and fusion. The fusion process is used to prepare the most commercial foaming powder. It should be noted that although these methods are intended for the preparation of fine granules, the formulations of the foaming salts of the present invention can also be prepared as troches according to artisan preparation techniques well known in the art. Wet fine granulation is the most well known method for fine particle preparation. The individual steps in the wet granulation process of tablet preparation include milling and screening of ingredients, dry powder mixing, wet concentration, fine granulation, and final grinding. Dry fine granulation involves compressing the powder mixture into a coarse lozenge or "elastic nine" in a heavy power rotary tablet press. The ball is then broken into granules by a grinding operation, usually by a vibrating granulator. Individual steps include mixing the powder, compressing (small pieces), and grinding (reducing the bomb nine or fine granulation). No steps involved in wet bonding or moisture. The fusion method is the best method for preparing the fine particles of the present invention. In this method, 'dry -30 - 1309168. V. DESCRIPTION OF THE INVENTION (29) The compression (small block) step of the fine granulation method has been eliminated. Heat the powder in an oven or other suitable heat source. IV.  PPI s and the gastric mucosal mites activator Applicants have unexpectedly discovered that certain compounds, such as chocolate, calcium and sodium bicarbonate, and other alkaline substances can stimulate the gastric parietal cells and enhance the pharmacological activity of the administered PPI. For the purposes of this application, "gastric wall cell activator" or "activator" shall mean any compound or mixture of compounds having such stimulating effects, including but not limited to chocolate, sodium bicarbonate, calcium (eg Calcium carbonate, calcium gluconate, calcium hydroxide, calcium acetate, and calcium glycophosphate), peppermint oil, spearmint oil, coffee, tea and cola (even decaffeinated), caffeine, theophylline, caffeine, and amine Base acids (especially aromatic amino acids such as phenylalanine and tryptophan), combinations thereof, and salts thereof. Such gastric wall cell activators are administered in an amount sufficient to produce the desired stimulatory effect without causing undesirable side effects to the patient. For example, chocolate, for unprocessed cocoa powder, is administered at a dose of about 5 mg to 2. per 20 mg of omeprazole (or other PPI at a comparable pharmacological dose). 5 g amount. The activator dose administered to a mammal (especially a human) is a reason that must be sufficient to affect the therapeutic response (i.e., enhance PPI efficacy) for a reasonable period of time. The dose intensity is determined by the particular composition used and the condition of the individual, as well as the individual weight of the subject. The size of the dose is also determined by the degree of adverse side effects that may accompany the experience, constitution, and administration of the particular composition. For each 20 rag dose of omegapril (or equivalent dose of other ρρι) -31 - 1309168 V. Inventive Note (3〇), the effective range of various gastric wall cell activators is: Chocolate (unprocessed cocoa) Powder) a 5 mg to 2. 5 g sodium carbonate - 7 mEq to 25 mEq calcium carbonate - 1 mg to 1 .  5 g gluconic acid fishing 1 mg to 1. 5 g calcium lactate - 1 mg to 1. 5 g hydration consumes 1 mg to 1. 5 g calcium acetate - 0. 5 mg to 1. 5 g Calcium Phosphate Calcium 0. 5 mg to 1. 5 g peppermint oil 1 (powder type) 1 mg to 1 g spearmint oil 1 (powder type) 1 mg to 1 g coffee a 20 ml to 240 ml tea a 20 ml to 240 ml cola a 20 ml to 240 ml caffeine a 0 . 5 mg to 1. 5 g theophylline a 0. 5 mg to 1. 5 g coffee test 0.  5 m g to 1 .  5 g phenylalanine- 0. 5 mg to 1. 5 g tryptophan 0. 5 rag to 1,5 g Pharmaceutically acceptable carriers are those well known to those skilled in the art. The choice of carrier depends on the particular composition and the particular method used to administer the composition. Therefore, the applicable formulation of the pharmaceutical composition of the present invention is quite broad. V. EXAMPLES - 32 - 1309168 V. DESCRIPTION OF THE INVENTION (31) The present invention is further illustrated by the following formulation, but should not be construed as limiting in any respect. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmacology and pharmacy. Example I L-Omeprezazole Fast-breaking Fragment Dispersion Lozenges Rapidly fragmented tablets are synthesized as follows: cross-carboxymethyl ether cellulose sodium 300 g added to contain 3 .  The vortex of 0 kg deionized water was quickly stirred in the beaker. Mix the mud for 10 minutes. Place 90 g of omeprazole into the Hobart mixer bowl. After mixing, the sodium silicidose sodium cellulose was slowly added to the memiprazole in the mixer bowl to form a fine granulation, which was then placed in a tray and dried at 70 ° C for 3 hours. The dried fines were then placed in a blender and 1,500 g of Avicel® AC-815 (composed of 85% microcrystalline cellulose and 15% calcium-sodium alginate complex) and i, 5 〇〇g were added thereto. Av1Cel® PH-3 02 (microcrystalline cellulose). After the mixture was thoroughly stirred, 35 g of magnesium stearate was added and mixed for 5 minutes. The resulting mixture was compressed into tablets on a standard tablet press (Hata HS). The average weight of these tablets is about 0. 75 g' and contains about 20 mg of omeprazole. These tablets have low friability and fast chipping time. This formulation is soluble in an aqueous solution containing an immediate oral administration buffer. In addition, the suspended tablet can be swallowed entirely with the buffer solution. In both cases, the preferred solution is sodium bicarbonate. 4%. In a further variation, about 975 mg of sodium bicarbonate powder is directly mixed into the tablet per 20 mg dose of omeprazole (or a comparable amount of other PPI). The tablet is then dissolved in water -33 - 1309168. V. Description (32) or sodium bicarbonate 8. 4%, or swallowed whole with aqueous diluent. B1.  10 ms botanical formula omeprazole 10 mg (or moxapril or tablets topirazole or other PPI equivalent) Calcium lactate 175 mg Calcium phosphate 175 mg Sodium bicarbonate 250 rag Aspen Sweet calcium (phenylalanine) 0. 5 mg Colloidal cerium oxide 12 mg Corn starch 15 mg Cross-carboxymethyl ether sodium 12 mg Dextrose 10 mg Peppermint oil 3 mg Maltodextrin 3 mg Mannitol 3 rag Pre-gelatinized starch 3 mg B2.  10 ms lozenge formulation PPI: one of the following: omeprazole 10 mg moxapril 15 mg tablets topiraw sodium 20 mg

-34- 1309168 V. INSTRUCTIONS (33) Ribip predazole sodium 10 mg Other potency PPI Calcium lactate 375 mg Calcium phosphate 375 mg Aspartame calcium (phenylalanine) 0.5 mg Colloidal cerium oxide 12 Mg Corn Starch 15 mg Cross Carboxymethyl Cellulose Sodium 12 mg Dextrose 10 mg Peppermint Oil 3 mg Maltodextrin 20 mg Mannitol 30 mg Pregelatinized Starch 30 mg B3. 10 ms Tablet Formulation PPI: One: omeprazole 10 mg moxapril 15 mg tablets topirazol sodium 20 mg ribopridone sodium 10 mg equivalent potency other PPI sodium bicarbonate 750 mg aspartame calcium (phenylalanine) 0.5 mg -35 - 1309168 V. INSTRUCTIONS (34) Colloidal cerium oxide 12 rug Corn starch 15 mg Cross carboxymethyl ether cellulose sodium 12 mg Dextrose 10 mg Peppermint oil 3 mg Maltodextrin 20 mg Mannitol 30 mg pregelatinized starch 30 mg C1 . 20 mg acute formula omeprazole 20 mg (or blue soprenazole or topiraprazole or other PPI equivalent) Calcium lactate 175 mg Calcium phosphate 175 Mg sodium bicarbonate 250 mg Bar sweet calcium (phenylalanine) 0.5 mg Colloidal silicon dioxide 12 mg corn starch 15 mg Cross carmellose sodium 12 mg Dextrose 10 mg Peppermint oil 10 mg calcium hydroxide 3 mg 3 mg Maltodextrin

-36 - 1309168 V. INSTRUCTIONS (35) Mannitol 3 mg Pregelatinized Starch 3 mg C2 . 20 mg Desiccant Formula PPI: One of the following: Omeprazole 20 mg Blue Thoraprazole 30 mg Tablet Top Reazole 40 mg Other potency PPI Calcium lactate 375 mg Calcium phosphate 375 mg Aspartame calcium (phenylalanine) 0.5 mg Colloidal cerium oxide 12 mg Corn starch 15 mg Cross carboxymethyl ether sodium 12 mg Right Spirulina 10 mg Peppermint Oil 3 mg Maltodextrin 20 mg Mannitol 30 mg Pregelatinized Starch 30 mg C3 . 20 ms Tablet Formulation PPI: One of the following:

-37 - 1309168 V. INSTRUCTIONS (36) Omniprezazole 20 mg Blue Sophorazole 30 mg Tablets Topirazole 40 rag Other potency PPI Sodium bicarbonate 750 mg Aspartame calcium (phenylalanine) 0.5 mg Colloidal cerium oxide 12 mg Corn starch 15 mg Cross-carboxymethyl ether sodium 12 mg Dextrose 10 mg Peppermint oil 3 mg Maltodextrin 20 mg Mannitol 30 mg Pre-gelatinized starch 30 mg D1. Fast涑 dissolved tablet omeprazole 20 mg (or blue soprenazole or tablet topiramate or equivalent PPI) Calcium lactate 175 mg Calcium phosphate 175 mg Sodium bicarbonate 500 mg Calcium hydroxide 50 Mg Cross Carboxymethyl Cellulose Sodium 12 mg

-38 - 1309168 V. INSTRUCTIONS (37) D2. Fast dissolving. Tablet PPI: one of the following: omeprazole 20 mg moxapril 30 mg tablets topirazole 40 mg ribipril Sodium oxazide 20 mg Essoproprazole magnesium 20 mg Other potency PPI Calcium lactate 300 mg Calcium phosphate 300 mg Calcium hydroxide 50 mg Cross-carboxymethyl ether sodium 12 mg D3. Fast-dissolving tablets PPI : one of the following · omeprazole 20 mg moxapril 30 mg tablets topirazole 40 mg riboprazole sodium 20 mg esapanopridazole magnesium 20 mg equivalent potency other PPI carbonic acid Sodium Hydroxide 700 mg

-39- 1309168 V. INSTRUCTIONS (3S) Trisodium phosphate dodecahydrate 100 mg Cross-carboxymethyl ether sodium 12 mg E1. Oral reconstituted powder (or nasogastric tube) Omeprezol 20 rag ( Or blue soprenazole or topiraprazole or other PPI of equivalent potency) Calcium lactate 175 mg Calcium phosphate 175 mg Sodium bicarbonate 500 mg Calcium hydroxide 50 mg Glycerin 200 mg E2. Oral reconstituted powder ( Or via nasogastric tube) PPI: one of the following: omeprazole 20 mg ransapride 30 mg tablets topiraw 40 mg riboprazole sodium 20 mg esapanopridazole magnesium 20 mg Other PPI Calcium Lactate 300 mg

-40 - 1309168 V. INSTRUCTIONS (39) Calcium Phosphate Calcium 300 mg Calcium Hydroxide 50 mg Glycerin 200 mg E3 . Oral Reconstituted Powder (or Nasogastric Tube) PPI: One of the following: Omeprezol 20 Mg moxapril 30 mg tablets topirazole 40 mg ribopridone sodium 20 mg esapanopridazole magnesium 20 mg equivalent potency other PPI sodium bicarbonate 850 mg trisodium phosphate 50 mg F1. 10 ms precipitant formulation Omegapril 10 mg (or blue soprenazole or topoterone or other PPI) Calcium lactate 175 mg Calcium phosphate 175 mg Sodium bicarbonate 250 mg Polyethylene glycol 20 mg

-41 - 1309168 V. INSTRUCTIONS (40) Cross-carboxymethyl ether cellulose sodium 12 mg Peppermint oil 3 mg Magnesium citrate 1 mg Magnesium stearate 1 mg F2. 10 ms tablet formulation PPI: one of the following: Omega Resorcin 10 mg moxapril 15 mg tablets topirazol sodium 20 mg riboprazole sodium 10 mg esprom proprazole magnesium 10 mg equivalent potency other PPI calcium lactate 475 mg calcium glycerophosphate 250 Mg polyethylene glycol 20 mg cross sodium carbocresol 12 mg peppermint oil 3 mg magnesium citrate 10 mg magnesium stearate 10 mg F3. 10 ms tablet formulation PPI: one of the following: -42 - 1309168 DESCRIPTION OF THE INVENTION (41) Omeprexazole 10 mg Blue Thorarum 15 mg Tablets Topotez sodium 20 mg Ribrepazole sodium 10 mg Aesopipprozol magnesium 10 mg A considerable amount of other PPI carbonic acid Sodium Hydroxide 700 mg Polyethylene Glycol 20 mg Cross Sodium Carboxymethyl Cellulose Sodium 12 mg Peppermint Oil 3 mg Magnesium Citrate 10 mg Magnesium Stearate 10 mg G1. 10 ms Recording Formulation Omegaprezazole 10 mg (or Blue Sopreva or tablets topirazole or equivalent PPI) calcium lactate 200 mg glycerol Calcium 200 mg 400 mg sodium bicarbonate cross carmellose sodium 12 mg Pregelatinized starch 3 rag G2. 10 mg starch formulation

-43 - 1309168 V. INSTRUCTIONS (42) PPI: One of the following: Omeprazole 10 mg Blue Thoraprazole 15 mg Tablets Topotez sodium Sodium 20 mg Ribrepazole sodium 10 mg Esso honey Reazole magnesium 10 mg Other potency PPI Calcium lactate 400 mg Calcium phosphate 400 mg Cross-carboxymethyl ether sodium 12 mg Pre-gelatinized starch 3 mg G3. 10 ms tablet formulation PPI: one of the following: Omega Rexen 10 mg saponin 15 mg tablets topirazol sodium 20 mg riboprazole sodium 10 mg escarpone praprazole magnesium 10 mg equivalent potency other PPI sodium bicarbonate 750 mg cross carboxymethyl Ether cellulose sodium 12 mg Pregelatinized starch 3 mg -44 - 1309168 V. Description of the invention (43) All the tablets and powders of this example can be swallowed whole, chewed or mixed with an aqueous medium before administration.

EXAMPLE II PIP and buffered standard granules 10 tablets were prepared using a standard tablet press, each tablet containing about 20 mg of omeprazole and 975 mg of sodium bicarbonate dispersed uniformly in the tablet. To test the rate of fragmentation of the tablets, each was added to 60 m of water. An advanced prepared liquid omeprazole/sodium bicarbonate solution was used as a visual comparison meter, and each tablet was observed to be completely dispersed within 3 minutes. Another study used the lozenges synthesized according to this example to evaluate the biological activity of the lozenges in 5 adult patients with acute care. Each subject was administered a small amount of water through a nasogastric tube and used a paper metric to detect the pH of the nasogastric tube. Each patient's pH was assessed for 6 hours and maintained above 4, thus demonstrating the therapeutic benefit of the lozenge in these patients. Tablets can also be prepared by knives drilling 975 mg of sodium bicarbonate in the center of sodium bicarbonate USP. Most of the removed sodium bicarbonate powder was then ground with 20 rog Prilosec® capsules and the resulting mixture was placed in a tincture cavity and sealed with glycerin. EXAMPLE III PPI Core Fraction Tablets are prepared in a two-step process. First, as it is conventionally, about 20 mg of omeprazole is formed in a tablet as a core. Second 'Using about 975 rog tablet sodium bicarbonate USP evenly surrounds the core to form an outer protective layer of sodium bicarbonate. -45 - 1309168 V. INSTRUCTIONS (44)

Both the core and the outer layer can be prepared using standard binders and other excipients to produce a final processed pharmaceutical acceptable lozenge. The lozenge can be swallowed with a cup of water. The swallowing tablet of Example IV foaming lozenge and fine powder time interval measurement t) H is close to the administration before 2 hours after administration 7 hours after administration 2 hours after administration 4 hours after administration 6 hours after administration 5 administration After 8 hours 4, 20 mg of Prilosec® capsules were poured into a crucible and ground to a fine powder. The omeprazole powder was then geometrically diluted with about 958 mg sodium bicarbonate USP, about 832 mg citric acid USP, and about 312 mg potassium carbonate USP to form a homogeneous mixture of foamed omeprazole powder. This powder was then added to about 60 ml of water, and the powder reacted with water to produce a bubble. The bubble solution produces omeprazole and the main antacids sodium citrate and potassium citrate. This solution was then orally administered to an adult male subject and the pH of the stomach was measured using a pHydrion test strip. The results are as follows: Those skilled in the art will recognize that large powders can be made using the above ingredients and that the powder is compressed into the tablet using standard binders and excipients. These tablets are then mixed with water to activate the blowing agent and produce the desired solution. This -46- 1309168 V. Inventive Note (45), it is possible to replace omeprazole with moxapril 30 nig (or other PPI of comparable potency). Foamed powders and lozenges can be formulated separately, using the above mixture but adding an additional 200 mg of sodium bicarbonate USP to produce a higher pH solution. Alternatively, 100 mg of calcium glycerophosphate or 100 rag of calcium lactate can be used in place of excess 200 mg of sodium bicarbonate. You can also add the same combination. EXAMPLE V Formulation and efficacy of the gastric cell wall activator "Choco-BaseTM" Children are affected by gastric and esophageal reflux disease (GERD) in atypical forms. Many of these atypical symptoms are difficult to control with traditional drugs, such as H2 _ histamine antagonists, cisapride (c i s ap r i de ) or sucralfate (s u c r a 1 f a t e ). PPI s is more effective than other agents in controlling gastric pH and GERD symptoms. However, it is not possible to obtain a dosage form of PPIs that is easy to administer to young children. To cope with this problem, Applicants used Omegapril or Choco-Base in a buffered chocolate suspension to express GERD in children. The applicant delivered the University of Missouri-Columbia for retrospective assessment of children with GERD and received experimental omeprazole or lansoprazole Choco-Base suspension prepared according to the following formula 1 from 1959 to 1998. Liquid therapy. The data includes all patient follow-up information, sufficient to infer conclusions about pre-/post-treatment (usually > 6 months). 25 patients met this assessment criteria. The annual range ranges from several weeks to more than 5 years old. Most patients have many unsuccessful attempts to improve the effects of GERD. Disease -47- 1309168 —---- V. INSTRUCTIONS (46) There have been many trials of various drugs. The main researcher reviews all the charts for consistency in data collection. When the data obtained from the university chart is insufficient, the follow-up data is attempted to review the chart at the local care physician's office. If you still can't get the data review, try to get in touch with the family for the follow-up data. If the data is still not available, these patients are considered unavoidable. Review the patient chart in detail. Data notes are the date of treatment initiation, the date of treatment termination, and any reason for termination of response to treatment. As with any other medical condition, the patient's ethnic statistics are also recorded. Medical diseases are roughly divided into those associated with or worsening GERD and those who do not associate with or worsen GERD. Review the patient chart to demonstrate response to treatment. Since this is a large number of references, retrospective review of symptomatic quantification based on scoring, office visits, and ED visits is difficult. Therefore, the applicant reviews the chart to demonstrate all changes in the patient's symptoms. Review and document any data that points to improvement, decline, or lack of change. Results All 3 3 pediatric patients were identified as having the above suspension in Un i v e r s i t y 〇 f Mi s sour i-Col umbi a. Nine of the 33 patients were excluded from the study, all of which were insufficient due to the onset, duration, or outcome of treatment with PPI. So 24 patients with enough data left to draw conclusions. Of the remaining 24 patients, 18 were male and 6 were female. Completion -48- 1309168 V. INSTRUCTIONS (47) The age range for PPI treatment ranges from two weeks to nine years. The median age of treatment initiation was 26 · 5 months [average of 37 months]. In the early stages, reflux is usually confirmed by endoscopic proof and pH probe. Finally, usually at another surgery (most often T-tube or adenoid proliferative resection), the PH probe is discarded and the endoscope is the only way to demonstrate reflow. Seven patients had a pH probe with GERD confirming that '18 endpoints with reflux endoscopy confirmed (including all 8 positions for pH probes) (see Figures 5 and 6). It is most common to diagnose reflux in an endoscope with a round petrochemical wall, a laryngeal and a pharyngeal petrochemical as found in some patients. Six patients did not have the pH of GERD and no endoscopy, but only in the PPI treatment based on symptoms. Past medical records were confirmed in each chart. Ten patients had a diagnosis associated with reflux. These are most commonly stroke, precocious and Pierre Robin sequences. Other diagnoses are Charcot-Marie-Tooth disease' Velocardiofacial syndrome, Down syndrome, and De George, s syndrome . Non-reflow medical records were also confirmed and recorded separately (see Table 2 below). Patients are usually referred from local family practice clinics, pediatricians, or other professional pediatric health care referral patients. Most patients are related to ENT. The above respiratory problems, sinusitis, or periodic/chronic otitis media, as reported by the care physician at the grassroots level, are resistant to medical treatment. Recording and scoring are most commonly seen in the symptoms and symptoms of three patients. All symptoms and symptoms are divided into 6 main types: (I) nasal; (2) ear; (3) respiratory tract; (4) gastrointestinal tract; (5) -49- 1309168 5. Description of invention (48) sleep related; (6) Others. The most common problems fall into one or all of the first three types (see Table 1 below). Most patients have in the past experienced medical treatment with antibodies, steroids, asthma medications, and other diagnostically appropriate forms of treatment. In addition, nine patients have had reflux therapy in the past, most commonly in the form of traditional treatments, such as an increase in bedside 30. Avoid evening snacks, avoid caffeine dips and cisapride and ranitidine (see Figure 7). The proton pump inhibitor suspension used in this group of patients was a Choco-Base suspension of moxapril or omepril. The administration was very consistent and the patient received 10 or 20 mg of omeprazole and 23 rag of blue spiropril. Initially, when treated in April 1996, 10 mg of omeprazole was first used. During this initial period, 3 patients initially received 10 mg of omeprazole daily. The subsequent 3 were all added to 20 mg of omeprazole or 23 mg of blue drusopyrazole per day. The remaining patients were treated with 20 mg of omeprazole or 23 mg of lansoprazole, except for one case using 30 mg of lansoprazole. The patient is instructed to take their dose once a day. Most of the cases are better at night. The suspension was completely filtered through the University of Missouri Pharmacy at Green Meadows. This allows you to track usage by re-arming data. Most patients responded more favorably and tolerated once a day to dose the Choco_ Ba s e proton pump inhibitor suspension. Two patients have demonstrated adverse effects -50 - 1309168 V. INSTRUCTIONS (49) Relevant to the use of PPI suspension. The mother of one patient described increased snoring and dyspepsia, which was thought to be associated with treatment failure. A small amount of blood stool is described according to the mother of another patient. The patient's stool has not been tested because the treatment interruption immediately eliminates the bloody stool without further sequelae. The other 23 patients had no evidence of adverse effects. Patients were classified according to clinical records review and chart review as: (1) improved; (2) unchanged; (3) failed: and (4) uncertain. Twenty-four patients had sufficient data to follow through, and 18 showed an improvement in symptoms with PPI treatment [72%]. The 7 unresponsive 7 were analyzed and classified. Three of them showed no change in symptoms and clinical outcomes during treatment, one complained that the symptoms worsened during treatment, one patient's treatment was surgical prevention, and two patients stopped treatment after the start (see Figure 8). Regardless of the case where the treatment was stopped before the conclusion was reached and the case where PPI treatment was purely a motive for prevention, the remaining (17/21) 81% of the patients responded to the Choco-Base suspension. This means that 19% (4/21) of patients did not receive significant benefit from PPI treatment. Only 4% of all patients complained of worsening symptoms and 4% (1/21) had side effects and mild bloody stools were completely resolved once treatment was discontinued. Discussion GERD is quite common in pediatric populations, affecting almost 50% of newborns. Even though most babies no longer have physiological reflux after they grow up, morbid regurgitation still affects about 5% of children in childhood. Recent important data point to reflux as a cause of disease outside the esophagus. GERD has been attributed to Baoyan, dental caries, otitis, asthma, apnea, arousal, pneumonia, bronchitis, -51 - 1309168, invention instructions (5〇) and coughing. Regardless of the common nature of reflux, it seems that there is little improvement in the treatment of reflux, especially in non-surgical situations. Therapeutic criteria for the treatment of GERD in the pediatric population have progressed from traditional treatment to the treatment of pro-kinetic agents and H-2 inhibitors. However, many patients fail in this treatment plan and become waiters for surgery. In adults, PPI is effective in 90% of patients treated with gastric and esophageal reflux. As a medical alternative to H-2 blockers, proton pump inhibitors have not been widely studied in pediatric populations. Part of the reason for the lack of this data may be related to the lack of proper dosage formula for such young populations, mainly under 2 years of age, who are unable to swallow capsules or lozenges. It is desirable to have a suitable liquid formulation (solution or suspension) with good palatability, such as antibiotics, decongestants, antihistamines, H-2* blockers, cisapride, and Metoprolap. Metoclopramide and the like. The use of moxapril fines (removed from gelatin capsules) and sprinkled on applesauce has been approved by the Food and Drug Administration as an alternative to the drug administration to adults (non-adoptable children). The published data lacks the efficacy of the blue-spirol prednisolone method in children. It has been investigated that omeprazole is highly entangled in adult organisms and can produce omeprezazole blood stasis compared to standard capsules. Once again, it is impossible to obtain data on the use of omeprazole. Another disadvantage of omeprazole is that it tastes like quinine. Even if it is suspended in juice, applesauce, etc., once it is chewed to a fine grain, the natural bitterness of the drug can be easily felt. For this reason, the applicant finally developed the use of blue botoprazole in Choco-Base. Topiprazole and ribiprazole can only be obtained by intestine-coated tablets -52 - ^09168 5. Inventive Note (51). Currently, no proton pump inhibitors have been approved for use in pediatrics in the United States. Because of some debates, how many appropriate doses are needed for this group of patients. A recent review by Israel D. et al. suggests that the effective PPI dose should be higher than the originally published dose, ie from 0.7 mg/kg to 2 or 3 mg/kg of omepril. Since no toxicity of PPIs was observed even with >50 mg/kg, little risk was shown to be associated with higher doses. Based on the findings of the University of Mi ssouri, the applicants developed a simple fixed-dose course of 10 ral Choco-Base suspension per day. This 1 〇 ml dose provides 20 mg of omeprazole or 23 mg of lansoprazole. For IC U settings, U niversity 〇f M iss 〇uri - C ο 1 umbia has used unflavored PPI suspension in a variety of different tubes (nasal tube, g-tube 'jejunal feeding tube, duodenal tube, etc.) per One day to prevent pressure ulcers. It seems only logical that if this treatment can be made into a palatable dosage form, then there are many desirable pharmaceutical properties for the pediatric population. First, it must be liquid, so it can be administered at an earlier age. Second, creating a taste can help reduce disobedience. Third, it can be provided once a day, which can also help reduce the situation of disobedience. In the midst of the applicant's discovery, the drug can be standardized, and the complexity of the drug is almost eliminated.

Cho c 〇 - Ba s e is a product that protects acid labile drugs (such as proton pump inhibitors) from acid degradation. The first pediatric patients who were given a Choco-Base prescription with reflux were the more ill patients. They have been treated with priority and diagnosed with pH probes and endoscopy. In the first few months, the applicant was given 10 mg of omeprazole (1 mg/kg) every day, and found that it could not afford 53 - 1309168 5. The effect of the invention (52), and immediately increased the dose to 20 rag Omega. Prezol (2 ra g / kg ). On the way to research, the applicant began to use 23 mg of blue drusopyrazole every day. The standard treatment for the applicant is then 20 mg of omegapril or 23 mg of lansopril once daily. The extra 3 mg of thuridine was only used at a final concentration of 2.25 tng/ml, and the applicant wanted to keep the administration simple, so 10 ml of suspension was used. The treated patients represent the ethnic group of the third care center, which was originally sick and resistant to past medical care. The overall 72% success rate is slightly lower than the 90% success rate of PPIs in the adult population, but this can be attributed to their intractable nature of the disease, mostly due to previous non-PPI treatment failure. The ethnic group of this study does not represent the ethnic group that is generally practiced. Conclusion PPI therapy is a beneficial medical option for the treatment of reflux-related symptoms in pediatric populations. This treatment combines a single administration and a standard dosing process with a palatable formula, making it an ideal agent. Table 1 Symptoms Number of patients Nasal: 35 Sinusitis 7 Congestion 8 Nasal discharge 16 Others 4 Ears: 26 -54- 1309168 V. Invention description (53) Otitis media 17 Otorrhea 9 Respiratory tract · ' 34 Cough 10 Wheezing 11 Respiratory pain · ' 5 Pneumonia 2 Other 6 Gastrointestinal tract: 10 Abdominal pain 1 Reflow / pivotation 4 Other 4 Sleep disorders: 11 Other 2 Table 2 Reflux correlation: 12 Early maturing 5 Pierre-Robin 2 Brain stroke 2 Dow syndrome (Down syndrome 1 Charcot-1 Marie-Tooth disease -55 -

1309168 V. Description of invention (54) Verocardiofacial syndrome 1 Other medical records 12 颚 颚 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Formulation 1 Formulation 1 Part A Component Quantity (mg) Omniprezol 200 Sucrose 26000 Sodium Bicarbonate 9400 Cocoa Powder 1800 Corn Syrup Solid 6000 Sodium Caseinate 1000 Soy Lecithin 150 Sodium Chloride 35 Tricalcium Phosphate 20 -56 -

1309168 V. INSTRUCTIONS (π) Dipotassium Phosphate 12 Ceria 5 Sodium Stearate Sodium Lactate 5 Part B Quantity (ml) Distilled Water 100 Synthesis Procedure Guide Add Part B to Part A to produce a total volume of about 130 ml containing omepruri The concentration of azole is about 1.5 mg/ml. Formulation 2 Part A (mg) Quantity (mg) Sucrose 26000 Cocoa powder 1800 Corn syrup solid 6000 Sodium caseinate 1000 Soy lecithin 150 Sodium chloride 35 Tricalcium phosphate 20 Dipotassium phosphate 12 cerium oxide 5

-57 - 1309168 V. INSTRUCTIONS (56) Stearic acid sodium lactate 5 B Partial quantity Distilled water 100 ml Sodium bicarbonate 8400 mg Omeprazole 200 mg Synthetic operation guide Thoroughly mix the components of Part B and then add to Part A . A total volume of about 130 ml was obtained containing a concentration of omeprazole of about 1.5 mg/ml.

Formulation 3 Part A (mg) Quantity (mg) Sucrose 26000 Sodium bicarbonate 9400 Cocoa powder 1800 Corn syrup solid 6000 Sodium caseinate 1000 Soy lecithin 150 Sodium chloride 35 Tricalcium phosphate 20 -58 - 1309168 V. Description of invention (57) Dipotassium Phosphate 12 Ceria 5 Stearic Acid Sodium Lactate 5 Part B Quantity Distilled Water 100 ml Omeprazole 200 mg Synthetic Procedures This formula is reconstituted by the pharmacist during use. Mix Part B first, then mix it evenly with the component of Part A. The final production volume is about 130 ml and contains omeprazole at a concentration of about 1.5 mg/ml.

Formulation 4 Part A (mg) Quantity (mg) Sucrose 26000 Cocoa Powder 1800 Corn Syrup Solid 6000 Sodium Caseinate 1000 Soy Lecithin 150 Sodium Chloride 35

-59- l3〇9l68 , invention description (58 ) <tricalcium phosphate 20 ^dipotassium phosphate 12 \2 cerium oxide 5 ^ stearin sodium lactate 5 < part B component quantity <saturated water 100 ml <carbonic acid Sodium Hydroxide 8400 mg <Omeprezol 200 rag — <Synthesis Instructions This formulation is reconstituted by the pharmacist when in use. Mix Part B first, then mix it evenly with the component of Part A. The final production volume of about 130 ml contains Omega <Reazole concentration of about 1.5 mg / ml. In all four of the above formulations, omeprazole can be replaced by a considerable amount of moxapril or other PPI. For example, 300 rag omeprazole can be replaced by 300 mg of moxaprilazole. In addition, aspartame can be substituted for sucrose and the following other ingredients can be used as carriers, adjuvants and excipients: maltodextrin, vanilla, carrageenan, mono or diglycerides, and lactic acid monoglyceride. Those skilled in the art will appreciate that not all ingredients are required to produce a safe and effective Choc(R)-Base formulation. -60 - 1309168 V. INSTRUCTIONS (59) Omniprezazole powder or intestinal coated fine particles can be used in each formulation. If the intestinal coated fine particles are used, the coating may be dissolved by aqueous solution diluent during the synthesis or by deuteration. In addition, the Applicant used a pH meter (Fisher Scientific) to analyze the effect of Ribuprid® C h 〇 c 〇 - B a s e formulation on gastric pH in a single patient compared to ribiprazole alone. The patient was given a 30 mg oral sac (Prevacid®), which was then measured at 0, 4, 8, 12 and 16 hours after administration. The results are illustrated in Figure 4. The ChocoBase product was synthesized according to Formulation 1 above, divided by 300 mg of dantrolazole to replace ribiprazole. 18 hours after the administration of ribopridazole alone, oral head and 30 mg dose of Chrysosporide Choco-Base. After administration of a single ribiprazole dose of 18, 19, 24, 28, 32, 36, 40, 48, 52 and 56 hours, the pH of the stomach was measured using a pH meter. Figure 4 illustrates that the combination of the blue psoprezazole/cocoa powder resulted in a higher pH at 19-56 hours compared to ribiprazole alone for 4-18 hours. Therefore, the combination of blue botoprez and chocolate enhances the pharmacological activity of blue prepizole. Probably due to the release of stomach hormones, it was confirmed that sodium bicarbonate, as well as chocolate and calcium, can stimulate the activation of the proton pump. Proton pump inhibitors act by functionally inhibiting the proton pump and effectively blocking the activated proton pump (mainly embedded in the secretory tubule). Further activation of the proton pump activation and absorption and subsequent suppression of concentrated proton pump inhibition by the gastric wall cells is achieved by further administration of a proton pump inhibitor with an activator or enhancer. As exemplified in Fig. 4, this combination has a longer-term pharmacological effect than when a proton pump inhibitor is administered alone, resulting in a -61- 1309168 V. invention description (6〇). EXAMPLES VT Combination Lozenges Convenient Drugs and Timed Release Dose ___££1 Using a known method to form a core of 7 50 mg sodium bicarbonate via 10 mg of omeprazole powder, and 10 mg The omeprazole enteric coated fines are mixed with the outer core of known binders and excipients to synthesize the tablets. After the entire tablet is taken, the tablet dissolves and the inner core is dispersed in the stomach' absorbed to produce immediate therapeutic efficacy. The intestinal coated fine particles are later absorbed in the duodenum to provide relief of symptoms in subsequent administration cycles. This lozenge is particularly useful for patients suffering from sudden gastritis between traditional administrations (e.g., when sleeping or at morning). Example VIT Therapeutic application patients are evaluable if they meet the following criteria: risk factors with two or more SRMDs (mechanical administration of oxygen, head injuries, severe burns, sepsis, multiple traumas, adult respiratory ailments) _, major surgery, acute renal failure, multiple procedures, coagulopathy, significant hypertension, acid-base disorders, and liver failure) 'Participate pH before the study of pH 尨 4, and no joint prevention method for SRMD. The omeprazole solution was prepared by mixing 1 〇m 1 of 8.4% sodium bicarbonate with 20 mg of omeprazole (Merck & Co. Inc., West Point, PA) to give a final concentration of 2 Omegaprezazole solution of mg/m丨. -62 - 1309168 V. INSTRUCTIONS (61) Omeprexazole in a patient's body and buffered 40 mg of omeprazole solution (2 mg of omeprazole / 1 ml of NaHC03-8_4%) The rule is that 40 mg of the same buffered omegapurine π sitting solution is then taken in 8 hours per day and then 20 rag of the same buffered omegaprezazole solution for 5 days. After each administration of the omeprazole solution, the nasal aspiration was stopped for 30 minutes. 11 patients were evaluable. All patients were given oxygen by mechanical means. Two hours after the start of administration of 40 mg of buffered omegaprezazole solution, all patients increased the pH of the stomach to greater than 8 as shown in Figure 1. When 20 mg of omeprazole solution was administered, 10 of 11 patients maintained a gastric pH greater than or equal to 4. One patient required 40 mg of omeprazole solution (closed head injury for a total of 5 SRMD risk factors) per day. Two patients changed to a clinically apparent upper gastrointestinal bleeding after receiving a conventional intravenous H2-antagonist, and were changed to the omeprazole solution. Both cases calmed the bleeding after 24 hours. Clinically, upper gastrointestinal bleeding did not occur in the other 9 patients. The overall mortality rate was 27%, and the mortality rate due to upper gastrointestinal bleeding was 0%. After the start of omeprazole, one patient developed pneumonia and appeared in another patient with the start of omeprazole. The average length of the preventive effect is 5 days. The analysis of the medical economy shows that the total cost of care for SRMD prevention is different from that of Zantac® continuous intravenous infusion (150 mg/24 hours) x 5 days for US$125.50; -63 - 1309168 V. Description of invention (62) Tagamet® continuous intravenous infusion (9050 mg/24 hours) x5 days for US$109.61; Sucralfate 1 g for four times a day Each nasogastric tube is US$73.0 for X5 days; and the treatment of buffered omeprazole solution is US$65.70 for each nasogastric tube x5 days. This example illustrates the efficacy of the buffered omeprazole solution of the present invention as a method of preventing SRMD based on increasing gastric pH, safety of buffered omeprazole solution, and cost. Example VIII Effect on pH An experiment was conducted to determine the effect of administration of omeprazole solution (2 mg of omeprazole / 1 ml of NaHC03-8.4%) on the correctness of subsequent pH measurements through the nasogastric tube. After preparing all 40 mg of the buffered omeprazole solution, the dose was administered to the stomach, usually through a nasogastric (ng) tube, by the method of Example VII. Nasogastric tubes from 9 different units were collected for evaluation. Artificial gastric juice (gf) was prepared according to USP. Two pH recordings were performed using a Microcomputer Portable pH meter type 6007 (Jenco Electronicx Ltd., Taipei, Taiwan). First, the last part (tp) of the nasogastric tube is placed in a glass beaker containing gastric juice. Aspirate 5 ml of whole gastric juice through each tube and record the pH: this is called "pre-omeprazole -64 - 1309168, (63) solution/suspension measurement". The first portion (tp) of each of the nasogastric tubes is removed from the beaker containing the gastric juice and placed in an empty beaker. Transfer 20 mg of omeprazole solution through each nasogastric tube and rinse with l〇ml of tap water. The last part of each nasogastric tube (tp) is returned to the gastric juice. After 1 hour of incubation, 5 ml of the whole gastric juice was aspirated through each tube and the pH was recorded; this was called "measured after the first administration of SOS [simplified omeprazole solution]". Third, after another hour, repeat the second step; this is called “measure after the second administration of SOS [simplified omeprazole solution]”. In addition to the pre-omeprazole solution measurement, the gastric juice pH was tested three times after the second and third steps. In the pH measurement, a change of +/- 0.3 units is considered meaningful. The comparison results were tested using F r i e d m a η. The f r丨e d m a n test is a two-way analysis of the variance, used when more than two related samples have an effect, as in repeated measurements. The results of these experiments are summarized in Table 3. _____ Table 3 ngl ng2 ng3 ng4 ng5 ng6 ng7 ng8 ng9 [l]gf Pre SOS 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 [2] gf p 1st administration 1.3 - test gf pH 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 1.3 [3 ]gf p 2nd administration 1.3 1.3 1.4 1.4 1.4 1.3 1.4 1.3 1.3

1.3—Test gf pH --- - SOS nH^Q·〇 -65- 1309168 V. INSTRUCTIONS (64) Table 3 illustrates the results of PH measurements during the experimental procedure. These results demonstrate the statistically significant potential impact of omeprazole solution administration on the correctness of subsequent pH measurements obtained through the same nasogastric tube. EXAMPLES X-Cychong Omegaprezazole solution for the efficacy of argon-administered patients was tested to determine the critical condition of a patient with a buffered omegaprezazole solution for mechanical oxygen administration (with at least one pressure-related mucosal damage) Additional factor) efficacy, safety and cost. &A: 75 adults, who are mechanically given oxygen, have at least one additional factor associated with pressure-related gastric mucosal damage. Intervention: At the beginning of the day, the patient receives 20 μm of omeprazole solution (prepared according to Example VII and contains 40 mg of omeprazole), and after 6-8 hours, the second dose is 20 ml, then 10 1» 1 (20 mg). The omegapurine solution according to the present invention is administered through a nasogastric tube followed by administration of 5-10 ml of tap water. The nasogastric tube was clamped 1 to 2 hours after each administration.涸1 amount and main results: The initial results were measured as clinically significant gastrointestinal bleeding, which was assessed by endoscopy, nasogastric aspiration, or could not be removed by lavage and reduced by hematocrit 5 % related to blood quality - positive coffee substrate material. The second efficacy measure was the pH of the stomach measured 4 hours after the first administration of omeprazole, the mean gastric pH measured after the start of administration of omeprazole, and the lowest stomach measured during the treatment with omeprazole. Part pH. Safety-related outcomes include the incidence of harmful conditions and the incidence of pneumonia. After receiving the omeprazole suspension, no patient experienced clinically -66 - 1309168. V. Inventive Note (65) Significant upper gastrointestinal bleeding. The gastric pH at 4 hours after omeprazole was 7.1 (mean), the average stomach after starting omeprazole was 1) 6.8 (average) and the lowest pH after starting omeprazole was 5. 6 (average). The incidence of pneumonia is 12%. No patient in this high-risk group suffered a harmful condition or was attributed to the drug interaction of omeprazole. Basket _: Omeprezazole solution prevents clinically significant upper gastrointestinal bleeding, and maintains gastric pH greater than 5.5 and does not produce toxicity in patients who are mechanically given oxygen. Materials and Methods: The study of the law was approved by the Institutional Review Board for the University of Missouri in Columbia. Study group: Enter Un i ve rsityof Mi ss ou ri Hos pita 1 Surgery intensive care unit and burn unit, complete stomach, proper disposal of a nasogastric tube, and all adult patients entering the intensive care unit for at least 48 hours (> 18 years old) are included in the study of this study. The patient to be included in the present invention also requires gastric pH < 4, mechanical oxygen administration, and the following additional risk factors for a minimum of 24 hours after the start of the omeprazole suspension: a head injury with a change in wakefulness, Extensive burns (>20% body surface area), acute renal failure, acid-base disorders, multiple traumas, coagulopathy, multiple procedures, coma, hypotension for more than 1 hour, or sepsis (see Figure 4). Sepsis is defined as the presence of aggressive pathogenic organisms or their toxins in the blood or tissues leading to systemic reactions, including two or more of the following: temperatures above 38 ° C or below 36 t, heart rate greater than 90 hrs / min, respiratory rate More than 20 breaths per minute - 67 - 1309168 5. Invention instructions (66) (or p〇2 less than 75 mniHg), and white blood cell counts greater than 12,000 or less than 4,000 cells / _3 or more than 10% (Bone, Let's Agree on Terminology: Definitions of Sepsis, CRIT. Care Med., 1 9:27 (1 991 )). Also included are patients who have failed H2-antagonist therapy or who have experienced an adverse condition when receiving H2-antagonist therapy. If you receive an azole antifungal agent through the nasogastric tube, you may swallow (such as facial and / or sinus fractures, oral tears), with severe thrombocytopenia (such as platelet count less than 30,000 cells / mm3), Patients who received feeding through the nasogastric tube, or who had a vagus nerve resection, pyloric ostomy, or gastrostomy were excluded from this study. In addition, patients with a stomach pH greater than 4 48 hours after entering the intensive care unit (without prevention) are not eligible to participate. Non-pressure-related mucosal damage (eg, variceal hemorrhage confirmed by endoscopy or Mallory-Weiss tears, oral damage, nasal tears caused by placement of nasogastric tubes) Patients who develop intra-abdominal tract bleeding are not included in the effective assessment and are classified as non-stress-related gastric mucosal hemorrhage. The reason for exclusion is the confounding effect of non-stress-related mucosal hemorrhage on effective relevant outcomes (eg, using a nasogastric aspiration review to define clinically significant upper gastrointestinal bleeding). Investigating drug administration: The omeprazole solution was prepared immediately by the patient's nurse prior to administration using the following instructions: Pour one or two 20 mg of omepruri capsule contents into a 10 ml empty syringe (with 20 caliber) Needle) where the piston has been removed. (Omeprezol delayed release capsule, Merck Co. Inc., West Point, PA); put back the piston and remove the needle cap; charge -68 - 1309168 5. Inventive Note (67) 10 m 1 of 8.4% sodium bicarbonate Solution (or 20 ml in 40 mg of omeprazole) (Abbott Laboratories, North Chic ago, IL) to give a final concentration of 2 mg of omeprazole in 8.4% sodium bicarbonate solution per m 1 » The coated omeprazole is completely broken, about 30 minutes (agitated to help). The omeprazole was partially dissolved and partially suspended in the resulting preparation. The preparation should be milky white with a fine precipitate and shake before casting. This solution is not administered with acidic substances. A high-pressure liquid phase stratification study demonstrated that the simplified omeprezazole suspension preparation maintained a >99% potency for 7 days at room temperature. The preparation was stored at room temperature while still using iffi y» fine fungus and no fungal contamination for 30 days (see Table 7). The initial dose of the omeprazole solution is 40 mg, followed by the second 40 mg dose after 6 to 8 hours, and then 20 rag dose per 曰 at 8 am 〇 Each dose is administered through the nasogastric tube. Rinse the nasogastric tube with 5_10 η 11 tap water and clamp for at least 1 hour. The omeprazole treatment continues until the prevention of pressure ulcers is no longer required (usually after the removal of the nasogastric tube and the patient can ingest water/food from the mouth, or after the patient removes mechanical oxygen). The initial results of the study were pressure-related mucosal hemorrhage as evidenced by endoscopy, or removal of nasogastric blood after 5 minutes of lavage, or sustained Gastroccult (SmithKline Diagnostic s, Sunnyv i 1 1 e , CA ) positive coffee The substrate material was irrigated (at least 100 ml) for 4 hours and was not removed and caused a 56⁄4 reduction in the hematocrit, a clinically significant pressure-related mucosal bleeding rate defined. -69- 1309168 V. INSTRUCTIONS ((10)) The second knot was measured: the second efficacy measurement was measured after the pH of the stomach measured 4 hours after administration of omeprazole and the start of administration of omeprazole. The average stomach pH, as well as the lowest gastric pH measured during the administration of omeprazole. The pH of the stomach was measured immediately after aspirating the contents of the stomach through the nasogastric tube. The pH of the gastric aspirate was measured using pH test paper (pHydr ion modified pH test paper, Microessential Lat oratory, Brooklyn, NY). The pH of the test strip ranges from 1 to 1, and increases in one pH unit. Before the start of treatment with omeprazole solution, the pH of the stomach was measured every 4 hours before the administration and between the administrations. Other second outcome measures were adverse events (including drug interactions) and the incidence of pneumonia. Record any adverse events that occurred during the study period. Pneumonia was defined using the Centers for Disease Control and Prevention to define indicators for the use of nosocomial pneumonia (Garner et al., 1 988). According to these criteria, patients with pneumonia refer to a rales or dullness in a chest examination, or a chest X-ray image showing new or ongoing infiltrates, firming, cavities, or pleura. Exudates, and has at least two of the following conditions: new changes in the characteristics of purulent or sputum, separation of birth objects from blood culture, fever or leukopenia, or significant infection from protective sampling brushes or bronchi and alveolar lavage. Patients who meet pneumonia criteria and who receive antimicrobial therapy for pneumonia are included in the calculation of the incidence of pneumonia. These criteria were also used as initial screening before the first dose of study drug was administered to determine whether pneumonitis occurred prior to the start of the omeprazole suspension. Cost analysis of Zhaozhao: For the prevention of the use of omeprazole solution in the pressure ulcer -70 - 1309168 5, invention (69) prevention of ulcers, medical economic evaluation. The assessment includes the total cost of the drug (acquisition and administration), the actual cost associated with the adverse event (eg psychiatric therapeutic counseling for mental disorders), and the cost associated with clinically significant upper gastrointestinal bleeding. The total cost of the drug was calculated from the omeprazole 20 mg capsule '50 ml sodium bicarbonate vial, and 10 ml syringe containing needle, care time (drug administration, pH detection), dispensing time (drug preparation), And the average customary cost of disposal costs add up. The costs associated with clinically significant upper gastrointestinal bleeding include endoscopic cost and accompanying counseling costs, steps required to stop bleeding (eg surgery, hemostatic agents, endoscopic procedures), increased hospital stay (by the care physician) Judging), as well as the cost of treating gastrointestinal bleeding agents. Statistical analysis: The stomach pH before and after administration of the omeprazole solution was compared using a paired t-test (two tails), and the pH of the stomach before administration of the omeprazole solution was compared with that after the start of the omeprazole solution. Mean and minimum stomach pH 値 results · 77 patients met the inclusion and exclusion criteria and received the omeprazole solution (see Figure 2). Two patients were excluded from the effective assessment because they did not continue the omeprazole dosing procedure. In one case, the first two doses of the previous dose of omeprazole was not completely fragmented, resulting in an unstable pH in the stomach. When a dose of omeprazole solution is administered to the patient, the pH of the stomach is increased as much as 6 or more (in which the enteric coating drug of omeprazole has been completely broken). -71 - 1309168 V. INSTRUCTIONS (7〇) The second reason for exclusion was that nasal aspiration was not switched off after administration of the dose of omeprazole. This causes a transient effect on the pH of the stomach. The subsequent dose of omeprazole is used to switch off the aspiration and achieve regulation of the pH of the stomach. Two patients were considered to have failed efficacy because omeprazole did not maintain proper gastric pH regulation at a standard dose of 20 mg/day of omeprazole. When the dose of omeprazole was increased to 40 mg/day (40 mg-times/day or 20 mg twice/day), the gastric pH was maintained above 4 in both patients. These two patients were included in safety and efficacy assessments, including gastric pH analysis. After the two patients failed, they were no longer tracking their pH. The remaining 75 patients ranged in age from 18 to 87 years, 42 patients were male and 33 patients were female. All patients were mechanically given oxygen during the study period. Table 4 shows the frequency of risk factors associated with stress-related bleeding in patients presented in this study. The most common risk factors in this group are mechanical oxygen and major surgery. The risk factor for any patient ranges from 2 to 10 with an average of 3 (±1) (standard deviation). Five patients enrolled in the study had clinically significant bleeding while continuing to receive either monidene (150 mg/24 hours) or ceramide (900 mg/24 hours). In all 5 cases, hemorrhage was subsided within 36 hours after the start of omeprazole treatment and the pH of the stomach was raised to above 5. Three patients participated after receiving two consecutive gastric pH 値 below 3 when receiving an H2-antagonist (as in the above-mentioned dose). In all 3 cases, the pH of the stomach was raised to 5 or more within 4 hours after the start of omeprazole. The other 4 patients participated in this study after suffering from mental disorder (n = 2) or thrombocytopenia (n = 2) during H2 • antagonist therapy. -72 - 1309168 V. Inventive Note (71). These adverse conditions were relieved within 36 hours after the transfer treatment. Pressure-related adhesives, sputum, blood and dead r rate: 65 patients received buffered omegaprezazole solution as their initial prevention of pressure-related mucosal bleeding, no significant or clinically significant upper gastrointestinal bleeding occurred . Four of the five patients who had progressed to upper gastrointestinal bleeding before participating in the study reduced bleeding within 18 hours of starting the omeprazole solution to only occult blood (G astr 〇ccu 1 t positive), while at 3 All patients had stopped bleeding within 6 hours. The overall mortality rate of this group of critically ill patients was 7%. No one died as a result of upper gastrointestinal bleeding or the use of omeprazole solution. Gastric pH: mean (± standard deviation) pre-omeprazole stomach pH was 3 _ 5 ± 1. 9. Within 4 hours of omeprazole administration, the pH of the stomach increased to 7.1 ± 1.1 (see Figure 3), and the difference was significant (? < 0.001). The difference between the pre-omegaprezil stomach pH and the mean and minimum stomach pH measured during the administration of omeprazole (6.8 ± 0.6 and 5.6 ± 1.3, respectively) was also statistically significant (p < 0 · 001 ). An-Full".: The omeprazole solution is well tolerated in the group of critically ill patients. Only one patient suffered from a bad condition of sepsis, which may be drug-related thrombocytopenia. However, the platelet count continued to decrease until it stopped after omeprazole. The platelet count then returned to normal regardless of the reconstitution of omeprazole treatment. It should be noted that one patient continuously discharges all the liquid in her stomach and discharges through the mouth in the ventilating ventilator, so that it is impossible to continue to give omeprazole. There was no clinically significant drug interaction with metoprazole during this study. As mentioned above, the disease of receiving sodium bicarbonate -73- 1309168 V. Description of the invention (72) People may be related to metabolic alkalosis. However, the amount of sodium bicarbonate in the omeprazole solution was small (= 12 mEq/I0 ml), and no electrolyte abnormality was observed. Pneumonia: Nine patients who received omeprazole solution developed pneumonia (12%). The other 5 patients had pneumonia before starting omeprazole. Medical Economics Assessment: The average duration of treatment was 9 days. The cost of care is listed in Tables 5 and 6. The costs of drug acquisition, preparation, and delivery of certain conventional agents for the prevention of pressure-related upper gastrointestinal bleeding are listed in Table 5. The omega prase solution has no cost associated with adding toxicity. Two of the 75 patients required 40 mg of omeprazole solution per day to properly regulate the pH of the stomach, and the cost of acquisition/preparation was demonstrated. An additional 20 mg of omeprazole containing excipients increased by 7% per day in care costs. Therefore, the daily care cost of the prevention of pressure-related mucosal bleeding with omeprazole solution is US$ 12.6 (see Table 6). The omeprazole solution is a safe and effective treatment for the care of patients with clinically significant pressure-related mucosal bleeding. Many risk factors that cause stress-related mucosal damage have recently been challenged. In this study, all patients had at least one risk factor that was known to be associated with stress-related mucosal damage - mechanical oxygenation. Previous trials and data recently published have shown that prevention of pressure ulcers is beneficial for patients at risk, and it is therefore unethical to consider this study to include a placebo group. There was no clinically significant upper gastrointestinal bleeding during the treatment with omeprazole solution. Seventy-seven of the 75 patients with 20 mg/day of omeprazole maintained the pH of the stomach at 4 -74 - 1309168. V. Inventive Note (73). No adverse events or drug interactions associated with omeprazole were encountered. Table 4 Mechanically significant multiple head hypotension renal failure septic multiple polyacids coma liver failure burns oxygen surgery traumatic injury process disorders 75 61 35 16 14 14 14 12 10 4 2 2 Appeared in this study patient Risk factors (n = 7 5 ) Table 5 Daily Taiping (Day 1-9) Lanitidine 150 mg/24 hours 6.15 Subordinate products (1) Backpack transport (60%) 0.75 Slave products (2) Microtubule delivery (etc.) 2.00 Slave product (3) Filter 0.40 Sterile preparation is RN time (US$24/hour) 20 minutes/day (including pH detection) 8.00 R.Ph. Time, fume hood maintenance 3 minutes (US$40/hour) 2.00 Pump cost US$29/24 hours x50% 14.50 9 days total 304.20 Cost per 曰芮尼丁丁33.80

-75- 1309168 V. INSTRUCTIONS (74) 3 Tuen Mun Tai Ding (Day 1-9) cimet idine 900 mg/24 hours 3.96 Subordinate products (1) Backpack transport (60%) 1.25 Dependent products (2) Microtube delivery (etc.) 2.00 Dependent product (3) Filter 0.40 Sterile preparation is RN time (US$24/hour) 20 minutes/day (including pH detection) 8.00 R.Ph. Time, ventilation The cabinet is kept for 3 minutes (US$40/hour) 2.00 The pump costs US$29/24 hours x50% 14.50 9 days total 288.99 The cost per door is 32.11 Sucralfate (Day 1-9) Sucralfate 1 gx4 2.40 Slave product (1) Syringe 0.20 Sterile preparation No RN time (US$24/hour) 30 minutes/day (including pH detection) 12.00 9 days Total 131.40 Cost per serving of sucralfate 14.60 Daily gate Ding costs 32.11 Notes = Does not include the cost of failure and / or adverse effects. The cost of obtaining, preparing, and shipping traditional reagents.

-76 - 1309168 V. INSTRUCTIONS (75) Table 6 The average duration of treatment is 9 days. The cost of care is calculated from these days. Total daily Omegapril (Day 1) Product acquisition cost 40 mg Loading x2 (5.66/administration) 11.32 11.32 Subordinate product Material for solution preparation 0.41 0.41 Slave product Syringe W needle 0.20 0.40 Sterile preparation No SOS preparation time (RN) 6 minutes 2.40 4.80 RN time (US$24/hour) 21 minutes/day (including detection pH) 8.40 8,40 R.Ph., Fume hood to maintain 3 Omega Puri (Day 2-9) Product acquisition cost 20 mg daily 2.80 22.65 Subordinate product Material for solution preparation 0.41 0.82 Slave product syringe W/ Needle 0.20 1.60 For aseptic preparation No SOS preparation time (RN) 6 minutes 2.40 4.80 RN time (US$24/hour) 18 minutes/day (including pH detection) 8.40 57.60 2/75 patients need 40 mg of simplified Omega per day Reazole solution (Days 2-9) No additional cost to adverse effects or failures Total per simplified cost of omeprazole solution -77 - 1309168 V. Description of invention (7 6) Omegaprezol care cost medical economic evaluation table 7 time control group 1 hour 24 hours 2 days 7 days 14 days concentration (mg/ml) 2.01 2.07 1.94 1.96 1.97 1.98 Simplified omeprezazole solution at room temperature ( 25 t) Stability, number 値 is the average of the three samples. Example X The effect of the bacteriophage and the direct bacteria of the solution of the omeprazole solution. The applicant analyzed the antimicrobial or bacteriostatic efficacy of the omeprazole solution. The omeprazole solution (2 mg/ml of 8.4% sodium bicarbonate) prepared according to the present invention was stored at room temperature for 4 weeks' and then analyzed for fungal and bacterial growth. After 4 weeks at room temperature, no bacteria or fungi were detected. The omeprazole solution (8.4 mg sodium bicarbonate at 2 mg / m 1 ) prepared according to the present invention was stored at room temperature for 12 weeks' and then analyzed for fungal and bacterial growth. After storage for 12 weeks at room temperature, no bacteria or fungi were detected. These experimental results illustrate the bacteriostatic and fungogenic properties of the omeprazole solution of the present invention. Example XTA. A study of more than 18-year-old healthy males and females who were over 18 years old, who received omeprazole in random form as follows: (A) A 20 mg liquid formulation of approximately 20 mg of omegapril In 4.8 mEq sodium bicarbonate, the amount of water is sufficient to 1 〇ΙΏ 1 ; -78- 1309168 5 , invention description (77) (B) about 2 mg of omegapril 20 mg liquid formula in 8 ml per 1 ml. 4% sodium bicarbonate; (C) Prilosec® 20 mg capsule; (D) Capsules prepared via non-intestinal coated omeprazole 20 mg in #4 empty gelatin capsule (Lilly) 'Equivalently dispersed in 2 40 mg sodium bicarbonate powder USP to form an inner capsule. The inner capsule was then embedded in a #〇〇空明胶胶囊 (Lilly) with a homogeneous 600 rag sodium bicarbonate USP and 1 10 mg of pregelatinized starch NF. After appropriate screening and consent, 'healthy volunteers will receive one of the following four treatments randomly assigned by Latin Square. Each subject will cross each course of treatment in a randomized sequence until all subjects receive all four courses (one course per week). Treatment A (20 mg of omeprazole in 4.8 mEq sodium bicarbonate at 10 mi volume); course B (20 mg of omeprazole in 10 ml of 8.4% sodium bicarbonate in l〇ml volume); course C (complete Omeprezazole capsules; course D (for capsules in capsule formula, see above). For each dose/week, the subject will stop intravenous saline for blood sampling. For each course of treatment, blood samples were taken 16 times for 24 hours (the last two samples were taken from 12 hours and 24 hours after drug administration). B. Patient Qualification 4 healthy women and 4 healthy men agreed to conduct this study. C. Inclusion of the signature Signing the consent. -79- 1309168 V. INSTRUCTIONS (78) D. Exclusion criteria 1. Currently ingesting H2-receptor antagonists, antacids, or sucralfate. 2. Recently (within 7 days) receiving treatment with moxaprazole, omeprazole or other proton pump inhibitors. 3. Recently (7 days) to receive warfarin treatment. 4. Cases of variceal bleeding. 5. Peptic ulcer disease or current active G. I. Bleeding cases. 6. Cases of vagus nerve resection or pyloric ostomy. 7. Patients who have received research drugs within 30 days. 8. Ketoconazole and itraconazole ° 9. Patients who are allergic to omeprazole. E. Pharmacokinetic Assessment and Statistical Analysis Blood samples were collected by centrifugation within 2 hours, then plasma was separated and frozen at -10 °C (or lower) until analysis. The drug dynamics change section includes: peak concentration time, average peak concentration, AUC (O-t) and (0-infinity). Use variation analysis to detect differences in statistics. Bioavailability was assessed by testing the 90% confidence interval of the natural logarithm of AUC with two unilateral tests. F. HPLC analysis using omeprazole and internal standard (H168/24). The omeprazole and internal standards were modified by the procedures described in Am antea and Narang (Amantea MA, Narang PK, a modified step using quantitative reverse phase high performance liquid chromatography to quantify omeprazole and metabolites, -80 - 1309168 V. INSTRUCTIONS (79) J, Chromatography 426; 216-222 (1988)). Briefly '20 ul of omeprazole 2 mg/ral NaHC03 or Choco-Base omeprazole suspension and 100 ul internal standard 'with 150 ul carbonate buffer (pH = 9.8), 5 ml hexane, And 980 ul sterile water vortex mixing. After centrifuging the sample, the organic layer was extracted and air dried with a stream of nitrogen. Each small nine was recovered with a 1 50 u 1 mobile phase (40% methanol, 52% 0.025 phosphate buffer '8% acetonitrile' pH = 7.4). The recovered sample was taken from a 75 ul injection C18 5U column using the same mobile phase at a concentration of 1.1 ml/min. Under these conditions, omeprazole was isolated for about 5 minutes, and the internal standard of isolation was about 7.5 minutes. The standard curve exceeding the concentration range of 0-3 mg/ml (previously performed by S0S) is a straight line, and the coefficient of the day of variation and daytime is at all concentrations < 8%. A typical average R2 of the standard curve previously performed with SOS was 0.98 (omeprazole 2 mg/ml NaHC03-8.4%). Applicants anticipate that the above experiments demonstrate faster absorption of formulations U), (b) and (d) when coated with fines than the intestine of formula (c). In addition, the applicant expects that although the rates of absorption between the dosage forms (a) to (d) are different, the degree of attraction between the formulations U) to (d) should be similar (measured by the area under the curve (AUC)). Example X11 Intravenous PPI combination and oral male gastric mucosal activator 16 male and female subjects over 18 years of age healthy, randomized to receive the following tablets of pantoprazole: (a) 40 rag intravenously for 15 to 30 minutes combined with 20 ml oral dose -81 - 1309168 5, invention instructions (8 〇) sodium bicarbonate 8.4%; and (b) 4 〇 mg intravenously for 15 to 30 minutes combination 20 ml oral dose of water. Subjects will receive the above (a) or (b) in a single dose and cross (a) and (b) in a random manner. The data of the tobraidazole blood sputum concentration versus time after the administration was collected, and the gastric pH regulation was measured by the pH probe present inside. Furthermore, similar studies were planned in which the gastric mucosal cell activator sodium bicarbonate was replaced by chocolate or other gastric wall cell activators, and topirazole was replaced with other PPIs. The gastric parietal cell activator can be administered 5 minutes prior to intravenous administration of the PPI, during administration, or within about 5 minutes after administration. Applicants anticipate that these studies may demonstrate that when combined with oral gastric parietal cell activators, only a significant amount of intravenous PPI is required to achieve therapeutic efficacy. In addition, the administration of intravenous PPI and oral gastric parietal cell activators can be packaged in many different dosage forms for slower administration and most efficient packaging and transport of products. These kits can be in unit dose or multiple dose dosage forms. Example XIII Omega Predrine suspension: > Stabilizer suspension was prepared from 8.4% sodium bicarbonate mixed with omeprazole to a final concentration of 2 mg/ml to determine omegapril after 6 months. Stability of the azole solution. The resulting preparation was stored in clear glass at room temperature, refrigerated and frozen. The sample is taken from the stored preparation after thorough shaking at the indicated time. The sample is then stored at 7 (TC. Frozen sample is maintained frozen until analysis -82 - 1309168. V. Description (81). When the collection process is complete, the sample is shipped to the laboratory and placed on dry ice overnight for analysis. Shake sample 3 Samples were dispensed for 0 seconds and analyzed by HPLC according to well-known methods. Omeprezazole and internal standard (H1 68/24). Omegapril and internal standards were measured by modified steps of the steps described by Amantea and Narang (Amantea MA, Narang PK, an improved procedure for the quantitative omeprazole and metabolites using reverse phase high performance liquid chromatography, J. Chromatography 426; 2 1 6 - 222 (1 988 )). 20 ul of omegapri Azole 2 mg/ml NaHC03 and 100 ul of internal standard solution, mixed with 150 ul carbonate buffer (pH=9.8), 5 ml of dichloroethane '5 ml of hexane, and 980 ul of sterile water. After the sample, the organic layer was extracted and air dried with a stream of nitrogen. Each small IX was recovered with 150 ul of mobile phase (40% methanol, 52% 0.025 phosphate buffer, 8% acetonitrile, pH = 7.4). The recovered sample was taken 75 ul. Inject C185u column using the same mobile phase at 1.1 ml/min The omeprazole was isolated for about 5 minutes, and the internal standard of separation was about 7.5 minutes. The standard curve exceeding the concentration range 〇-3 mg / m 1 was a straight line, and the coefficient of the day of variation and the daytime was at all concentrations <8 %. The average R2 of the standard curve is 0. 980. The 6-month sample shows an initial concentration of 2 mg/ml greater than 90% (ie 1.88 mg/ml, 1,94 mg/ml, 1.92 mg/ml). Example VT ΕΡΙ Composition and most effective buffering agent for administration in combination with hydrazine A. The composition of the present invention is designed to produce a rapid release active drug to delivery -83- 1309168. Location (usually the stomach), which does not require an enteric coating or a delayed release dosage form to prevent acid degradation of the drug. For example, acid labile PPIs can be formulated or buffered with one or more sufficient environmentally friendly PPIs. Co-administered to deliver the PPI to the stomach (or other environment) through a liquid, powder or solid dosage form that produces an immediate release of the active drug to the delivery site for the ultimate purpose of rapidly absorbing PPI. Therefore, Applicants found that when buffer The pH produced in the stomach or other environment is equal to the pKa of the PPI plus a sufficient amount of buffer or specific PP to be administered when administered to adequately protect the PPI from acids and provide undegraded and bioactivating PPI to the blood. Is mixing prevents acid degradation of PPI (eg, the final pH of the pKa of pPI + 0.7 log値 reduces degradation to about 1 〇%). These buffers should interact with the hydrogen ions at a rate that exceeds the interaction of the hydrogen ions with the PPI. The solubility of the buffer and PPI is therefore an important consideration because solubility is the key to determining the rate of interaction of hydrogen ions with another compound. The PPI formulation of the present invention typically contains two basic components: a PPI and an essential buffer. The necessary buffer may include a buffer or combination of buffers (the buffers interact with HC 1 (or other acids in the environment) faster than the PPI interacts with the same acid]. When placed in the liquid phase (usually in water), the buffer is necessary to produce and maintain at least the pH of the pKa of PP I. In one embodiment, the desired degradation (ionization) can be reduced from about 50% to about 10% by increasing the ambient pH to the pKa of the same PPI plus about 0.7 log Torr (or greater). As used herein, "essential pH" refers to the minimum pH required to minimize or eliminate the acid-induced degradation of PPI. Buffer used -84- 1309168 V. INSTRUCTION DESCRIPTION (83) The agent can increase the ambient pH to the necessary pH so that 30%, 40% or 50% of the PPI is not degraded' or is substantially protected (ie greater than 50% stabilized) The amount of PpI exists. In another specific example, the required pH is the pKa of the PPI. In yet another embodiment, the required pH is the sum of the pKa plus 7.7 log P of the PPI. The log 値.7 log 値 plus pKa ′ performance is reduced by about 5.01187% PPI stability compared to pKa plus 1 i〇g ,, thus resulting in about 90% stability, which is widely accepted for pharmaceutical products. In some cases, it is acceptable to accept a number less than log 0.7. Part of the present invention provides a buffer that is sufficient to provide neutralizing ability (Required Buffer Capacity ("EBC")) to maintain the environment (usually the stomach) during the passage of PPI from the environment and into the bloodstream. High pH. B. Essential Buffers The necessary buffers can be divided into two groups: a primary essential buffer (p r i ma r y Essential Buffer)' and a secondary essential buffer (Secondary Essential Buffer). Each formulation is combined, directly or indirectly, with at least one of the primary necessary buffers. When the primary essential buffer is used alone or in combination, the buffering activity is provided below the enthalpy that causes tissue irritation or injury, and the lower limit of the necessary pH greater than the PPI. Secondary essential buffers are not required for each formulation, but can be combined with the primary necessary buffer to produce a higher pH and increase the neutralizing power of the formulation. The type and dosage of buffers used to protect acid-labile substituted benzopyrene π pp I s (and other drugs) can be used to efficiently transport ρρι to -85- 1309168. V. INSTRUCTIONS (84) The gastric lining cells act, especially the pp I administered, which is designed to break the immediate release of the stomach, rather than being designed to break in the higher pH environment after the stomach (eg duodenum) Delayed release of the product. The compositions and methods of the present invention use the basic characteristics of the buffers used, as well as the calculations of their respective solubilities and pKa's to determine the necessary pH, buffering capacity, and individual PPI dose volume measurements. Such an improved method can be applied to the determination of powders, lozenges, capsules, liquids, etc. in a range of environments (e.g., oral, esophagus, stomach, duodenum' jejunum, rectal fistula, nasogastric tube, or pre-dose storage. The stored dosage forms can be exposed to a variety of environments' but typical storage conditions include storage at room temperature (65 _ 80 Y) with little or no exposure to conventional heat, cold, light or moisture. The method of the present invention includes all substituted benzimidazole PP I s, salts thereof, esters 'guanamine' mirror image 'racemates', prodrugs, derivatives and the like, and is not limited to the following estimations. PP I s. The necessary buffer capacity ("EBC") is the ability of the PPI/buffer formulation to combat degradation from the environment. The buffering capacity of the PPI/buffer formulation is primarily derived from formula ingredients that are capable of binding to environmental acids (H + ions). EBC promotes acid neutralization (acid production) and maintains the environment j)H>pK;a + ().7 to protect PP I s from acid degradation during the presence. The primary necessary buffer is designed to maintain the pH of the stomach (or other environment) within a desired range of micro-fixation for a period of time such that the PPI can be absorbed from the stomach or other environment. Therefore, the necessary buffer is usually combined with HC 1 (or other acid) more rapidly than the administered ppI, so that the necessary buffer can protect the PPI. -86- 1309168 V. INSTRUCTIONS (85) Any weak test or combination thereof may be used as a suitable buffer. 0 Required buffers include, but are not limited to, electrolytes containing sodium, potassium, calcium, magnesium or barium cations. Amino acid, protein, or egg yolk hydrolysate can provide an essential buffer for the ability to rapidly neutralize acids. When pp I s is mixed with an essential buffer, the PPI s can be in a free base dosage form, such as omeprazole or blue soprenazole in a sodium salt dosage form, such as aesthepyrone, sodium, and omeprazole sodium. Biprirez sodium, topoterone sodium, etc.; or magnesium salt dosage form such as esculine meprior magnesium or omeprazole magnesium or calcium salt dosage form or other salt dosage form 〇 necessary buffer can be used alone or in combination with The secondary essential buffer combination provides the necessary buffering capacity. 0 Sodium phosphate and sodium carbonate are examples of secondary essential buffers for adjusting the pH of any primary essential buffer. A secondary essential buffer can assist the first necessary buffer to produce the desired pHE during use. Secondary essential buffers are similar to the first need for buffers to neutralize HC1 (or other acids in the environment), but they produce a pH of the cartridge that cannot be used alone, as excessive pH will cause gastric mucosal irritations. They are used to increase pH and provide additional buffering capacity when combined with the primary necessary buffer. A secondary buffer must not be required to protect the PPI from acid-induced degradation during the initial phase. Because they did not act quickly, they did not play a major role during the PPI protection period. Other buffers ("non-essential buffers,") may be added to the primary and/or secondary essential buffers to provide the potential for acid production to extend beyond the acidity of the necessary buffers. Many additional buffers may be used alone or in combination 'Achieves the effective buffering capacity of PPIs -87- l3〇9l68 -~__________ V. Description of invention (86) or acid labile drugs. The desired properties of buffers include the rapid neutralization of acidic environments, allowing for consideration Drugs greater than pKa + 〇7 0 Non-limiting primary and secondary essential buffers are shown in Tables 8 and 9 below. - 88 - 1309168 V. INSTRUCTIONS (87) Table 8 Examples of essential buffers necessary for buffer solubility 氺2S§ MW Sodium Bicarbonate 9.96 g/100 mL 8-8.4 84 Sodium sesquicarbonate 6.3 g/100 mL 9.9-10 174 Dibasic Sodium Phosphate 10 g/100 mL 8.6-9.3 142 Sodium Tripolyphosphate 6 Gm /100 mL 9.7-10 368 Tetrasodium pyrophosphate 5 g/100 mL 9.8-10.3 266 Sodium citrate 72 g/100 mL 5 294 Calcium citrate 10 rag/100 mL 6.8 498 Calcium carbonate 1.5 mg/100 mL 6.1- 7.1 100 oxidation 0.62 mg/100 mL 9.5-10.5 40 Sodium Gluconate 60 g/100 mL 6-8 218 Sodium lactate 40 g/100 mL 7 112 Sodium acetate 119 g/100 mL 8.9 82 Dipotassium hydrogen phosphate 150 g/100 mL 9.3 174 Coke Tetrapotassium phosphate 185 g/100 mL 10.4 330 Potassium hydrogencarbonate 36 g/100 mL 8.2 100 Calcium lactate 6 g/100 mL 7 218 Calcium phosphate 6 g/100 mL 7 210 Calcium gluconate 3 g/100 mL 7.4 430 Lactic acid Magnesium 10 g/100 mL 5.5-7.5 269 Magnesium Gluconate 16 g/100 mL 7.3 414 *Solubility as a function of temperature § pH varies with concentration and temperature Note: Acceptable if hydrated and anhydrous forms meet the criteria for primary buffers

-89- 1309168

V. INSTRUCTIONS (88) ____: __ Minor must be buffered. These buffers are corrosive and cannot be used alone, but are suitable for low-level addition to the primary essential buffer in Table 8. Required buffer solubility 氺pH§ MW sodium carbonate 45.5 g/100 mL 10.6-11.4 106 Potassium carbonate 11.5 138 Sodium phosphate (three tests) 8 g/100 mL 10.7-12.1 -------- 163 Calcium hydroxide 185 mg/100 mL 12 74 Hydrogen Sodium Oxide 11.4-13.2 40 * Solubility as a function of temperature § pH varies with concentration and temperature Note: If the hydrated and anhydrous forms meet the criteria for a secondary essential buffer, the acceptable amino acid can also be used as a primary or secondary buffer. 'The dose can be calculated based on the following information. -90 - 1309168 V. INSTRUCTIONS (89) Table 10 Single letter symbol Three letter symbol Amino acid MW pH Solubility (g/io〇g h2o at 25 ° C) A Ala Alanine 89 6 16.65 C Cys Cysteine 121 5.02 Very D Asp Aspartic acid 133 2.77 0,778 E Glu glutamic acid 147 3.22 0.864 F Phe phenylalanine 165 5.48 2:965 G Gly Glycine 75 5.97 24.99 Η His histidine 155 7.47 4.19 I lie Isoleamine Acid 133 5.94 4.117 K Lys lysine 146 9.59 Very L Leu leucine 131 5.98 2.426 Μ Met methionine 149 5.74 3.381 Ν Asn Aspartic acid 132 5.41 3.53 Ρ Pro Proline 115 6.30 162.3 Q Gin Proline 146 5.65 2.5 R Arg arginine 174 11.15 15 S Ser Serine 105 5.68 5.023 Τ Thr lysine 119 5.64 Very V Val lysine 117 5.96 8.85 W Trp Tryptophan 204 5.89 1.136 Υ Tyr tyramine Acid 181 5.66 0.0453

-91 - 1309168 V. INSTRUCTIONS (9〇) REFERENCES: IUPAC-IUB Biochemical Nomenclature Commission (CBN), the nomenclature of synthetic modification of natural peptides (1 966); human 1^11.810 (: service ^1. ;610?3. 1 2 1:6 - 8 (1 967) ; BIOCHEM. 1 04:1 7 - 1 9 ( 1 967 ); Correction 135:9 (1973); BIOCHEMISTRY 6:362-364 (1967) BIOCHEM. BIOPHYS. ACTA 1 33:1 - 5 ( 1 967 ) ; BULL . SOC. CHIM. BIOL. 49:325 - 3 30 ( 1 967 ) (French); EUR. J. BIOCHEM. 1:3 79 - 381 (1967); Correction 45:3 (1 974); Hoppe-Seyler's, Z', PHYSIOL. CHEM. 348:262 - 265 (1 967) (German); J. BIOL. CHEM_ 242:555 - 557 ( 1 972); IUPAC-IUB Organic Chemistry Nomenclature Commission (CNOC), Nomenclature of Organic Chemistry, STEREOCHEM. REC. E: (1974); PURE APPL. CHEM · 45:11-30 (1976). See also Biochemical Nomenclature and Related Document, PORTLAND PRESS. 2:1 - 1 8 (1 992 ) C. Essential pH (pHE) Substituted benzimidazole PPIs are unstable under acidic conditions. PPIs administered orally must avoid strong acid in the stomach. Whether the acidity is from stomach acid or through tube feeding or other sources Introduced acid. Usually, when the pH of the stomach environment is high, the PPI is stable, so there is more time to be absorbed into the blood and reach the proton pump that acts on the cells of the gastric mucosa. "pH" refers to the minimum pH required to minimize or eliminate the acid-induced degradation of the environment of interest for the PPI to be present in the environment. It is generally referred to herein as the pH range. These pHs are the ambient pH in which the PPI/buffer formulation is present. For example, the environment can be a storage container or a stomach. The environment presents a set of conditions to -92-1309168. 5. Description of the invention (91) PPI/buffer, such as temperature, pH, and presence or absence of water. The presence time means that PP I is present. The time of the special environment, that is, the gastrointestinal tract * which is the blood flow before entering the environment. The shelf life is an example of another time of existence. In this case, the special environment may be a container of dry powdered formula. As used herein, "pH result" refers to the pH of a PPI/buffer formulation added to the environment of interest. "Formulation pH" refers to the pH at which the PPI/buffer formulation is in a liquid dosage form. What is the PPI dose calculated for? The range 1 is designed to ensure adequate PPI protection for acid degradation, such as transport to the proton pump that appears. In a specific example, the PHE is the sum of the pKa of the supplied PPI plus about 0.7. The pKa is defined as the pH at which 50% of a chemical is in ionized form. When the ambient pH is equal to the pKa of the PPI, a PPI of 50% ionization (degradation) occurs. The stability range factor ("SRF") is the range in which the pH rises, where the lower limit is the sum of the pKa of PPI + 0.7 log, and the upper limit is the pH of the tissue stimulus that eliminates acid degradation and does not produce extreme alkalinity. The SRF is calculated based on the desired shelf life (or time of presence), the ambient pH, and the amount of acid expected to be encountered, along with the expected exposure time after administration of the drug and before the drug reaches the blood (i.e., time of presence). The upper limit of SRF is the tolerance function of gastric mucosa to alkaline substances, which is determined by the pH of the formula and the concentration of alkaline substances present. For implementation purposes, ph=1 0.9 describes the upper limit of the SRF. The buffer dose is known to be an important aspect of the tissue destruction potential of alkaline substances. Thus the SRF for any given PPI begins with the sum of the pKa of -93 - 1309168 V, invention note (92) PPI +0.7, and extends up to about pH 1 0.9. The use of the necessary pH and SRF determines the desired range of H+ ions (or other acidic components) for the stability of the PPI/buffer formulation. Sufficient cushioning capacity Maintain the "required buffering capacity" of the required pH as described below. Examples of pHE calculations for specific PPIs by SRF are as follows: pHE of PPI = pKa of PPI + 0.7 SRF = range: pHE to 10.9 SRF of omeprazole = (pKa omeprazole + 0.7) to 10.9 = (3.9 + 0 · 7) = 4.6 to 10. 9 Srp of resorprazole = (pKa moxaprazole + 0.7) to 10.9 = (4.1 + 0.7) = 4.8 to 10-9 SRF = (by Ripridazole) pKa ribiprazole +0.7) to 10.9 = (4.9 + 0.7) = 5.6 to 10.9 tablets of topiramate SRF = (pKa tablets topirazole + 0.7) to 10.9 = (3 + 0.7) = 3.7 to 10.9 In most cases, the lower limit of the above range is increased by one pH unit, and reduction by factor 10 may produce any intra-soil local effects of PPI degradation in the low pH region. By observing the weak base, it is most effective to neutralize the acid at + 1 log 高于 above PKa, and it can also support +1 log 値. For example, in the stomach of an adult fasting, it is expected to encounter about 100-150 ml of 0.11 to 0.16 N HC1, which is equivalent to about 12-24 mEq of HC1. Therefore, an equivalent amount of base can neutralize the acid. If about 12-24 mEq of sodium bicarbonate is used as a buffer, the resulting pH is sodium bicarbonate conjugate acid (carbonic acid) -94 - 1309168 5. The pKa of the invention (93), about 6.14 or higher. This 値 is higher than the lower pHE of omeprazole 4. 6 . Thus, when encountering HC1 of 12-24 mEq, administration of 12-24 mEq of sodium bicarbonate and omeprazole can protect more than 95% of the drug. Since sodium bicarbonate complexes with HC1 at a rate that exceeds the rate of interaction with omeprazole, it is considered a suitable buffer. It should be noted that the amount of acid encountered with age and disease may be significantly more or less than the range of 12-24 mEq, but usually from about 4 mEq to about 30 mEq. The use of magnesium oxide or magnesium hydroxide in an amount of 12-24 mEQ also provides sufficient neutralization to bring the pH to about 7 (slightly reduced only due to the extremely slight hydrolysis of magnesium). However, magnesium hydroxide did not start quickly and care should be taken to determine that early degradation of PPI did not occur. Early degradation can be avoided by making a two-layer tablet: the inner layer of PPI and sodium bicarbonate, and the outer layer of magnesium hydroxide xerogel or magnesia with a suitable disintegrating agent that rapidly disintegrates the magnesia in the stomach. Further, the inner layer may contain a magnesium buffer and the outer layer contains PPI and sodium hydrogencarbonate. In addition, the slower effect of the buffering agent can be used to enhance the ability of the buffer to bind to the acid. Calcium carbonate (and many other calcium buffers) are buffers that act similarly slowly (compared to sodium bicarbonate) but are effective. Therefore, it is preferred to use an outer layer (or vice versa) of a formulation containing a rapid acting buffer and PPI in the inner layer. Alternatively, a buffer mixture can be used for the outer layer. If the formula or powder is to be reconstituted, a mixture of a rapid acting buffer and a slower buffer (for example, sodium bicarbonate and magnesium oxide, respectively) may be used. Modifications to the formulation may require alkaline or acidic chemicals (including but not -95-1309168)

5. The description of the invention (μ) is limited to the adjustment of the product m by the chemical agent described in this incorporation. Modification of the buffer pH according to PHE may or may not be done in a particular situation, depending on the species, age, disease, and other changes between patients. The solubility of D · pKa and PPI s as described above, 'pP supplied' [the pKa indicates the inherent stability of acid degradation: ppi is more stable with lower pKa. The solubility of PPI also indicates the rate at which PPI is complexed with acid and degraded by acid. In the presence of acid, the two physicochemical properties (pKa and solubility) interact with the physicochemical properties of the buffer (pH, buffering capacity and buffering rate) to determine the degradation of PPI during this period. The less soluble PPI is in water and reduces the initial degradation when placed in an acidic environment. Table 11 below outlines the time at which 50% of the drug is degraded (tl/2), the solubility of pKa and several PPIs in water. Table 11___ PH Tablets Topolezole sodium Omeprazole Moletropeprazole Rebprezazole sodium 1.2 4.6 minutes 2.8 minutes 2.0 minutes 1.3 minutes 5 2.8 hours 1.0 hours 1.1 hours 5.1 4.7 hours 1.4 hours 1.5 hours 7.2 minutes 6 21 hours 7.3 hours 6.4 hours 7 73 hours 39 hours 35 hours Pka 3 3.9 4.1 4.9 Solubility easily dissolved slightly dissolved very slightly soluble and soluble -96 - 1309168 V. Description of invention (95) Kromer W. et al., substituted benzimidazole PH-dependent activation rate difference and biological in vitro correlation, PHARMACOL〇gY 1998; 56:57-70 〇 Although tablets topirazol sodium has a pKa of 3, it is more stable in acidic environments than other PPIs, but also It is easily soluble in water, so it undergoes 50% degradation in less than 5 minutes in an acidic stomach with a pH of U. Thus, the interaction of the buffer with the topotefazole sodium with H+ ions (or other acidic substances) is faster than the interaction of the tablet topiramate sodium with these acids and is maintained rapidly during the lifetime. Compounding is important, otherwise additional buffering may be required. The overall pH of the stomach contents should be maintained at at least pKa + 0.7 (i.e., 3.7) from the time the PPI is in contact until the gastric acid is in contact. An essential buffer for the liquid formulation of the tablet topiramate sodium includes a buffer having a conjugated acid having a pKa > 3.7 and having a rapid recombination potential. Most magnesium, calcium and aluminum salts are not suitable, unless the tablet topiramate sodium (with or without additional buffer) is placed inside the tablet or in capsules containing these antacids, as well as fast acting buffers and fast The disintegrating agent surrounds. Another method for the topical topiramate is to reduce its solubility, for example by selecting a lower soluble salt or non-salt dosage form of topiraprazole. Ribip predazole sodium is also readily soluble in water and undergoes 50% degradation in less than 5 minutes in an acidic stomach having a pH of 1.2. Due to its higher pKa of 4.9, it is very unstable to acid degradation. The interaction of buffers suitable for riboprazole sodium with H+ ions (or other acidic substances) is faster than the interaction of ribiprazole sodium with these acids to prevent early degradation, and has -97- 1309168 V. INSTRUCTIONS (96) High neutralizing ability allows ribiprazole sodium to survive during its lifetime. Sodium bicarbonate or potassium is a good choice in this case. Another alternative dimension of 'ribiprazole sodium (and any sodium salt of a proton pump inhibitor that will dissolve more readily than the base salt) when in a liquid dosage form is to reduce the solubility of ribopridone sodium, for example, Lower soluble salt dosage forms or non-salt dosage forms. This reduces early degradation' because ribiprazole must first be dissolved in water before it undergoes acid degradation. In this particular example, a buffer suitable for ribiprazole sodium needs to have a high degree of neutralization ability to allow ribiprazole sodium to survive during its lifetime. A PPI with a high pKa, such as sodium ribiprazole, can be used in a two-part liquid formulation. The liquid portion has a PPI and a high pH' but a low niEq buffering capacity. The liquid portion is added to the second portion with a low pH but a higher mEq buffering capacity. Adding these two parts together before they are administered to produce a formulation with low pH and high buffering capacity neutralizes stomach acid but does not corrode the tissue too much. Examples of such formulations are provided below. For highly soluble PPIS, a formulation can be made in a solid dosage form, such as a buffer containing lozenge, capsule or powder, which breaks at a rate above the PPI and reaches the solution, thereby allowing the PPI to dissolve and interact with the acid of the environment before it Provides the necessary pH to protect the PPI. Further, the tablet or capsule may be formulated into a buffer-containing exterior and a PPI-containing interior, or a mixture of PPI and a buffer. Additional methods include formulating the buffer in smaller particle sizes (e. g., micro) and PPI in larger particle sizes. This causes fragmentation of the buffer component before the PPI component breaks. The formulation of all such methods is intended to be -98- 1309168. V. Inventive Fragmentation (97) creates a stable environment during the existence of the PPI. Dosage dosage forms can affect the suitability of the buffer for the formulation. For example, magnesium oxide is a buffer with high buffering capacity, but it starts slowly when formulated as a tablet. However, the formula is a powder or a low-extruded tablet, or a tablet-containing disintegrating agent such as a gelatinized starch, which is more rapidly broken. The omeprazole base is only slightly soluble in water, so less drug is subject to early and subsequent degradation. The soluble portion of omeprazole is more susceptible to damage in the early degradation of the stomach environment. The remaining insoluble dissolution is expected to occur within a few minutes of encountering gastric secretion fluid. This dissolution time provides partial protection against early degradation, but requires relatively low volume of water during transport or in the product formulation. After a few minutes in the stomach environment, with complete dissolution, omeprazole undergoes 50% degradation in less than 3 minutes. Since omeprazole has a pKa of 3.9, it is moderately stable. Suitable buffers for omeprazole are rapid acting and have at least moderate neutralizing ability to allow omeprazole to survive during their lifetime. The use of "quick action" in the context of a buffer means that the buffer can raise the ambient pH to a temperature above or equal to a particular ρ during the time sufficient to prevent significant degradation of the PPI. In one embodiment, the fast acting buffer raises the pH to at least the pKa of the PPI plus 0.7 log 于 in 10 minutes. Preferably, the resulting pH of the buffer manufacturing environment is equal to or higher than the necessary pH, such that: (1) the initial change in pH to equal to or higher than phe+0.7 is initiated before the acid-induced degradation of the PPI occurs, and (2) Equivalent or higher than -99 - 1309168 V. Description of the invention (9ε 0 pHE+〇. 7 obtained pH knot: the fruit persists throughout the period of existence, typically at least 30 minutes in the case of adult empty stomach. Desirable buffer Quick action to minimize early acid-induced degradation. The fastest acting buffer is soluble in water (or soluble in the environment). However, high solubility is not necessarily that magnesium oxide and calcium carbonate are only slightly soluble. Even at a slower rate, it can be significantly complexed with gastric acid. If a dry formulation, such as a tablet, is used, the buffer particle size can be reduced to enhance the dissolution rate, while at the same time increasing the PPI size and adding a disintegrating agent. Reinforcing weaker dissolved buffers. 0 Blue Thorium yui-m azole base is very slightly soluble in water. Less drug is subject to early degradation. The soluble fraction is more susceptible to early degradation. The remaining insoluble dissolution is expected to occur within a few minutes of encountering the gastric secretion water. This dissolution time provides a fraction against early degradation. Protection, but a relatively low volume of water is required during transport or in the product formulation. After a few minutes, 50% degradation is experienced with less than 2 minutes of total dissolution of the blue saponin. The pKa of .1 is moderately stable. Suitable buffers for moxaprilazole should be fast acting and should have moderate to high neutralizing ability to allow the precipitation of moxaprilazole in the presence of PPI from solution to solution. Frtm The pH of the stomach contents (or other environment) should be maintained at approximately higher than 4 80 when the gastric acid is sustained. The acid neutralization capacity of the buffer is calculated. The acid neutralization capacity of the soluble buffer ("ANC") ) can usually be used to assist in the selection of A preferred amount of buffer is provided to the EBC. The ANC uses the formula weight (FW •) and the valence measurement buffer capacity. -100- 1309168 V. Description of the invention (") Examples of ACC calculations for sodium bicarbonate are as follows: Sodium bicarbonate, Na + HC (V, FWt. = 84, valence = 1. The formula for converting from equivalent to gram is: (equivalent ("EW")) (1 / 1 000 mmol) (l mmol / 1 mEq) = NaHC03 g . EW = (FWt.) / (atomic price) = 84 / 1 = 84 g/mol (84 g/mol) (l mol / 1 000 nimol) (l mmol / 1 mEq) (4 mEq) = 0.34 g palpitations 03 is required for 4 raEq buffering capacity. Therefore, 0 · 840 g NaHC03 is required for 10 mEq and 2.52 gm for 30 mEq. The range of 4-30 mEq is used as the range of acid mEq encountered by most patients. The ANCs of other buffers were similarly calculated. The ANC assay is from Drake and Hollander, the buffering capacity and cost effectiveness of antacids, ANN INTERN. MED. 1 09:2 1 5 - 1 7 (1 981). Typically, the formulations of the present invention require a buffering capacity of from about 4 to about 30 mEq, although some patients may use a higher amount of strontium bicarbonate in solution having the pH & pKa of omeprazole and rapidly neutralizing the acidic environment. As described above, rapid compounding with HC1 is a desirable property of the necessary buffer. Ideally, but not necessarily, as required by the formulation, the tablet is required to contain a tablet in the tablet. The required buffer is complexed with the acid at a faster rate than the PPI to be protected. When the necessary buffer is selected, it is also useful to know the buffering capacity since the buffer has different pHs at various concentrations. The strength of the buffer against pH changes is called buffer capacity (none). It is described by Koppel Spiro and Van-101- 1309168. V. INSTRUCTION (1 〇〇) S 1 yk e is defined as increasing the ratio of a strong acid (or base) to a pH change caused by the addition of an acid. Use the following formula to measure buffer capacity. · Buffer capacity = increase the addition of strong acid (in grams per liter equivalent) to the buffer solution to produce a pH change (change measured in absolute enthalpy), or buffer capacity = acid change / pH change. This formula has been improved to improve accuracy, and this forms a mathematical basis for the consideration of buffers. See Koppel, BioChem, Z. (65) 409-439 (1 9 1 4), Van Slyke, J. BIOL. CHEM. 52:525 (1922). When the PPI/buffer formulation is placed in the environment, the PPI suffers from acid degradation in the environment. As indicated in Figure 9, the PPI solubility encountered in the environment, the pKa of the PPI, and the amount and concentration of the acid (H+ ions) are variable factors that can be used to determine a suitable candidate as an essential buffer. Early degradation occurs when the soluble portion of the PPI (which can be obtained by immediately interacting with H+ ions) is hydrolyzed via H+ ions. The solubility of PPIs varies, so that the more soluble ones have the potential to degrade PPI via a higher interaction with H + ions. The pKa of the PPI after addition of the PPI/buffer formulation and the pH of the stomach environment (or other location of interest) (pH results) can be used to determine the desired buffer. By measuring the pH results for a period of time, the pH data versus time plot is shown in Figure 9. A pH plot for a period of time can be used to evaluate various buffers. These diagrams detail the possible buffer or buffer compositions, using the Rossett-Rice test (Rosset NE, Marion L • • more frequently used antacids and special treatments for the in vitro evaluation of the efficacy of lozenges, - 102- 1309168 V. INSTRUCTIONS (1〇1) ANTACIDS 26:490 -95 (1 954)), modified to continuously add simulated gastric juice. See USP XXIII, United States Pharmacopoeia, 23rd Edition, United States Pharmacopeia, Inc. Briefly, this test used 150 mL of simulated gastric fluid consisting of 2 Gm sodium chloride and 3.2 Gm gastrin' dissolved in 7 mL of IN HC1 and distilled water to 1 000 mL. The pH of the simulated gastric juice was 1.2. 150 mL of the liquid was stirred in a vessel with a magnet stirrer at 300 rpm ± 30 rpm and maintained at 37.1 °C. The pH electrode is maintained in the upper region of the solution. Add the test buffer or test formulation to the container to begin the assessment. At 10 minutes, the simulated gastric fluid that was continuously dripped was added to the test container at a rate of 1.6 ral/rain to simulate gastric secretion. Remove from the test vessel at approximately 1.6 mL/mi η to maintain the volume of the test vessel unchanged. The assessment lasts at least 90 minutes. This method takes into account the kinetic evaluation of buffering capacity in a stomach model designed to simulate fasting. Partially described in Bene yto Je et al. (Assessment of the novel antacid Almagate, ARZNEIM-FORSCH/DRUG RES 1 984; 34(10A): 1 350 - 4 ), Kerkhof NJ et al. (pH of the aluminum hydroxide gel) - State titration, J. PHARM. SCI. 1977; 66: 1528-32), used to evaluate antacids. Using this method, pH tracking can be exploited to evaluate buffers as well as to complete the product. In addition, a sample of the test solution can be taken during the experiment to assess the extent of PPI degradation at different times. A buffer having an appropriate condition as exemplified in Fig. 9 can be considered as a suitable buffer for maintaining a pH greater than or equal to pHE for 30 minutes or longer. In a specific embodiment, the pH is recorded over a 1 second interval as described in Fig. 9 - 103 - 1309168 5. Invention Description (1〇2). B-buffered buffer can be applied as an essential buffer. Therefore, once selected as an essential buffer, the necessary amount of EBC is required to be calculated. As used herein, EBC is the amount of buffering capacity or alkaline buffer included in the dosage and calculated to maintain the necessary pH range and thereby protect any substituted benzimidazole PPI in the stomach (or other) environment. Patients who require continuous PPI administration (eg, daily) may require better buffering capacity for the first dose or the first dose than for subsequent doses, as the PPI may experience more acid at the start of administration. Subsequent doses require less buffering capacity because the initial PPI dose will reduce gastric acid production. Therefore EBC may be reduced in subsequent doses. The buffering capacity of the product can be formulated as required (e.g., regarding patient age, sex, or race). Experimental data from adult subjects show that the first dose of omeprazole has an effective EBC range of from about 4 to about 20 mEq ("EBC-0 range") of sodium bicarbonate, which in most cases is suitable for about 12 to about 25 mEq range. Subsequent doses of omeprazole require a smaller EBC, which is sodium bicarbonate in the range of from about 4 to about 15 mEq. In one embodiment, the latter's EBC range has been shown to be most suitable for omeprazole suspensions with varying degrees of gastrointestinal delivery and acid yield (based on known basis and maximum of 2 and 25 mEq/hr, respectively. Acid production) is administered to the patient. These studies have been published in Phillips 0. et al., CRIT. CARE MED. 1996; Lasky et al., J. TRAUMA 1998. ο According to the EBC-0 range, the above ANC calculations can be used. In addition, about 100 to 150 mL of 0.1 N HCl is expected to be encountered in the fasting stomach (equivalent to about 12-104- 1309 168 V, invention description (1 〇 3) 24 mEq acid). Changes in acidity encountered in the environment will affect the required buffering capacity. The above EBC range is for adult patients. However, children produce less acid per unit time than adults. Therefore, the amount required for the patient's population to be buffered may vary. A number of references are available to assist the skilled artisan to identify suitable buffers with PPI to determine the desired properties described herein. Since the buffer has different pHs at various concentrations, it is also useful to know that the buffer is also present. For example, see Ho 1 be rt et al., Research on acid buffer: I · Time factor for neutralizing gastric acidity, J·AMER, PHARM.ASSN·36:1 49 -5 1 (1 947 ); Lin et al. Evaluation of human, antacid buffering capacity and acid neutralization pH time, J. FORMOSA MED. ASSN. 97(10)704-710; Physical Pharmacy, pp 169-189; Remington: The Science and Practice of Pha rmacvC 2000). F. Desirable Volume The desired volume of the PPI dose ("DV") can affect the delivery of PPI to the cell membrane proton pump. The DV of the dose is based in part on EBC. For liquid formulations, the desired volume should be delivered with sufficient buffer to act as an antacid to neutralize substantial amounts of gastric acid or other acids. For solid formulations such as lozenges, a normal amount of water or other liquid should be taken to aid in the swallowing of the tablet. The liquid preparation of the present invention uses a small amount of about 2 m 1 or an excess of about 60 m 1 . Volumes of less than 2 ml and more than 60 ml should be carefully considered and desired to be suitable for each patient, such as an elderly or very young or different. Very large volume can result in higher amounts of less soluble PP Is (eg, omeprazole, lansop-105-1309168, invention instructions (1 04) ribazole base dosage form) in solution, causing damage Early degradation. For example, a volume of less than about 2 ml can be used for neonatal or premature fetuses or small animals because their stomach is small. Similarly, large DV may be required for the dosage form of the formulation and the dilution buffer concentrate to achieve EBC. The relationship between EBC and DV is shown as follows: If EBC (mg buffer) = buffer concentration (mg / ml) x DV (ml), then DV (ml) = EBC (mg) / buffer concentration (mg / ml) . In addition, mEq can be substituted for mg in the formula. G. Secondary components of the formula The second component is not required, but can be used to enhance pharmacological effects or as a pharmaceutical adjuvant. Secondary components can include, but are not limited to, gastric wall cell activators and other components. The gastric cell wall activator is discussed above as a compound that causes an increase in the activity of the proton pump, so that the proton pump is relocated from the storage site of the gastric parietal cells (ie, the thin tube) to the H+ and K+ exchange sites located in the secretory tubule. . The gastric wall cell activator can also provide other functions. For example, sodium bicarbonate is an essential buffer and a gastric cell wall activator, chocolate is a gastric mucosal cell activator and flavoring agent, and phenylalanine-containing aspartame is a sweetener and a gastric wall cell activator. The gastric wall cell activator can be divided into four groups: 1) a fast acting buffer, which is a weak base 'strong base or a combination thereof' can lead to a rapid onset of its efficacy (the pH does not suddenly drop after the buffer is depleted, These buffers usually cause the pH of the stomach to rise above 5); 2) amino acid 'protein hydrolysates and proteins; 3) calcium-containing compounds such as calcium chloride or calcium carbonate; and 4) compositions such as

-106- 1309168 V. INSTRUCTIONS (105) Coffee, cocoa, caffeine and mint. Other ingredients contain formula ingredients that are secondary to the primary ingredient. Other ingredients include, but are not limited to, thickeners, flavoring agents, sweeteners, anti-foaming agents (such as simethicone), preservatives, antibacterial agents or antimicrobial agents (eg, cefazolin) , amoxicillin, sulfamethoxazole, sulfisoxazole 'erythromycin, and other macrolides such as clarithromycin or stacks Azithromycin, as well as minor components. Suitable flavoring agents can be added to the dosage unit and may or may not be necessary for buffering to pHE. The natural pH of the flavoring agent is suitable for the pHE range of PPI s including but not limited to apple, caramel, meat, chocolate, sarcophagus, maple syrup, cherry, coffee, mint, licorice, stone fruit, cream, butterscotch And peanut butter flavors, used alone or in combination. Likewise, all materials included in the formulation of any PPI product include, but are not limited to, activators, anti-foaming agents, latent energy (ρ 〇tentiat 0 rs ), antioxidants, antimicrobial agents, chelating agents, sweeteners, Thickeners, preservatives, or other additives that can be buffered to pHE. Η. Examples of calculations pH The doses of pHE, EBC, and DV can affect the transport of sputum and the action of the proton pump on the gastric wall. The following calculations modify the necessary buffer dose to apply to any substituted benzimidazole ρρ I for oral administration to promote sputum efficacy. -107- 1309168 V. INSTRUCTIONS (1〇6) Example 1: Delivery of 20 mg dose of omeprazole to sodium bicarbonate (pKa = 3.9): Step 1: pH of omeprazole = omepripri The azole has a pKa + 0.7 = 4.6. The osmideprazole SRF = pHE to 10.9 = 4.6 to 10.9. The conjugate base (carbonic acid) of sodium bicarbonate has a pKa of 6.14 at a formulation pH of 4.6 to 10.9. Thus the amount of sodium bicarbonate is equivalent to the amount of acid encountered, resulting in a pH of 6.14, which is in the range of 4.6 to 10.9 for SRF. This makes sodium hydrogencarbonate a suitable choice as a buffer. Step 2: EBC = 4 to 30 mEq buffering capacity is quite awkward. Step 3: To determine the amount of sodium bicarbonate administered with omeprazole, calculate the ANC of sodium bicarbonate. ANC of sodium bicarbonate (MW = 84 at 4-30 mEq) = (EW) (1/1000 mrao1) (1 mmol/1 mEq) (EBC) ° EW = MW / (atomic valence) = 84/1 = 84 g/mol (8 4 g / m ο 1 ) ( 1 m ο 1 / 1 0 0 0 mm ο 1 ) ( 1 mm ο 1 / 1 m E q ) ( 4 to 30 mEq) = 0.34 g to 2.52 g Step 4 = As for the liquid formulation, if DV = 20 ml, then DV = required buffer (EB) (mg) / buffer concentration (mg / m 1 ) Buffer concentration = EB / DV = 340 mg to 2520 mg / 20 Ml = 17 mg/ml to 126 mg/ml. Therefore, for 20 mg of omeprazole fully buffered in 20 ml of solution, the sodium bicarbonate concentration should be between 17 mg/ml and 126 mg/ml. Example 2: Delivery of 20 mg dose of omeprazole to dibasic sodium phosphate (pKa=3·9): -108- 1309168 V. Description of the invention (1〇7) Step 1 ··pHE of omeprazole = omeprazole pKa + 0.7. The SRF of omeprazole is (3.9 + 0.7) to 10.9 = 4.6 to 10.9. Step 2: EBC = 4 to 30 mEq buffering capacity is quite awkward. Step 3: To determine the amount of sodium dibasic phosphate administered with omeprazole, calculate the ANC of dibasic sodium phosphate. ANC of dibasic sodium phosphate (MW=142) = (EW)( 1 / 1000 ramol1 ) (1 mmol/1 mEq)(EBC) 0 EW = MW/(atomic valence) = 142/2 = 71 g/mol ( 71 g/mol) (l mol/1000 mmol) (l mmol/1 mEq) (4 to 30 mEq) two 0.28 g to 2.13 g Step 4: As for the liquid formulation, if DV = 20 ml, then DV = EB (mg ) / Buffer concentration (mg / ml) Buffer concentration = EB / DV = 280 mg to 2130 mg / 20 mU 14 mg / ml to 107 mg / m1. Therefore, for 20 mg of omeprazole fully buffered in 20 ml of solution, the sodium dibasic phosphate concentration should be 14 to 107 mg/ml. The pKa of dibasic sodium phosphate is 7.2 丨. Therefore, the amount of sodium dibasic phosphate is equivalent to the amount of acid encountered, and a pH of about 7.2 is produced. Thus, sodium dibasic phosphate is selected as a buffer. Example 3: Delivery of a 30 mg dose of sodium bupoxime to sodium bicarbonate (pKa = 4·1): Step 1: pHE of lansoprazole = pKa + 0.7 of lansoprazole. The SRF of (lanespril) is (4.1 + 0.7) to 10.9 = 4.8 to 10.9. Step 2: EBC = 4 to 30 mEq buffering capacity is quite awkward. -109- 1309168 V. INSTRUCTIONS INSTRUCTIONS (1〇8) Step 3: Calculate the ANC of sodium bicarbonate for the determination of the amount of sodium bicarbonate administered with the spinosole. ANC of sodium bicarbonate (MW = 84) = (EW) (1 / 1000 mmol) (1 mm.1/1 mEq) (EBC). EW = MW / (atomic valence) = 84 / 1 = 84 g / mol (84 g / mol) (l mol / 1000 mmol) (l mmol / 1 mEq) (4 to 30 mEq) =0·34 g to 2 · 52 g Step 4: As for the liquid formulation, if DV = 20 ml, then DV = required buffer (EB) (mg) / buffer concentration (mg / m 1 ) buffer concentration = EB / DV = 340 mg to 2520 mg/20 ml = 17 mg/ml to 126 mg / m 1. Therefore, for 30 rag blue soprenazole that is sufficiently buffered in a 20 m 1 solution, the sodium bicarbonate concentration should be between 17 mg/ml and 126 mg/ml. Example 4: Delivery of a 40 rag dose of sodium bicarbonate to topirazole (pKa = 3): Step: 1 : pH of the tablet topiramate = pKa + 0.7 of the tablet topirazole. Tablets Topirazol SRF = (3 + 0.7) to 10.9 = 3.7 to 10.9. Step 2: EBC = 4 to 30 mEq buffering capacity is quite awkward. Step 3: To determine the amount of sodium bicarbonate administered with the tablet topirazole, calculate the ANC of sodium bicarbonate. Sodium bicarbonate (:(Μΐί=84;) = (ΕΝ)( 1/1000 _〇1) (1 _〇1 / 1 mEq ) ( EBC ) EW = MW / (atomic price) = 84/1 g/mol (8 4 g / m ο 1 ) ( 1 πι ο 1 / 1 〇〇〇mm ο 1 ) ( 1 mm 0 1 / 1 eq ) ( 4 to 30 mEq) = 0.34 g to 2.52 g -110- 1309168 V. INSTRUCTIONS (1〇9) Step 4: As for the liquid formulation, if DV = 20 m 1, then DV = required buffer (EB) (mg) / buffer concentration (mg / m 1 ) buffer concentration = EB/DV = 340 mg to 2520 mg/20 ml = 17 mg/ml to 126 mg/ml. Therefore, for a 40 mg tablet topiramate fully buffered in 20 ml, the sodium bicarbonate concentration should be 17 mg/ Ml to 126 mg/ml. Example 5: Delivery of a 20 mg dose of dipyridyl sodium to the ruthenium (p K a = 5): Step 1: ribiprozol pHe = ribby Prazol PKa + 0.7. Ripridazole SRF = (4.9 + 0.7) to 10.9 = 5.6 to 10.9. Step 2: EBC = 4 to 30 mEq buffer capacity is equivalent. Step 3: For determination and RUBI The amount of sodium alkaloid phosphate was calculated by predazole, and the ANC of dibasic sodium phosphate was calculated. ANC of dibasic sodium phosphate (MW=174)=(EW)(1/1000 mmol) (l mmol/1 mEq) (EBC) EW = MW / (atomic valence) = 178 / 1 g / mol (178 g / mol) (l mol / 1000 mmol) (l mmol / 1 mEq) (4 to 20 raEq) =0.712 g to 5.34 g dikaline sodium sodium Sodium Step 4: As for the liquid formulation, if DV = 20 ml, then DV = EB (mg) / buffer concentration (mg / ml) Buffer concentration = EB / DV = 0.712 2 to 2 g/20 ml = 35.6 mg/ml to 100 mg/ml. In this case, the solubility of disodium phosphate (sodium dibasic phosphate) will limit the amount soluble in 20 m 1 . Obviously 'this will Exceeds the solubility of disodium oxalate (sodium dibasic phosphate). Therefore 'for adequate buffering in 20 ml solution - 1 1 1 -

1309168 V. INSTRUCTIONS (110) 20 mg of ribopridazole in the solution, the concentration of sodium dibasic phosphate in the pH range of about 6.9 to 10.9 should be 35.6 mg/ml to 1 〇〇 mg/ml. The pKa of dibasic sodium phosphate was 7.21. Thus, the amount of sodium dibasic phosphate is equivalent to the amount of acid encountered, resulting in a pH of about 7.2. Thus, sodium dibasic phosphate is selected as a buffer. It is important to note that the solubility of the buffer is related to their immediate use. To enhance shelf life, higher pH is expected to be within the acceptable pHE2 range for the PPI administered. For example, ribopyrazole suspensions containing various buffers can be evaluated for color change because the degradation of PPIs causes a color change of brown or black. All buffer suspensions began to be white. After 2 weeks, the following observations were obtained: 20 mg of riboprazole was stored in suspension in various buffers under refrigeration. The pH of the buffer was 14 days after the original color. pH 14 days later sodium bicarbonate 800 mg/10 ml white Brown 8.3 disodium phosphate 800 mg/10 ml white white 10.3 disodium phosphate 700 mg; trisodium trisodium 100 mg/10 ml white white 10.3 similarly calculated for any substituted benzimidazole PPI and known buffers, including However, it is not limited to those exemplified above. It will be apparent to those skilled in the art that the order of the above steps is not critical to the invention. The above calculations can be used for formulations containing one or more PPIs and one or more buffers. I. Veterinary Formula The horse continues to produce stomach acid throughout the day. This is the basic from the stomach when no feeding -112- 1309168 V. Description of the invention (111) Acid secretion, which is the cause of corrosion of squamous mucosa and ulcers in the stomach. When the horse grazes, it will normally secrete a persistent supply of saliva, which can buffer gastric acid. When horses are often riding, training to perform or ready to sell, they are usually placed in the stable for many days. In these cases, the buffering mechanism of natural saliva is interrupted and usually causes acid indigestion. A buffer capacity of almost 40 to 100 mEq provides about 2.5 hours of horsepower per horse. The usual dose of omeprazole ranges from 0.7 to 1.5 mg/kg/day (up to 4 mg/kg/day can be required), and the representative weight of the horse is 500 kg. Similar doses are also expected for ribiprazole and lansoprazole. Dogs can also develop ulcers at a dose of about 1 mg/kg/day. The following formula is designed for horses, but a smaller amount can be used for dogs with EBC of 10 to 20 mEq. Formula 5: Veterinary formula for omeprazole This formula is especially suitable for animals because of the high dose of PPI. Applicable to human EBC=75 mEq Essential pH (omiprazole pKa=3.9+0.724.6) PPI: omeprazole powder 500 mg (range 350 to 700 mg) Primary essential buffer: sodium bicarbonate 5 g (59.5 mEq) Sodium dibasic phosphate (anhydrous) 2 g (14 mEq) Selective secondary essential buffer: Tribasic sodium phosphate 200 mg (1.2 mEq) (* Any secondary essential buffer may be added higher or lower Adjusting pH to desired stability and additive antacid or buffering effect) -1 1 3- 1309168 V. INSTRUCTION DESCRIPTION (112) Powders of the above compounds are combined as known in the art to produce and add thickeners For example, guar gum 350 mg, artificial maple syrup powder 100 mg, thaumatin powder 10 mg (to mask the bitter taste of omeprazole), and a homogenous mixture of sucrose 25 mg. Add distilled water to 1 〇〇 ml to achieve a final omeprazole concentration of 5 mg/ml. Different volumes of water may be added to achieve a concentration of omeprazole ranging from about 0.8 to about 20 mg/ml. In addition, the recipe can be divided into two parts. When in use, the dry portion can be partially recovered from the liquid. Formulation 6: Physic formula for lansoprazole essential pH (lansoprazole pKa = 4.1 + 0.734.8) EBC = 71.4 mEq PPI : randopridazole powder 750 mg Primary essential buffer: sodium bicarbonate 6 g (71.4 mEq) (* Any secondary necessary buffer may be added at a higher or lower level to adjust the pH to the desired stability and additive antacid or buffering effect). The powder of the above compound is known as the art. Combine to produce a homogeneous mixture with added thickeners such as xanthan gum 300 mg, artificial peanut flavor powder 1 rag, and sucrose 35 Gm. Distilled water was added to 100 ml to achieve a final concentration of 7.5 mg/ml of the final blue druspole. The suspension should be refried after recovery. Different volumes of water can be added to achieve a concentration of lansoprazole ranging from 〇.8 to 20 m g / m 1 . -114- 1309168 V. INSTRUCTIONS (1Ί3) In addition, this formula can be divided into two parts. When in use, the dry portion can be partially recovered from the liquid. Formulation 7: The pH of the veterinary formula for the treatment with moxapril (blue praprazole pKa = 4.1 + 0.724.8) EBC = 63.3 mEq PPI : lansapril powder 750 mg Primary essential buffer: sodium bicarbonate 5 g (59.5 mEq) Minor Essential Buffer: Sodium Carbonate 400 mg* (3.8 mEq) (* Any minor buffer may be added to adjust the pH to the desired stability and additive antacid or buffering effect) Powders of the compounds are combined as known in the art to produce a homogeneous mixture with added thickeners such as hydroxypropyl methylcellulose 300 mg, artificial maple syrup powder 100 rog, and sucrose 35 mg. Distilled water was added to 100 ml to a final concentration of 7.5 mg/ml of the final blue druspole. Different volumes of water can be added to achieve a concentration of moxaprilazole ranging from 0.3 to 20 mg/ml. In addition, the recipe can be divided into two parts. When in use, the dry portion can be partially recovered from the liquid. -115- 1309168 V. INSTRUCTIONS (114) Formulation 8: Essential pH for veterinary formulations of Isoproxazole magnesium (Isoproprazole pKa = 3.9 + 0.724.6) EBC = 53.2 mEq PPI : Ai Someropridazole magnesium powder 500 rag Primary essential buffer Z Sodium bicarbonate 5 g (47.6 mEq) Dibasic sodium phosphate 800 mg (5.6 mEq) (* Any secondary essential buffer can be added higher or lower Adjusting the pH to the desired stability and additive antacid or buffering effect) The powders of the above compounds are combined as known in the art to produce a thickening agent such as hydroxypropylcellulose 300 mg, margarine candy flavor A homogeneous mixture of 100 mg, Martin powder 5 mg, and sucrose 30 Gm. Distilled water was added to 100 ml to a final concentration of 7.5 mg/ml of the escarpopremiazole. Different volumes of water can be added to achieve a concentration of from about 0.8 mg to 20 mg / m1 of Isotrope. -116- 1309168 V. INSTRUCTIONS (115) Formulation 9: veterinary formula for tablet topiramate sodium or topiraprazole base powder pH required (tabler prednisol sodium pKa=3+〇.723.7) HBC =53.8 mEa Tablets Topotezol sodium or Topiprazole base powder 1000 mg Primary essential buffer: Sodium bicarbonate 4 g (47.6 mEq) Minor essential buffer: Tribasic sodium phosphate 1000 mg* (6.28 mEq) (* Any secondary necessary buffer may be added in higher or lower amounts to adjust the pH to the desired stability and additive antacid or buffering effect.) The powders of the above compounds are combined as known in the art to produce and add Thickeners such as hydroxypropylcellulose 300 mg, margarine candy flavor 100 mg, Martin powder 5 mg, and sucrose 30 Gin homogenous mixture. Distilled water was added to 100 ml to achieve a final tablet topiramate concentration of 10 mg/ml. Different volumes of water can be added to achieve a tablet topiramate concentration ranging from 0.2 to 20 mg / m1 ° Formulation 10: Veterinary formula: Buffer-free base EBC = 71.4 mEq Primary essential buffer: Sodium bicarbonate 6 g ( 71.4 mEq) Selective secondary essential buffer: Tribasic sodium phosphate 1000 mg* (* Any secondary essential buffer may be added higher or lower to adjust pH to desired stability and additive antacid or buffer Effect) -117- 1309168 V. DESCRIPTION OF THE INVENTION (116 The powders of the above compounds are combined as known in the art to produce and add thickeners such as propylcellulose 3Q〇mg, margarine candy flavor 100 mg, meal A homogenous mixture of Martin powder 5 mg and sucrose 3 〇 Gm. Add distilled water to 100 ml. Add ρρι or other acid labile drugs, which are obtained from synthetic pharmacists from available ppl s or from It is selected from powder or enteric coated oral solid dosage forms of acid labile drugs. Different volumes of water can be added to achieve a concentration range of pp. 8 to 2 〇 mg/mL. If other acid labile drugs are used, Required concentration range To deliver a normal dose in an acceptable volume of 1 mL to 30 niL. The amount of buffer required to protect the drug in question' can also determine the minimum suitable volume. For example, 'this formulation can be part of the product dosage form (liquid or dry) Or a two-part product dosage form (liquid or dry). In the two-part embodiment, the drug to be added to the formulation may be added to the dry formulation and the liquid portion, or the drug may be added to the liquid portion to be buffered to high. The pH required for the intestine-coated drug formulation to be fragmented (typically pH 6-8 or higher). For all veterinary and human oral dosage forms disclosed herein, sweeteners, gastric wall cell activators, and so on may be added. Thickeners, preservatives, and flavoring agents. Sweeteners include, but are not limited to, corn syrup, single syrup, sugar, diet Martin, and aspartame. Thickeners include, but are not limited to, methylcellulose, xanthogen Gum, carrageenan, and guar gum. Preservatives can be added to delay damage. Preservatives include, but are not limited to, sodium benzoate, methylparaben, and propylparab. En). Flavoring agents in these formulations include, but are not limited to, apple, caramel, maple syrup, peanut butter -118-1309168, invention instructions (117), meat, etc. j. Other formulations must be buffered for all formulations in the text. The total amount of the agent ranges from about 4 mEq to about 30 mEq per dose.__ Formulation 11: Oral buffer without uncomplexed PPI (usually used to protect acid labile drugs) Multi-dose composition primary buffer required'· Sodium dibasic sodium phosphate or sodium bicarbonate 10g (range 2g to 10g) Selective secondary essential buffer: 200 mg Tribasic sodium phosphate or sodium carbonate Other ingredients: Sucrose 26 g Maltodextrin 2 g Cocoa powder processed with alkali 1800 mg Corn Syrup Solid 6000 mg Sodium Caseinate 100 mg Soy Lecithin 80 mg (* Any secondary essential buffer can be added higher or lower to adjust the pH to the desired stability and additive antacid or buffer Effect) Mix the powder thoroughly and store in a light and humidity container, for example in a foil package. Preservatives may be added to delay damage. Preservatives include, but are not limited to, sodium benzoate, methyl pala, and propyl paladium. Thickeners such as xanthan gum, guar gum, or hydroxymethyl propyl cellulose may be these formulations -1 1 9 - 1309168 5. Flavoring agents of the invention (118) include but are not limited to chocolate, coke Sugar, maple sugar, American shell pecan sauce and others as already explained. Different volumes of water can be added to achieve a PPI fe-degree SI from 0.8 to 20 mg/nil. Weigh approximately 60 g of the formula. Usually a PPI (or other acid labile drug) is added in an amount equivalent to 1 sputum (ranging from 1 to 30). Add distilled water to 100 ml. Formulation 12: general pp for the protection of acid labile drugs; [oral buffer; protein-free multi-dose embodiment primary essential buffer: sodium bicarbonate 5 g (range 2 g to 10 g) ( 59.5 mEq) Selective Secondary Requirement Buffer: None* (* Any secondary necessary buffer may be added higher or lower to adjust pH to desired stability and additive antacid or buffering effect) Other Ingredients: Sucrose 26 g Maltodextrin 2 g Alcohol-processed cocoa powder 1800 mg Corn syrup solid 6000 mg Soy lecithin 80 mg Note: Cocoa powder is a gastric mucosal cell activator. The powder is thoroughly mixed and then stored in a container that is protected from light and humidity, for example, in a foil package. Weigh approximately 60 g of the formula. A PPI (or other acid labile drug) in an amount equivalent to 10 doses (-120-1309168, invention (119) range = 1 to 30 doses) is usually added. Add distilled water to 1 〇〇 ml. Different volumes of water can be added to achieve a PPI concentration of 0.8 from 0.8 to 20 rag/ml. ___ Formulation 13: Buffer for uncomplexed PPI used to protect acid labile drugs; multi-dose without protein, lactose. Example PPI: None (added later, for example by synthetic pharmacist) Primary essential buffer = sodium bicarbonate 8 g (range 2 g to 10 g) Other ingredients = sucrose 26 g maltodextrin 2 g corn syrup solid 6000 mg partially hydrogenated soybean oil 400 mg dipotassium phosphate 300 mg caramel Perfume 270 mg Soy lecithin 80 mg Sodium aluminosilicate 20 mg Titanium dioxide 10 mg Thoroughly mix the powder and store it in a light and humidity container, for example in a foil package. Selective secondary essential buffer: sodium tribasic phosphate 1 000 mg -1 21 -

1309168 V. INSTRUCTIONS (12〇) Formulation weighing approximately 60 g. A PPI (or other acid labile drug) in an amount equivalent to 10 doses (range = 1 dose to 3 doses) is usually added. Add steamed water to 100 ml. Different volumes of water can be added to achieve PPI concentrations ranging from 〇3 to 20 mg / m1 〇 Formulation 14 : Buffers for uncomplexed PPIs commonly used to protect acid labile drugs; multi-dose embodiments without protein PPI: None (will be added later, for example by synthetic pharmacists) Requires buffer: ^ Sodium alkali phosphate 8 g (range 2 g to 1 〇 $ he ingredients: sesame 26 g maltodextrin 2 g oil Candy 270 mg iE Rice Syrup Solid 6000 mg Thoroughly mix the powder and store it in a light and humidity container, for example in a foil package.

Weigh about 60 g of the formula. A PPI (or other acid labile drug) in an amount equivalent to one dose (range = 1 to 30 doses) is usually added. Add guanshui to 100 ml. Different volumes of water can be added to achieve PPI concentrations ranging from 〇 $ to 20 rag/m1. —122- 1309168 f,Inventive Note (1 21 ) 酉 方 15 15 : Buffer for uncomplexed PPI generally used to protect acid labile drugs; multi-dose without protein - PPI : None (will be later Add, for example, by a synthetic pharmacist.) 霁 Buffer: Sodium bicarbonate 8 g (range 1 g to 10 g) Buffer: Trisodium phosphate 1.5 g (range 0 g to 5 g) Other ingredients: Sucrose 26 g Maltodextrin 2 g Creamy candy 270 mg Corn syrup solid 6000 mg Thoroughly mixed powder 'then stored in a light and humidity container, for example in a foil package. Weigh about 60 g of the formula. A PPI (or other acid labile drug) in an amount equivalent to 1 sputum (range = 1 to 30 doses) is usually added. Add distilled water to 100 ml. Different volumes of water can be added to achieve PPI concentrations ranging from 0.8 to 20 mg/ml. -123- u----- 1309168 V. INSTRUCTIONS (122) --- One formula K: ~ Stage blue botoprazole 30 mg tablet azole has a pKa of 4; then ph=4.1+0.7 2 4.8 A buffer solution which produces a solution having a pH of 4.8 or greater and which produces the necessary buffering capacity includes j|not limited to sodium hydrogencarbonate, carbonic acid carbonate 1, sodium alkali phosphate, and monopotassium phosphate. Sufficient powder weighing 11 lozenges: ΡΡΙ : Lansoprazole 330 mg Primary essential buffer: Sodium bicarbonate USP 5500 mg * Sodium dibasic phosphate 2200 mg The resulting powder was thoroughly mixed. 720 mg of this homogeneous mixture was then poured into a tablet stocker (1/2 inch diameter) and compressed as is known in the art by full operation of the mold press. The resulting lozenge contains: moxapril 30 mg sodium bicarbonate USP 500 mg disodium hydrogen phosphate 200 mg This tablet contains 6 mEq sodium bicarbonate and 1.4 mEq dibasic sodium phosphate. This difference in lozenges may include that the tablet contains all of the sodium dibasic phosphate or all of the sodium bicarbonate or other buffer from the necessary buffer list. The amount of effective buffering capacity per tablet can vary from as little as 4 mEq to as much as 30 mEq. Additional tablet disintegrating agents such as sodium cross-carboxymethyl ether, pre-gelatinized starch, or polyvinylpyrrolidone, and tablet binders such as potato flour-124- 1309168 can be added. V. Inventive Note (123), Gelatin , or pvp. Further %, can be placed - the film is applied to the tablet to reduce light penetration and facilitate ease of swallowing. Formulation 17: - Stage omeprazole 20 mg tablet omeprazole has a pKa of 3.9: then ph = 3.9 + 0.7 2 4.6 can produce a solution of pH 4.6 or greater to; g but not limited to hydrogencarbonate The buffering agent for producing the necessary buffering capacity of sodium, sodium carbonate and citric acid C includes: disodium hydrogen (sodium dibasic phosphate) and dipotassium phosphate. Sufficient powder weighing 11 tablets: PPI: omeprazole powder USP 220 mg Primary essential buffer: sodium bicarbonate USP 6500 mg magnesium oxide powder 1650 mg cross-carboxymethyl ether cellulose 300 mg The mixed powder was thoroughly mixed. 788 mg of this homogeneous mixture was then poured into a tablet reservoir (1 / 2 inch in diameter) and compressed as is known in the art by full operation of the mold press. The resulting lozenge contains: omeprazole USP 20 mg sodium bicarbonate USP 590 mg magnesia 15 0 mg cross-carboxymethyl ether sodium cellulose 27.27 rag This lozenge contains 7 mEq sodium bicarbonate and 3.75 mEq magnesium oxide. The amount of effective buffer capacity can vary from as little as 4 mEq to as much as 30 mEq. Tablet extenders, tablet binders, and film coatings of Formulation 16 can also be added. -125- 1309168 V. INSTRUCTIONS (124) Formulation 18: One-stage omegapril 40 mg tablets weighing enough of 11 tablets: PPI: omeprazole powder USP 440 mg Primary essential buffer: Carbonated Sodium Hydrogen USP 6500 mg Magnesium Oxide 1650 mg Pregelatinized Starch 500 mg The resulting powder was thoroughly mixed. 826 mg of this homogeneous mixture was then poured into a tablet stocker (1/2 inch diameter) and compressed as is known in the art by full operation of the mold press. The resulting lozenge contains: omeprazole USP 40 mg sodium bicarbonate USP 590 mg magnesia 150 rag pregelatinized starch 45.45 mg This lozenge contains 7 mEq sodium bicarbonate and 3.75 mEq magnesium oxide. The amount of effective buffer capacity can vary from as little as 4 mEq to as much as 30 mEq. It is also possible to add a tablet excipient, a tablet binder, and a film of formula 丨6 coated with oxime meperrolazole or a low solubility proton pump inhibitor (for example, an alkaline dosage form), which can be used in place of the above formula. Omeprezazole or blue soprenazole. Tablet lotion, tablet binder, and film coating of Formulation 16 can also be added. In addition, any of the formula powders disclosed herein can be produced by the intimate mixing of the powder and the omission of the tablet by the ingot of the invention when the tablet is manufactured in the form of -1 26 - 1309168. This powder is packaged in a suitable container, such as a foil package or sachet, to protect the formulation from air humidity and light. When added to some water (for example, 3 to 20 mL), the formula can be administered orally or fed or NG tube or the like. A caramel flavor of 0.1% w/w can be used. For PPIs that taste bitter, such as topiraprazole, omeprazole, escarpone, and ribiprazole, thaumatin is used to mask bitterness from 5 to 10 ppm. Sweetening, such as sucrose or aspartame, can also be used. A tablet disintegrating agent such as sodium carboxymethyl ether acetate, and a running agent such as magnesium stearate may be additionally used. Formulation 19: omeprazole powder fragrant "3 side (single dose) PPI: omeprazole powder USP (or oxime meprior magnesium) 20 mg or 40 mg primary essential buffer: sodium bicarbonate USP powder (60 microns) 1000 mg Magnesium Oxide USP Powder 500 mg Selective Secondary Essential Buffer: Tribasic Sodium Phosphate 200 mg* Other Ingredients: Dextrose 60 mg Xanthan Gum (Rhodigel Ultrafine) 15 mg Dietary Martin (Spice Enhancement) 5) 10 ppm thoroughly mix the powder, recover all the powder from 5 ml to 20 ml of steamed crane water' and then inject the suspension from the intestine to the patient. -127- 1309168 V. INSTRUCTIONS (126) Formulation 20: Fragrance-free omeprazole powder (single dose) Omniprezazole powder USP 20 mg or 40 mg Sodium bicarbonate USP powder 1500 mg Gastric parietal cell activator: Calcium Chloride 200 mg* Other Ingredients: Dextrose 60 mg Xanthan Gum (Rhodigel Ultrafine) 15 mg Dietary Martin (Flavour Enhancer) 5 to 10 ppm Thoroughly mix powder. The whole powder was reconstituted with 5 mL to 20 mL of distilled water, and then the suspension was administered to the patient by the intestine. Formulation 21: Fragrance-containing omepril quinone powder (single dose) omeprazole powder USP 20 mg sodium dibasic phosphate dihydrate 2000 mg sodium bicarbonate USP powder 840 mg to 1680 mg sucrose 2.6 g maltodextrin 200 Mg Cocoa powder processed by alkali* 180 mg Corn syrup solid 600 mg Xanthan gum 15 mg Aspartame 15 mg Dietary Martin 2 mg Soy lecithin 10 mg * Gastric parietal cell activator-1 28 - 1309168 V. Invention Description (127) Mix the powder thoroughly. Use 10 mL to 20 m L of steamed water to restore the entire powder. _ Formulation 22: Fragrance-free Blue Soprenazole Powder (single dose) Blue Soprenazole Powder USP 15 mg or 30 mg Sodium Bicarbonate USP Powder 400 mg to 1500 mg Selectively: pH adjustment with sodium tribasic phosphate Longer-term stability and enhanced buffering capacity (other essential buffers can be used). Mix the powder thoroughly. Recover all powders in 5 mL to 20 mL distilled water when in use. Ffi side 23: Fragrance-containing blue soprenazole powder (rice, PPI: lansopridazole powder USP 30 mg Primary essential buffer: sodium dibasic phosphate USP or 1500 mg sodium bicarbonate USP sucrose 2.6 g malt Dextrin 2 g Cocoa powder processed with alkali * 18 mg Corn syrup solid 600 mg Soy lecithin 80 mg * Gastric parietal cell activator thoroughly mixes the powder. Use the .5 mL to 20 mL distilled water to recover all the powder. - 1309168 V. INSTRUCTIONS (128) Formulation 24: fragrance-free ribiprozol powder (single dose) PPI: ribopyrazole sodium powder USP 20 mg Primary essential buffer: sodium dibasic phosphate dihydrate USP 2000 Mg selective secondary essential buffer: sodium tribasic phosphate 100 mg thoroughly mixed powder and reconstituted with distilled water prior to administration. Thickeners and flavoring agents can be optionally added as described in this application. The expected volume of powder is per 20 mL. This formula is designed to enhance the stability of riboprazole, by using a common ion effect, so that sodium causes "salting out" of ribopyrazole sodium. This causes ribopyrazole sodium to remain Insoluble This increases its stability. Formulation 25: Fragrance-free ribopyrazole powder (single dose) PPI: Ribipazole sodium powder USP 20 mg Primary essential buffer: Sodium bicarbonate USP 1200 mg Minor essential buffer : Tribasic sodium phosphate USP 300 mg Selective secondary essential buffer: Sodium or tribasic potassium can be added in higher or lower amounts to adjust the pH to the desired stability and additive antacid or buffering capacity. Mix the powder and reconstitute it with 15 5 L of distilled water at the time of use. -1 30 - 1309168 5. Inventive Note (129) In addition, a two-part product can be used, containing a portion of about 5 to about 15 raL of distilled water with a low concentration of A buffer (eg, trisodium phosphate (100 rag) or sodium hydroxide (50 mg)) is required to dissolve the intestinal coated lozenge of ribiprazole to thereby produce a stable solution/suspension. An alkaline suspension has a low neutralizing capacity and can be followed by the addition of ribiprazole sodium with a second portion of the primary essential buffer containing significant neutralizing ability. If necessary, other minor essential buffers may be included in the secondary necessary buffer. Agent. This formula is An enteric coated lozenge that can be used with the purchased ribiprazole is a source of PPI. This tablet needs to be disintegrated into a liquid formulation before use. Part 1 (low concentration of secondary essential buffer) causes delayed release The rapid dissolution of the tablet and the extended stability of the ribipridone sodium in the liquid dosage form. This allows the preparation to be prepared prior to administration and simply added to the primary essential buffer prior to use (Part 2). Formulation 26: fragrance-free ribiprozol powder (single dose) PPI: ribopyrazole sodium powder USP 20 mg Primary essential buffer: Calcium lactate USP 700 mg Calcium phosphate 700 mg Secondary essential buffer: Hydroxide Calcium USP 15 rag (other secondary essential buffers with sodium or potassium cations may be added in higher or lower amounts to adjust the pH to the desired stability.) -1 3 1 - 1309168 V. Description of invention (1 3〇) Mix the powder thoroughly. The powder was partially reconstituted with a liquid containing 10 mL of glycerin and 10 raL of distilled water. In addition, the liquid used for recovery may be only water (e.g., distilled) and contain some buffering agent. The liquid used for reconstitution can be supplied as a buffered product (to pH 9-11) for dissolving the delayed release tablet of Ribiriva sodium (if ribiprazole sodium is used as the source). _ Formulation 27: Fragrance-free Isoproprazole powder (single dose) PPI: Isoproprazole magnesium powder USP 20 mg Primary essential buffer: Calcium lactate USP 800 mg Calcium phosphate 800 mg Secondary essential buffer : Hydroxide USP 15 mg (Other secondary buffers with calcium or magnesium cations may be added in higher or lower amounts to adjust the pH to the desired stability.) Mix the powder thoroughly. The powder was recovered in a portion containing 10 mL of distilled water at the time of use. The liquid used for reconstitution can be supplied as a buffered product (to PH8-11) for dissolving the delayed release of fine particles of the escarpopremiazole magnesium (if the use of acesulfameprazole magnesium as a source). -132- ---- 1309168 V. INSTRUCTIONS (131) Formulation 28: omeprazole two-part tablet Two-part tablet contains an external buffer phase and an internal buffer/PPI core. Weighing 6 tablets in sufficient amount of core: PPI: omeprazole powder USP (or Isoproprazole magnesium or omeprium sodium) 120 mg Primary essential buffer: sodium bicarbonate USP 1200 mg External phase: Sodium bicarbonate USP 3960 mg (Other minor essential buffers such as trisodium phosphate, tripotassium phosphate or sodium carbonate or others may be added to increase the neutralizing capacity.) Thoroughly mix the powder for the inner core and weigh approximately 220 mg The resulting mixture was added to a 3/8" diameter stamp. The powder mixture was then formulated into small tablets in a conventional pharmaceutical procedure. The other 5 tablets were then refilled and the small tablets were placed aside. The outer layer of the agent is provided as a pH buffer. About 2 80 mg per tablet, all 1 680 mg of sodium bicarbonate USP weighs 6 tablets of sodium bicarbonate enough. Then weigh about 280 mg of the resulting mixture and Add a stamp to the 1/2" diameter. The powder is compressed into a tablet by full running compression. Place the tablet back into the 1/2 inch impression and place the smaller 3 / 8" tablet (internal tablet) on the apex of the 1/2" tablet and concentrate. Add about 380 mg -133 - 1309168 V. INSTRUCTIONS (132) Sodium bicarbonate on the apex of the 1 / 2" lozenge and 3 / 8" lozenge of the impression. The material is pressed into a lozenge by full running compression. Each lozenge weighs approximately 815 mg to 890 mg and contains 20 mg of omeprazole. A binder such as potato flour or PVP, and a disintegrating agent such as pregelatinized starch may be added. The outer layer may also contain a pharmaceutically acceptable lozenge excipient. It is also possible to use a selective coating layer, e.g., a light film coating layer and a UV resistant coating layer which are well known in the art. Magnesium oxide or magnesium hydroxide can be substituted for the external phase of sodium hydrogencarbonate. About 2 80 mg per tablet, all 1680 mg of magnesium oxide USP weighed 6 tablets of magnesium oxide. Approximately 280 mg of the resulting mixture was then weighed and added to a 1/2" diameter stamp. The powder was compacted into a lozenge by full running compression. The tablet was placed back to a 1/2 inch impression and then more A small 3 / 8" lozenge (internal tablet) is placed at the apex of the 1/2" tablet and concentrated. Add about 380 mg of magnesium oxide to the impression of the 1 / 2" lozenge and 3 / 8" lozenge The apex. The material is compressed into a tablet by full-running pressing. Each tablet weighs approximately 81 5 mg to 890 mg 'containing 20 mg of omeprazole. A binder such as potato flour or PVP' can be added. Disintegrating agents such as pregelatinized starch, sodium carboxymethylether cellulose, or microcrystalline cellulose (MCC) and colloidal cerium oxide (CSD). The outer layer may also contain pharmaceutically acceptable tablet excipients. A selective coating layer, such as a light film coating layer and an ultraviolet resistant coating layer which are well known in the art. The external phase may alternatively comprise a composition of sodium hydrogencarbonate and magnesium oxide. -134- 1309168 V. Description of the Invention (133) Formulation 29: Blue psoprene two-part tablet weighing 6 tablets in sufficient amount of core: PPI: blue Prezol powder USP 180 mg Primary essential buffer = sodium bicarbonate USP 1200 mg External phase: sodium bicarbonate USP 3960 mg Thoroughly mix the powder for the inner core, then weigh approximately 230 mg of the resulting mixture and add to 3/8" The impression of the diameter. The inner and outer lozenges are then formed as described in Formulation 28. Each lozenge weighs approximately 825 rog to 900 mg. A binder such as potato flour or PVP may be added, as well as a disintegrating agent such as pregelatinized starch. Formulation 30: Tablets topiramate two-part tablet weighing 6 tablets in sufficient amount of core: PPI: tablet topiraprazole powder USP (or topoterone sodium) 240 mg primary essential buffer: hydrogen bicarbonate Sodium USP 1200 mg External phase: Sodium bicarbonate USP 3960 mg

-135- 1309168 V. INSTRUCTIONS (134) Thoroughly mix the powder for the inner core, then weigh approximately 220 rag of the resulting mixture and add it to the 3/8" diameter stamp. Then form the inner and inner portions as described in Formulation 28. The external sputum agent has a weight of about 835 mg to 910 mg per surfactant. A binder such as potato flour or PVP may be added, as well as a disintegrating agent such as pregelatinized starch or sodium cross-carboxycarboxylate. _ Formula 31: Omega Residazole or Isoproxil two-part lozenge weighing 6 ounces of sufficient core: PPI: omeprazole powder USP (or Isophorine or omeprazole sodium) 120 mg Essential buffer: Sodium bicarbonate 1200 mg External phase '· Sodium bicarbonate 3960 mg Thoroughly mix the powder for the inner core, then weigh approximately 220 mg of the resulting mixture and add to the 3 / 8" diameter stamp. Internal and external bonds are then formed as described in Formulation 28. Each lozenge weighs approximately 815 mg to 890 mg. A binding agent such as potato flour or PVP may be added, as well as the disintegrating agent already mentioned. Other secondary essential buffers such as trisodium phosphate, tripotassium phosphate or sodium carbonate or others may be added to increase the neutralizing capacity. -136- 1309168 V. INSTRUCTIONS (135) Formulation 32: Blue-Poppreoazole Two-Piece Lozenges Weigh 6 Insufficient Amounts Core: PPI: Lansoprazole Powder USP 180 mg Primary Essential Buffer: Sodium bicarbonate 1200 mg Outer phase: . Sodium bicarbonate 3960 mg Thoroughly mix the powder for the inner core, then weigh approximately 230 mg of the resulting mixture and add to the 3/8" diameter stamp. Then form as described in Formulation 28. And an excipient. Each lozenge weighs about 825 mg to 900 rag. A binder such as potato flour or PVP can be added, as well as the disintegrating agent already mentioned. Other minor essential buffers such as trisodium phosphate can be added. Tripotassium Phosphate or Sodium Carbonate or Others to Increase Neutralization Capacity._ Formulation 33: Tablet Topiradazole Two-Piece Lozenges Weigh 6 Insufficient Amounts of Core: PPI: Topiprazole Powder USP 240 mg Essential Buffer = Sodium Bicarbonate 1200 mg External Phase: Sodium Bicarbonate 3960 mg

-137- 1309168 V. INSTRUCTIONS (136) Thoroughly mix the powder for the inner core, then weigh approximately 220 mg of the resulting mixture and add to the 3/8" diameter stamp. Then form the inner and outer as described in Formulation 28. Tablets. Each tablet weighs about 835 mg to 910 mg. A binder such as potato flour or PVP can be added, as well as the disintegrating agent already mentioned. Other minor essential buffers such as trisodium phosphate, phosphate III can be added. Potassium or sodium carbonate or others to increase neutralization capacity. Formulation 34: omeprazole 20 mg two-part lozenge core: PPI: omeprazole intestine coated fines (Isoproprazole sodium or magnesium) Alkali or sodium salt) 20 rag Outer phase: Sodium bicarbonate powder USP 1000 mg The inner core is produced as is known in the art so that the intestinal coating on the fine particles remains substantially intact. The outer phase is bonded to the inner core as described in Formulation 28. Other variations of this tincture include replacing the separate intestinal coated fines with a uniform intestinal coating around the inner core PPI. ----- Formulation 35: Blue Sophorazole 30 mg Two-part lozenge core: PPI · Lansoprazole intestine coated fine particles 30 mg : Sodium bicarbonate powder USP -~ 1000 ms -138- 1309168 V. INSTRUCTIONS (137) The two-part lozenge is based on Formula 34. Formulation 36: Ribiprilazole 20 mg Two-part lozenge core: PPI: Rebiprezazole Intestine Coated Fines 20 mg External Phase: Sodium Bicarbonate Powder USP 1000 mg This two-part tablet is based on Formula 34. Formulation 37: Omegaprene two-part tablet weighing 6 tablets in sufficient amount Inner core '·Omeprezol 120 mg Sodium bicarbonate powder USP 1200 mg External phase: Magnesium oxide 1500 mg Selective-calcium carbonate 3000 mg The core of the omeprazole and sodium bicarbonate are homogeneously mixed and as formulated 28 Forming. The external phase is combined with the inner core as in Formulation 28. Formulation 38: Combination of antacid and enteric coated dosage form omeprazole enteric coated fine or enteric coated tablets 20 mg (or equivalent dose of another PPI) Calcium Carbonate 1000 mg

-139- 1309168 V. INSTRUCTIONS (138) The above ingredients are carefully combined so that the intestinal coating is not broken or otherwise compromised. The resulting composition is then formed into a compacted lozenge or placed in a capsule as is known in the pharmaceutical literature. If enteric coated fines are used, it is usually, but not necessarily, required to be dispersed throughout the lozenge or capsule. Alternatively, if an enteric coated lozenge is used, a central core is formed which is uniformly surrounded by the calcium carbonate to the compacted lozenge or larger capsule. In another embodiment, the capsule containing the PPI enteric coated fine particles can be placed in a larger capsule containing uniform calcium carbonate. It should be noted that other buffers may be used instead of or in combination with calcium carbonate. The buffering dose used is at least about 5 mEq per composition, preferably from 7.5 to 15 mEq. For example, sodium bicarbonate is preferred over calcium carbonate and other antacids (e.g., magnesium or aluminum salts) because sodium bicarbonate lowers gastric pH more rapidly. Formulation 39: Combination of fast release and delayed release PPI and antacid core: omeprazole enteric coated fine or enteric coated tablets 10 or 20 mg (or equivalent PPI) External phase: Omega Prezolium powder 10 or 20 mg (or equivalent PPI) Calcium carbonate powder 1000 mg of external phase components are mixed non-uniformly. The inner core is produced as is known in the art so that the intestinal coating on the fine granules or lozenges remains substantially intact. The outer phase is bonded to the inner core as is known in the art. Formulation 40: soft chewable pp I - buffer dosage form 10 or 20 rag omeprazole (or another PPI equivalent) and soft -140 - 1309168 V. Description of the invention (139) Chewable acid lozenge ( For example, the Viactiv® combination, which contains calcium carbonate 500 or 1 000 mg, corn syrup, sugar, chocolate skimmed milk, cocoa butter, salt, soy lecithin, glyceryl monostearate, flavorings (eg caramel), Carrageenan, and sodium phosphate. Vitamin D3 and/or vitamin K1 may also be added. The finished chewable tablet can be administered once or three times per patient for a stomach acid-related disease.

For all formulations in the text, multiple doses can be synthesized in proportion to the art. The present invention has been described by way of illustration, and it should be understood that All patents and other references cited herein are hereby incorporated by reference in their entirety. Many modifications, equivalents, and variations of the invention are possible in light of the above teachings. Therefore, it is to be understood that the invention may be practiced otherwise than as specifically described within the scope of the appended claims.

-141 -

Claims (1)

1309168 VI. Patent Application No. 9 1 1 1 5305 "Solid Pharmaceutical Composition of Proton Pump Inhibitor" Patent Case (Amended in September 2008) VI. Patent Application Range 1. Solid Proton for Proton Pump Inhibitor The composition comprises: (i) a proton pump inhibitor in an amount of from about 2 mg to about 300 mg selected from the group consisting of omeprazole, lansoprazole, and sheet topper Pantoprazole, rabeprazole, perprazole (S-omeprazole), pariprazole, dontoprazole, habbipril a group consisting of (habeprazole), rissoprazole, and leminoprazole, or a mirror image thereof, an alkali salt, an isomer, or a salt of a mirror image, and Non-intestine coating; and (ii) at least one buffer selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate , sodium carbonate, sodium polyphosphate, potassium polyphosphate, Sodium pyrophosphate, potassium pyrophosphate, disodium phosphate, dipotassium phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide 'magnesium carbonate, magnesium citrate, calcium acetate, calcium glycerophosphate, hydroxide A group of calcium 'calcium lactate, calcium carbonate, calcium bicarbonate, and mixtures thereof. 2. The solid pharmaceutical composition of claim 1, wherein at least the buffering agent is selected from the group consisting of sodium hydrogencarbonate, magnesium hydroxide and calcium carbonate. 1309168 VI. Scope of Application Patent 3. The solid pharmaceutical composition of claim 2, wherein the buffer is a mixture of sodium hydrogencarbonate and magnesium hydroxide. 4. The solid pharmaceutical composition of claim 1, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of a gastric cell wall activator, an anti-foaming agent, a flavoring agent, and an increase Sweeteners, preservatives, antibacterial preservatives, antioxidants, chelating agents, penetrants, thickeners, glidants, lubricants, lozenge adjuvants, disintegrating agents, colorants, diluents, humectants, binders And a group of medically compatible carriers. 5. A solid pharmaceutical composition according to claim 1, wherein the proton pump inhibitor is omeprazole or a mirror image thereof, an alkali salt, an isomer, or a salt of a mirror image. 6 · The solid pharmaceutical composition of claim 1 of the patent scope, wherein the proton pump inhibitor is lansoprazole (1 ans 〇 pra ζ ο 1 e ) or its mirror image, the alkali salt of the mirror image, and the isomer Things, or salt. 7. A solid pharmaceutical composition according to claim 1 wherein the amount of proton pump inhibitor is from about 10 mg to about 40 mg. 8. The solid pharmaceutical composition of any one of claims 1 to 7 wherein at least a portion of the proton pump inhibitor is micronized. The solid pharmaceutical composition of any one of the above-mentioned claims, which further comprises a disintegrating agent, a flavoring agent and a lubricant. 10. The solid pharmaceutical composition according to claim 1 of the patent application, wherein the solid dosage form is selected from the group consisting of a powder for use in suspension, a lozenge, a chewable tablet I3〇9l68, and a patented range of ingot tablets. Or capsules. U. For example, the solid pharmaceutical composition of claim 1 can be used for the immediate absorption of gastric acid by a patient in need thereof. 1 2 . The solid pharmaceutical composition according to claim 11 of the patent application, wherein the solid dosage form is selected from the group consisting of a chewable tablet, a lozenge or a capsule. 1 3 . The solid pharmaceutical composition of claim 2, wherein the solid dosage form is a chewable tablet. 1 4 . The solid pharmaceutical composition of claim 2, wherein the solid dosage form is a capsule. 1 5 . The solid pharmaceutical composition of claim 1, wherein the therapeutically effective amount of the proton pump inhibitor is absorbed through the stomach within about 10 to 60 minutes after administration to the patient. 1 6 · The solid pharmaceutical composition of claim 1 of the patent scope, wherein the proton pump inhibitor is omepruri (哗mepra ζ ο 1 e ) or its mirror image, alkali salt of the mirror image, isomer Or salt. 1 7 . The solid pharmaceutical composition of claim 11 wherein the proton pump inhibitor is 1 ans 〇 pra ζ ο 1 e or its mirror image, alkali salt of the mirror image, Isomer, or salt. 18. The solid pharmaceutical composition of claim 11 further comprising a thickening agent to reduce precipitation of the proton pump inhibitor after recovery from the aqueous medium. 1 9 . The solid pharmaceutical composition of claim 1 of the patent scope, wherein the stomach acid is 1309168. 6. The diseases related to the scope of patent application are duodenal ulcer, gastric ulcer, stomach and esophageal reflux disease, severe corrosive esophagitis, and pathological excessive secretion disease. , Zollinger Ellison syndrome and acid dyspepsia.