WO2000026185A9 - Solution d'omeprazole et methode d'utilisation associee - Google Patents

Solution d'omeprazole et methode d'utilisation associee

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Publication number
WO2000026185A9
WO2000026185A9 PCT/US1999/025592 US9925592W WO0026185A9 WO 2000026185 A9 WO2000026185 A9 WO 2000026185A9 US 9925592 W US9925592 W US 9925592W WO 0026185 A9 WO0026185 A9 WO 0026185A9
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WO
WIPO (PCT)
Prior art keywords
omeprazole
patients
gastric
proton pump
suspension
Prior art date
Application number
PCT/US1999/025592
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English (en)
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WO2000026185A3 (fr
WO2000026185A2 (fr
Inventor
Jeffrey O Phillips
Original Assignee
Univ Missouri
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Filing date
Publication date
Application filed by Univ Missouri filed Critical Univ Missouri
Priority to AU19071/00A priority Critical patent/AU1907100A/en
Publication of WO2000026185A2 publication Critical patent/WO2000026185A2/fr
Publication of WO2000026185A3 publication Critical patent/WO2000026185A3/fr
Publication of WO2000026185A9 publication Critical patent/WO2000026185A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients

Definitions

  • the present invention relates to a pharmaceutical preparation containing a substituted benzimidazole, more specifically known as proton pump inhibitor (s) (ppi) . More particularly, the present invention relates to a substituted benzimidazole solution/suspension suitable for oral administration.
  • a substituted benzimidazole more specifically known as proton pump inhibitor (s) (ppi) . More particularly, the present invention relates to a substituted benzimidazole solution/suspension suitable for oral administration.
  • Omeprazole is a substituted benzimidazole, 5-methoxy- 2-[ (4-methoxy-3 , 5 -dimethyl-2 -pyridinyl) methyl] sulfinyl] - lH-benzimidazole, that inhibits gastric acid secretion.
  • Omeprazole belongs to a class of antisecretory compounds, the proton pump inhibitor that do not exhibit anti- cholinergic or H 2 histamine antagonist properties. Drugs of this class suppress gastric acid secretion by the specific inhibition of the H + /K + ATPase enzyme system (proton pump) at the secretory surface of the gastric parietal cell.
  • omeprazole and lansoprazole or other proton pump inhibitors in the form of a delayed-release capsule is prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD) , severe erosive esophagitis, poorly responsive systematic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome.
  • GFD gastroesophageal reflux disease
  • severe erosive esophagitis severe erosive esophagitis
  • poorly responsive systematic GERD and pathological hypersecretory conditions
  • pathological hypersecretory conditions such as Zollinger Ellison syndrome.
  • H 2 antagonists antacids, and sucralfate are commonly administered to minimize the pain and the complications related to these conditions.
  • These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the aforementioned conditions and/or produce adverse side effects, such as mental confusion, constipation, diarrhea, thrombocytopenia, (lowered platelet count) and/or are relatively costly modes of therapy as they require the use of automated infusion pumps for continuous intravenous delivery.
  • a recent cohort study challenges other risk factors previously identified such as acid-base disorders, multiple trauma, significant hypertension, major surgery, multiple operative procedures, acute renal failure, sepsis, and coma (Cook et al . , 1994) . Regardless of the risk type, stress-related mucosal damage results in significant morbidity and mortality. Clinically significant bleeding occurs in at least twenty percent of patients with one or more risk factors who are left untreated (Martin et al . , 1993) . Of those who bleed, approximately ten percent require surgery (usually gastrectomy) with a reported mortality of thirty percent to fifty percent (Czaja et al . , 1974; Peura and Johnson, 1985) . Those who do not need surgery often require multiple transfusions and prolonged hospitalization. Prevention of stress-related upper gastrointestinal bleeding is an important clinical goal.
  • prophylactic agents are withdrawn in fifteen to twenty percent of patients in which they are employed because of failure to prevent bleeding, or control pH (Ostro et al . , 1985; Siepler, 1986; Ballesteros et al . , 1990), or because of adverse effects (Gafter et al . , 1989; Sax, 1987; Vial et al . , 1991; Cantu and Korek, 1991; Spychal and ickham, 1985) .
  • Omeprazole and lansoprazole and the other proton pump inhibitors reduce gastric acid production by irreversibly inhibiting the H+/K+ ATPase of the parietal cell - the final common pathway for gastric acid secretion (Fellenius et al . , 1981; Wallmark et al . , 1985; Frylund et al . , 1988). Because this drug maintains gastric pH control throughout the dosing interval and has a very good safety profile, it is a logical choice for stress ulcer prophylaxis. The absence of an intravenous or oral liquid dosage form in the United States, however, has limited the testing and use of omeprazole in the critical care patient population.
  • H 2 -antagonists fall short of being the optimal pharmacotherapeutic agents for preventing of stress-related mucosal bleeding. Another controversy surrounding stress ulcer prophylaxis is which drug to use.
  • antacids and sucralfate are other treatment options for the prophylaxis of stress-related mucosal damage.
  • An ideal drug in this setting should possess the following characteristics: prevent stress ulcers and their complications, be devoid of toxicity, lack drug interactions, be selective, have minimal associated costs (such as personnel time and materials) , and be easy to administer (Smythe and Zarowitz, 1994) .
  • sucralfate is possibly the ideal agent for stress ulcer prophylaxis (Smythe and Zarowitz, 1994) . Randomized, controlled studies support the use of sucralfate (Borrero et al . , 1986; Tryba, 1987; Cioffi et al . , 1994; Driks et al . , 1987), but data on critical care patients with head injury, trauma, or burns are limited. In addition, a recent study comparing sucralfate and cimetidine plus antacids for stress ulcer prophylaxis reported clinically significant bleeding in three of forty-eight (6%) sucralfate-treated patients, one of whom required a gastrectomy (Cioffi et al .
  • H 2 -antagonists fulfill many of the criteria for an ideal stress ulcer prophylaxis drug. Yet, clinically significant bleeds can occur during H 2 -antagonist prophylaxis (Martin et al . , 1993; Cook et al . , 1991; Schuman et al .
  • a gastric pH > 3.5 has been associated with a lower incidence of stress-related mucosal damage and bleeding (Larson et al . , 1984; Skillman et al . , 1969; Skillman et al . , 1970; Priebe and Skillman, 1981) .
  • H 2 - antagonists even in maximal doses, do not reliably or continuously increase intragastric pH above commonly targeted levels (3.5 to 4.5) . This is true especially when used in fixed-dose bolus regimens (Ostro, 1985; Siepler, 1986; Ballesteros et al . , 1990).
  • Proton pump inhibitors such as omeprazole represent an advantageous alternative to the use of H 2 antagonists, antacids, and sucralfate as a treatment for complications related to stress-related mucosal damage.
  • proton pump inhibitors can be difficult or impossible to administer to patients who are unable (critically ill patients, children, elderly, patients suffering from dysphagia) or patients who are either unwilling or unable to swallow tablets or capsules. Therefore, it would be desirable to formulate a proton pump inhibitor solution or suspension which can be enterally delivered to a patient thereby providing the benefits of the proton pump inhibitor without the drawbacks of the current capsule dose form.
  • Omeprazole the first proton pump inhibitor introduced into use, has been formulated in many different embodiments such as in a mixture of polyethylene glycols formed a mixture of adeps solidus and sodium lauryl sulfate in a soluble, basic amino acid to yield a formulation designed for administration in the rectum as shown in United States Patent No. 5,219,870 to Kim.
  • United States Patent No. 5,395,323 to Berglund discloses a device for mixing a pharmaceutical from a solid supply into a parenterally acceptable liquid form for parenteral administration to a patient.
  • the '323 patent teaches the use of an omeprazole tablet which is placed in the device and dissolved by normal saline, and infused into the patient.
  • This device and method of infusing omeprazole does not provide the omeprazole solution as an enteral product nor is this omeprazole solution directly administered to the diseased or affected areas, namely the stomach and upper gastrointestinal tract, nor does this omeprazole formulation provide the immediate anti -acid effect of the present formulation.
  • United States Patent No. 4,786,505 to Lovgren et al . discloses a pharmaceutical preparation containing omeprazole together with an alkaline reacting compound or an alkaline salt of omeprazole optionally together with an alkaline compound as a core material in a tablet formulation.
  • the use of the alkaline material which can be chosen from such substances as the sodium salt of carbonic acid, are used to form a "micro-pH" around each omeprazole particle to protect the omeprazole which is highly sensitive to acid pH.
  • the powder mixture is then formulated to small beads, pellets, tablets and may be loaded into capsules by conventional pharmaceutical procedures .
  • omeprazole does not provide an omeprazole dose form which can be enterally administered to a patient who may be unable and/or unwilling to swallow capsules or pellets nor does it teach a convenient form which can be used to make an omeprazole or other proton pump inhibitor solution or suspension.
  • omeprazole solutions described in these references were administered orally and were given to healthy subjects who were able to ingest the oral dose.
  • omeprazole was suspended in a solution including sodium bicarbonate, as a pH buffer, in order to protect the acid sensitive omeprazole during administration.
  • the buffered omeprazole solutions of the above cited prior art require large amounts of sodium bicarbonate to be given by repeated administration. This is necessary to prevent acid degradation of the omeprazole.
  • the administration of large amounts of sodium bicarbonate can produce at least four significant adverse effects which can dramatically reduce the efficacy of the omeprazole in patients and reduce the overall health of the patients.
  • basically healthy volunteers rather than sick patients were given only one or two dosages of omeprazole utilizing pre-dosing and post-dosing with large volumes of sodium bicarbonate. This dosing protocol would not be suitable for sick or critically ill patients who must receive multiple doses of omeprazole.
  • the oral omeprazole administration protocol calls for administering to a subject who has been fasting for at least ten hours, a solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five minutes later, the subject ingests a suspension of 60 mg of omeprazole in 50 ml of water which also contains 8 mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of 8 mmoles sodium bicarbonate solution.
  • the subject ingests 50 ml of bicarbonate solution (8 mmoles) . This is repeated at twenty minutes and thirty minutes post omeprazole dosing to yield a total of 48 mmoles of sodium bicarbonate and 300 ml of water in total which are ingested by the subject for a single omeprazole dose.
  • omeprazole suspension can be stored at refrigerator temperatures for a week and deep frozen for a year while still maintaining 99% of their initial potency. It would be desirable to have an omeprazole or other proton pump inhibitor solution or suspension which could be stored at room temperature or in a refrigerator for periods of time which exceed those of the prior art while still maintaining 99% of the initial potency.
  • omeprazole and bicarbonate which can be utilized to instantly make the omeprazole solution/suspension of the present invention which is supplied in a solid form which imparts the advantages of improved shelf-life at room temperature, lower cost to produce, less expensive shipping costs, and which is less expensive to store.
  • the present invention provides a solution/suspension of proton pump inhibitors such as omeprazole, lansoprazole or other proton pump inhibitor (pantoprazole, rabeprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontoprazole, dontopraz
  • a method of treating gastric acid disorders by administering to a patient a pharmaceutical composition including a proton pump inhibitor in a pharmaceutically acceptable carrier including a bicarbonate salt of a Group IA metal where the administering step consists of a single dosage form without requiring further administering of the bicarbonate salt of the Group IA metal.
  • the present invention further provides a pharmaceutical composition includes a dry formulation of a proton pump inhibitor in a pharmaceutically acceptable carrier including a bicarbonate salt of a Group IA metal.
  • the present invention further provides a phannaceutical composition for making a dry formulation of a proton pump inhibitor which includes a proton pump inhibitor and a bicarbonate salt of a Group IA metal in a form for convenient storage, whereby the composition is in a dry formulation which is suitable for enteral administration.
  • Figure 1 is a graph showing the effect of the omeprazole solution/suspension of the present invention on gastric pH in patients at risk for upper gastrointestinal bleeding from stress-related mucosal damage;
  • Figure 2 is a flow chart illustrating a patient enrollment scheme
  • Figure 3 is a bar graph illustrating gastric pH both pre- and post -administration of omeprazole solution/suspension according to the present invention.
  • Figure 4 is a graph illustrating the stomach pH values of both chocolate plus lansoprazole in powder form and lansoprazole alone.
  • a pharmaceutical composition which can include an aqueous solution/suspension, or dry formulation, of proton pump inhibitors, such as omeprazole or other substituted benzimidazoles which are proton pump inhibitors such as lansoprazole, pantoprazole, rabeprazole, dontroprazole, perprazole, donprazole, and derivatives thereof in a pharmaceutically acceptable carrier including a bicarbonate salt of a Group IA metal is disclosed.
  • the composition includes dry formulations, solutions and/or suspensions of the omeprazole or other proton pump inhibitors.
  • solution includes solutions and/or suspensions of the substituted benzimidazoles.
  • the pharmaceutical composition of the present invention is prepared by mixing omeprazole (Merck & Co. Inc., West Point, PA) or other proton pump inhibitors or derivatives thereof with a solution including a bicarbonate salt of a Group IA metal.
  • omeprazole or other proton pump inhibitor powder or granules which can be obtained from a capsule, are mixed with a sodium bicarbonate solution to achieve a desired final omeprazole concentration.
  • the concentration of omeprazole in the solution/suspension can range from approximately 0.5 mg/ml to approximately 6.0 mg/ml .
  • the preferred concentration for the omeprazole in the solution/suspension ranges from approximately 1.0 mg/ml to approximately 4.0 mg/ml with 2mg/ml being the standard concentration .
  • the pharmaceutically effective carrier includes the bicarbonate salt of the Group IA metal and can be prepared by mixing the bicarbonate salt of the Group IA metal, preferably sodium bicarbonate, with water.
  • the concentration of the bicarbonate salt of the Group IA metal in the composition generally ranges from approximately 5.0 percent to approximately 60.0 percent.
  • the concentration of the bicarbonate salt of the Group IA metal ranges from approximately 7.5 percent to approximately 10.0 percent .
  • sodium bicarbonate is the preferred salt of the Group IA metal and is present in a concentration of approximately 8.4 percent.
  • enterically-coated omeprazole particles are obtained from delayed release capsules (Astra Merck) alternatively omeprazole powder can be used.
  • the coated omeprazole particles are mixed with a sodium bicarbonate (NaHC0 3 ) solution which dissolves the enteric coating and forms an omeprazole solution/suspension in accordance with the present invention.
  • the omeprazole solution/suspension has significant pharmacokinetic advantages over standard time-release omeprazole capsules including: a decreased drug absorbance time (-10 to 12 minutes) following administration for the omeprazole solution versus (-2-3 hours) following administration for the enteric coated pellets; the NaHC0 3 solution protects the omeprazole from acid degradation prior to absorption; the NaHC0 3 acts as an antacid while the omeprazole is being absorbed; and the solution/suspension can be administered through an existing indwelling tube without clogging, for example, nasogastric or other feeding tubes (jejunal or duodenal) including small bore needle catheter feeding tubes .
  • proton pump inhibitors can be substituted for the omeprazole or lansoprazole, or other suitable substituted benzimidazoles without departing from the spirit of the present invention.
  • proton pump inhibitors can include, but are not limited to, lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole, donprazole and other proton pump or acid pump inhibitors.
  • Proton pump inhibitors are membrane impermeable and form disulfide covalent bonds with cysteine residues in the alpha subunit which inhibit the activity of the acid secreting pump. The data presented provides a factual basis for suggesting the use of this group of proton pump inhibitor compounds in accordance with the present invention.
  • the pharmaceutical composition including the proton pump inhibitors such as omeprazole or lansoprazole or other proton pump inhibitors and derivatives thereof in a pharmaceutically acceptable carrier of a bicarbonate salt of Group IA metal can be used for the treatment of gastrointestinal conditions including, but not limited to, active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive systematic GERD, and pathological hypersecretory conditions such as Zollinger Ellison Syndrome. These conditions are caused by imbalances between acid and pepsin production, called aggressive factors, and mucous, bicarbonate, and prostaglandin production, called defensive factors. Treatment of these conditions is accomplished by administering to a patient an effective amount of the pharmaceutical composition according to the present invention.
  • GUD gastroesophageal reflux disease
  • severe erosive esophagitis severe erosive esophagitis
  • poorly responsive systematic GERD poorly responsive systematic GERD
  • the proton pump inhibitor is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" for purposes herein thus determine by such considerations as are known in the art.
  • the amount must be effective to achieve improvement, including but not limited to, raising of gastric pH, reduced gastrointestinal bleeding, reduction in the need for blood transfusion, improved survival rate, more rapid recovery, or improvement or elimination of systems and other indicators as are selected as appropriate measures by those skilled in the art .
  • omeprazole or other proton pump inhibitors such as substituted benzimidazoles and derivatives thereof can range from approximately 2 mg/day to approximately 100 mg/day.
  • the standard daily dosage is typically 20 mg omeprazole in 10 ml of solution.
  • the omeprazole solution suspension can be administered in various ways. It should be noted that the omeprazole solution/suspension can be administered as the compound or as the pharmaceutically acceptable salt form (dry) and can be administered alone or in combination with pharmaceutically acceptable carriers. The compounds can be administered orally or enterally. The formulations can be made more palatable by adding flavorings such as chocolate, root beer, and others.
  • the combination of the lansoprazole with chocolate enhanced the pharmacologic activity of the lansoprazole.
  • the results establish that the sodium bicarbonate as well as chocolate flavoring and calcium were all able to stimulate the activation of the proton pumps, perhaps due to the release of gastrin.
  • Proton pump inhibitors work by functionally inhibiting the proton pump and can only block activated proton pumps.
  • By further administering the proton pump inhibitor with one of these potentiators or enhancers there is a synchronization of activation of the proton pump with the absorption of the proton pump inhibitor. This combination produced a much longer pharmacologic effect than when the proton pump inhibitor was administered alone.
  • the formulations of the present invention can also be manufactured in a concentrated form, such as an effervescent tablet or powder, so that upon reaction with water, the aqueous form of the present invention would be produced for oral or enteral administration.
  • the present invention can be manufactured by utilizing micronized compounds in place of the granules or powder. This process is known as micronization and is utilized in order to produce a particle having a greater diameter. Micronization is the process by which solid drug particles are reduced in size. Since the dissolution rate is directly proportional to the surface area of the solid, and reducing the particle size increases the surface area, reducing the particle size increases the dissolution rate.
  • micronization results in increased surface area causing particle aggregation, which can negate the benefit of micronization and is an expensive manufacturing step, it does have the significant benefit of increasing the dissolution rate of relatively water insoluble drugs, such as omeprazole and other proton pump inhibitors.
  • a pharmacological formulation of the proton pump inhibitors utilized in the present invention can be administered orally to the patient.
  • a pharmacological formulation of the omeprazole solution/suspension utilized in the present invention is preferably administered enterally. This can be accomplished, for example, by administering the solution/suspension via a nasogastric tube or other indwelling tubes.
  • the omeprazole solution of the present invention is administered in a single dose which does not require any further administration of bicarbonate following the administration of the omeprazole solution.
  • the formulation of the present invention is given in a single dose which does not require administration of bicarbonate either before administration of the omeprazole or after administration of the omeprazole.
  • the present invention eliminates the need to pre-or post-dose with additional volumes of water and sodium bicarbonate.
  • the amount of bicarbonate administered via the single dose administration of the present invention is less than the amount of bicarbonate administered as taught in the prior art references cited above.
  • the amount of sodium bicarbonate used in the solution/suspension of the present invention is approximately 1 meq (or mmole) sodium bicarbonate per 2 mg omeprazole, with a range of approximately 0.75 meq (mmole) to 1.5 meq (mmole) per 2 mg of omeprazole.
  • the present invention further includes a pharmaceutical composition for making a solution/suspension of proton pump inhibitors, which consists essentially of omeprazole or other proton pump inhibitors and derivatives thereof and a bicarbonate salt of a Group IA metal in a form convenient for storage, whereby when the composition is placed into an aqueous solution, the composition dissolves yielding a solution/suspension suitable for enteral administration to a subject.
  • the pharmaceutical composition is in a solid form prior to dissolution in the aqueous solution.
  • the omeprazole or other substituted benzimidazoles and derivatives thereof and bicarbonate can be formed into a tablet, capsules, or granules, by methods well known to those skilled in the art.
  • the pharmaceutical composition suitable for making a solution/suspension according to the present invention can further include an effervescing agent to aid in the dissolution of the pharmaceutical composition in the aqueous solution.
  • the effervescing agent is sodium bicarbonate.
  • the resultant omeprazole solution is stable at room temperature for several weeks and inhibits the growth of bacteria or fungi as shown in Example IV below.
  • a pharmaceutical composition including the omeprazole or other substituted benzimidazole and derivatives thereof with bicarbonate in a solid form which is dissolved in a prescribed amount of aqueous solution to yield the desired concentration of omeprazole and bicarbonate
  • the cost of production, shipping, and storage are greatly reduced as no liquids are shipped (reducing weight and cost) and there is no need to refrigerate the solid form of the composition or the solution.
  • the resultant solution can be formulated and then used to provide dosages for a single patient over a course of time or for several patients.
  • the solid formulation of the present invention could be in the form of a powder, a tablet, a capsule, or other suitable solid dosage form (e.g. a pelleted form or an effervescing tablet or powder) .
  • the solid formulation would then create the present invention when acted upon by a suitable vehicle, for example water.
  • the water may be added either prior to ingestion or the dry formulation may be ingested first and then acted upon by the water utilized to swallow the solid formulation.
  • a third mechanism enables water in the stomach secretions to produce the present invention.
  • SRMD mechanical ventilation, head injury, severe burn, sepsis, multiple trauma, adult respiratory distress syndrome, major surgery, acute renal failure, multiple operative procedures, coagulatherapy, significant hypotension, acid-base disorder, and hepatic failure
  • gastric pH of : ⁇ 4 prior to study entry and no concomitant prophylaxis for SRMD.
  • Nasogastric (ng) tubes were placed in the patients and an omeprazole dosage protocol of 40 mg omeprazole solution/suspension followed by 40 mg omeprazole solution/suspension in eight hours, then 20 mg omeprazole solution/suspension per day, for five days. After each omeprazole solution/suspension administration, nasogastric suction was turned off for thirty minutes.
  • a pharmacoeconomic analysis revealed a difference in the total cost of care for the prophylaxis of SRMD: ranitidine (Zantac ® ) continuous infusion intravenously (150 mg/24 hours) x five days $125.50;
  • cimetidine (Tagamet ® ) continuous infusion intravenously (900 mg/24 hours) x five days $109.61;
  • This example illustrates the efficacy of the simplified omeprazole solution of the present invention based on the increase in gastric pH, safety and cost/convenience of the omeprazole solution/suspension as a method for SRMD prophylaxis.
  • Example II Experiments were carried out in order to determine the effect of the omeprazole solution/suspension (omeprazole/sodium bicarbonate solution) administration on the accuracy on subsequent pH measurements through a nasogastric tube.
  • omeprazole solution/suspension was prepared by mixing 10 ml of 8.4% sodium bicarbonate with the contents of a 20 mg capsule of omeprazole (Merck & Co. Inc., West).
  • omeprazole solution/suspension having a final omeprazole concentration of 2 mg/ml.
  • ng nasogastric
  • Nasogastric tubes from nine different institutions were gathered for an evaluation 400 mg omeprazole solution/suspension was prepared as described above.
  • Artificial gastric fluid (gf) was prepared according to the USP. pH recordings were made in triplicate using a Microcomputer Portable pH meter model 6007 (Jenco Electronics Ltd., Taipei, Taiwan). [1] First the terminal portion (tp) of the nasogastric tubes was placed into a glass beaker containing the gastric fluid.
  • Table 1 illustrates the results of the pH measurements that were taken during the course of the experiment. These results illustrate that there were no statistically significantly latent effects of omeprazole solution/suspension administration (per nasogastric tube) on the accuracy of subsequent pH measurements obtained through the same nasogastric tube.
  • omeprazole suspension containing 40 mg of omeprazole
  • a second 20 ml dose six-eight hours later, then 10 ml (20 mg) daily.
  • Omeprazole solution/suspension according to the present invention was administered through a nasogastric tube, followed by 5-10 ml of tap water. The nasogastric tube was clamped for one-two hours after each administration.
  • the primary outcome measure was clinically significant gastrointestinal bleeding determined by endoscopic evaluation, nasogastric aspirate examination, or heme-positive coffee ground material that did not clear with lavage and was associated with a five percent decrease in hematocrit .
  • Secondary efficacy measures were gastric pH measured four hours after omeprazole was first administered, mean gastric pH after omeprazole was started, and the lowest gastric pH during omeprazole therapy.
  • Safety-related outcomes included the incidence of adverse events and the incidence of pneumonia. No patient experienced clinically significant upper gastrointestinal bleeding after receiving omeprazole suspension.
  • the four-hour post omeprazole gastric pH was 7.1 (mean)
  • the mean gastric pH after starting omeprazole was 6.8 (mean)
  • the lowest pH after starting omeprazole was 5.6 (mean) .
  • the incidence of pneumonia was twelve percent. No patient in this high-risk population experienced an adverse event or a drug interaction that was attributable to omeprazole.
  • Omeprazole suspension prevented clinically significant upper gastrointestinal bleeding and maintained gastric pH above 5.5 in mechanically ventilated critical care patients without producing toxicity.
  • Sepsis was defined as the presence of invasive pathogenic organisms or their toxins in blood or tissues resulting in a systematic response that included two or more of the following: temperature greater than 38°C or less than 36°C, heat rate greater than 90 beats/minute, respiratory rate greater than 20 breaths/minute (or p 0 2 less than 75 mm Hg) , and white blood cell count greater than 12,000 or less than 4000 cells/mm 3 or more than 10 percent bands (Bone, 1991) . Patients in whom H 2 -antagonist therapy had failed or who experienced an adverse event while receiving H 2 -antagonist therapy were also included.
  • Patients were excluded from the study if they were receiving azole antifungal agents through the nasogastric tube; were likely to swallow blood (e.g., facial and/or sinus fractures, oral lacerations) ; had severe thrombocytopenia (platelet count less than 30,000 cells/mm 3 ) ; were receiving enteral feedings through the nasogastric tube; or had a history of vagotomy, pyloroplasty, or gastroplasty . In addition, patients with a gastric pH above four for forty-eight hours after ICU admission (without prophylaxis) were not eligible for participation.
  • ICU admission without prophylaxis
  • Omeprazole solution/suspension was prepared immediately before administration by the patient's nurse using the following instructions: 1) Empty the contents of one or two 20 mg omeprazole capsule (s) into an empty 10 ml syringe (with 20 gauge needle in place) from which the plunger has been removed. (Omeprazole delayed-release capsules, Merck & Co., Inc., West Point, PA). 2) Replace the plunger and uncap the needle. 3) Withdraw 10 ml of 8.4% sodium bicarbonate solution or 20 ml if 40 mg given (Abbott Laboratories, North Chicago, IL) . The resultant preparation should contain 2 mg omeprazole per ml of 8.4% sodium bicarbonate.
  • omeprazole solution/suspension The initial dose of omeprazole solution/suspension was 40 mg, followed by a second 40 mg dose 6-8 hours later, then a 20 mg daily dose administered at 8:00 AM. Each dose was administered through the nasogastric tube. The nasogastric tube was then flushed with 5-10 ml of tap water and clamped for at least one hour. Omeprazole therapy was continued until there was no longer a need for stress ulcer prophylaxis (usually after the nasogastric tube removed and the patient was taking water/food by mouth, or after the patient was removed from mechanical ventilation) .
  • the primary outcome measure in this study was the rate of clinically significant stress-related mucosal bleeding defined as endoscopic evidence of stress-related mucosal bleeding or bright red blood per nasogastric tube that did not clear after a 5- minute lavage or persistent Gastroccult (SmithKline Diagnostics, Sunnyville, CA) positive coffee ground material for four consecutive hours that did not clear with lavage (at least 100 ml) and produced a 5% decrease in hematocrit .
  • the secondary efficacy measures were gastric pH measured four hours after omeprazole was administered, mean gastric pH after starting omeprazole and lowest gastric pH during omeprazole administration.
  • Gastric pH was measured immediately after aspirating gastric contents through the nasogastric tube.
  • pH paper pH paper (pHydrion improved pH papers, Microessential Laboratory, Brooklyn, NY) was used to measure gastric aspirate pH.
  • the pH range of the test strips was 1 to 11, in increments of one pH unit.
  • Gastric pH was measured before the initiation of omeprazole solution/suspension therapy, immediately before each dose, and every four hours between doses.
  • a patient who has pneumonia is one who has rales or dullness to percussion on physical examination of the chest or has a chest radiograph that shows new or progressive infiltrate (s) , consolidation, cavitation, or pleural effusion and has at least two of the following present: new purulent sputum or changes in character of the sputum, an organism isolated from blood culture, fever or leukocytosis, or evidence of infection from a protective specimen brush or bronchoalveolar lavage.
  • Patients who met the criteria for pneumonia and were receiving antimicrobial agents for the treatment of pneumonia were included in the pneumonia incidence figure. These criteria were also used as an initial screen before the first dose of study drug was administered to determine if pneumonia was present prior to the start of omeprazole suspension.
  • Cost of Care Analysis A pharmacoeconomic evaluation of stress ulcer prophylaxis using omeprazole solution/suspension was performed. The evaluation included total drug cost (acquisition and administration) , actual costs associated with adverse events (e.g., psychiatry consultation for mental confusion) , costs associated with clinically significant upper gastrointestinal bleeding. Total drug cost was calculated by adding the average institutional costs of omeprazole 20 mg capsules, 50 ml sodium bicarbonate vials, and 10 ml syringes with needle; nursing time (drug administration, pH monitoring) ; pharmacy time (drug preparation); and disposal costs.
  • Costs associated with clinically significant upper gastrointestinal bleeding included endoscopy charges and accompanying consultation fees, procedures required to stop the bleeding (e.g., surgery, hemostatic agents, endoscopic procedures) , increased hospital length of stay (as assessed by the attending physician) , and cost of drugs used to treat the gastrointestinal bleeding.
  • omeprazole enteric-coated pellets had not completely broken down prior to the administration of the first two doses, which produced an erratic effect on gastric pH.
  • the gastric pH increased to above six as soon as the patient was given a dose of omeprazole solution/suspension (in which the enteric coated pellets of omeprazole had been allowed to completely breakdown) .
  • Pneumonia developed in nine (12%) patients receiving omeprazole solution/suspension. Pneumonia was present in an additional five patients before the start of omeprazole therapy.
  • Omeprazole solution/suspension is a safe and effective therapy for the prevention of clinically significant stress-related mucosal bleeding in critical care patients.
  • the contribution of many risk factors to stress-related mucosal damage has been challenged recently (6) .
  • All of the patients in this study had at least one risk factor that has clearly been associated with stress-related mucosal damage - mechanical ventilation.
  • Previous trials and data from a recently published study show that stress ulcer prophylaxis is of proven benefit in patients at risk and, therefore, it was thought to be unethical to include a placebo group in this study.
  • Gastric pH was maintained above 4 on omeprazole 20 mg/day in seventy-three of seventy- five patients. No adverse events or drug interaction associated with omeprazole were encountered.
  • An omeprazole solution/suspension made according to the present invention was stored at room temperature for four weeks and then was analyzed for fungal and bacterial growth.
  • An omeprazole solution/suspension made in accordance with the present invention was stored at room temperature for twelve weeks and then was analyzed for fungal and bacterial growth.
  • Ancillary Product (I) Piggyback (60%) 0.75 Ancillary Product (2) micro rabing (etc.) 2.00 Anc ⁇ laiy Product (3) filter .40 Sterile Prep required y « . . R.N. time ($24/fcx) 20 m utea day (includes pH momto ⁇ ng) 8.00 R.P time, hood maint. 3 minutes ($ 0/hr) 2.00 Pomp cost $29/24 h ⁇ - x 50% 14.50 TOTAL for 9 days 304-20
  • Ancillary Product (1) Piggyback 1-25 Ancillary Product (2) micro tubing (etc.) 2.00 An Uary Product (3) filter .40 Sterile Prep required y s , , R.N. rime (S24 hr) 20 minutes day (includes pH monitoring) 8.00 R-P . tune, hood maint. 3 minutes ($40/hr) 2.00 Pump cost $29/24 hre x S0% 14.50 TOTAL for 9 days 288.99
  • the average length of treatment was 9 days. Cost of care was calculated from these data:

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Abstract

La présente invention concerne une méthode de traitement d'acidité gastrique par administration, à un patient, d'une composition pharmaceutique contenant un inhibiteur de pompe à proton dans un support acceptable sur le plan pharmaceutique, comprenant un sel bicarbonaté d'un métal du groupe IA, qui consiste à administrer une forme à dosage unique qui ne nécessite aucune administration ultérieure de sel bicarbonaté de métal du groupe IA. Une composition pharmaceutique comprend une formulation sèche d'inhibiteur de pompe à proton dans un support acceptable sur le plan pharmaceutique, comprenant un sel bicarbonaté d'un métal du groupe IA. L'invention concerne aussi une composition pharmaceutique destinée à fabriquer une formulation sèche d'un inhibiteur de proton qui comprend un inhibiteur de pompe à proton et un sel bicarbonaté d'un métal du groupe IA sous une forme adaptée au stockage, la formulation sèche de la composition convenant à l'administration par voie entérale.
PCT/US1999/025592 1998-10-30 1999-10-29 Solution d'omeprazole et methode d'utilisation associee WO2000026185A2 (fr)

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US5840737A (en) 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6645988B2 (en) * 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6489346B1 (en) * 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
MY137726A (en) 2000-11-22 2009-03-31 Nycomed Gmbh Freeze-dried pantoprazole preparation and pantoprazole injection
US8697094B2 (en) 2002-10-16 2014-04-15 Takeda Pharmaceutical Company Limited Stable solid preparations
AU2004257864A1 (en) * 2003-07-18 2005-01-27 Santarus, Inc. Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

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GB2189699A (en) * 1986-04-30 1987-11-04 Haessle Ab Coated acid-labile medicaments
SE9402431D0 (sv) * 1994-07-08 1994-07-08 Astra Ab New tablet formulation

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