Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1611—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

• the present invention is directed to pharmaceutical compositions for the treatment of gastrointestinal disorders, and particularly for the treatment of gastroesophogeal reflux disease.
• the pharmaceutical compositions contain a core or a plurality of particles with a therapeutically effective amount of a proton pump inhibitor (ppi).
• ppi proton pump inhibitor
• the core, or each particle is surrounded by a coating that delays the release of drug.
• the compositions have a separate outer coating that contains either a proton pump inhibitor or an H2 blocker and which is designed to release drug immediately after ingestion by a patient.
• Gastroesophogeal reflux disease is a common disorder which, if untreated, can have serious health consequences. Symptoms of esophageal reflux can be acute, commonly arising from a provocative meal or recumbent posture in susceptible individuals. In GERD, symptoms of esophageal reflux are chronic, occurring throughout the day, frequently without any provocative cause. Effective treatment of GERD requires management of both acute and chronic reflux.
• Two types of agents frequently prescribed for the treatment of GERD are H2 blockers and proton pump inhibitors. H2 blockers prevent interaction between gastric cells that produce acid and histamine, an agent known to stimulate acid secretion. These drugs have a relatively rapid onset of action but a short duration of effectiveness (typically 8-12 hours).
• H2 blockers examples include cimetidine (Tagamet®); famotidine (Pepcid®); nizatidine (Axid®); and ranitidine (Zantac®). Unfortunately, many patients with more severe forms of GERD do not get adequate relief from these H2 blockers.
• Proton pump inhibitors are typically prescribed for GERD patients that cannot be effectively treated with H2 blockers alone. PPIs bind to and inhibit the cellular enzyme responsible for secreting acid into the stomach. These drugs are more effective than H2 blockers at reducing acid secretion and typically have a duration of action long enough that they only need to be taken once a day. This has made the proton pump inhibitors of interest in therapies designed to provide long-term protection to the stomach by maintaining an elevated pH (see published U.S. application 2003069255; and WO 2004/060372).
• omeprazole (Prilosec®); esomeprazole (Nexium®); lansoprazole (Prevacid®); pantoprazole (Protonix®); rabeprazole (Aciphex®).
• proton pump inhibitors are typically acid labile, they have usually been formulated as tablets with an enteric coating (see U.S. application 4,853,230; see also: U.S. 4,786,505; EP 0277,741; and EP 0342,522) and this may contribute to a slow onset of effectiveness. Patients usually do not get substantial relief from their symptoms for at least 24 hours after ingestion of a tablet and several days may be required (Clin. Pharmakinet 20:38-49(1991)). Recently, attempts have been made to reduce the time needed for achieving a therapeutic effect by using dosage forms which include an antacid buffer, instead of an enteric coating, to protect against acid degradation (U.S. 5,840,737; 6,489,346; 6,645,988; 6,780,882; 4,786,505; and 6,183,776).
• a dosage form should provide for both the rapid relief of patient symptoms and for long term effectiveness to prevent a recurrence of symptoms.
• the present invention is based upon the development of tablet dosage forms that provide for a multi-phase release of acid inhibitor.
• the tablets have an outer coating or an immediate release component that quickly dissolves in the stomach of a patient immediately after ingestion (within 60 minutes and preferably within 15 minutes) and which releases either an H2 blocker or a proton pump inhibitor.
• proton pump inhibitors may be acid labile, a sufficient amount can be incorporated into the immediate release component or outer coatings to inhibit the production of stomach acid.
• Oral dosage forms also include a core or a delayed release component that may be enterically coated and which contains a proton pump inhibitor.
• An enteric coating should be present in all dosage forms in which the core contains an acid labile proton pump inhibitor and may, or may not, be present in cases where the core contains a non-acid labile proton pump inhibitor, i.e., an inhibitor that is stable at a pH of 1.0-3.0.
• the enteric coating prevents the release of inhibitor from the core until the pH of the stomach has risen or this component of the dosage form has entered a patient's intestine.
• an acid labile proton pump inhibitor is protected from degradation and, as a result, a higher percentage will eventually enter a patient's blood stream and provide long-term relief of symptoms.
• enterically coated proton pump inhibitor there may be numerous particles of enterically coated proton pump inhibitor within a tablet or capsule.
• the enteric coating prevents the release of drug until the pH of the surrounding medium is at least 3.5 and may, if desired, also provide for the timed release of drug.
• This coating should be present for all acid labile proton pump inhibitors but is not necessarily enteric in cases where the in the core ppi is not acid labile.
• Sufficient proton pump inhibitor is contained within the particle cores so that, following release, gastric pH rises to or is maintained at 3.5 or higher.
• Each particle may include an outer coating that surrounds the enteric coating or the tablet or capsule may have one or more outer coatings that surround a plurality of particles.
• outer coating may refer to either a single coating or to multiple coatings.
• the outer coating is not itself enteric and is not surrounded by a separate enteric coating.
• one or more layers of material ⁇ e.g., containing excipients or active ingredients) may be included between the particles containing proton pump inhibitor and the outer coating.
• sufficient acid inhibitor is released from the outer coating into a patient's stomach within 60 minutes, and preferably within 15 minutes, to prevent reduction in gastric pH by production of new stomach acid.
• the invention also includes methods of making these dosage forms and methods in which they are used to treat patients.
• the invention is directed to a pharmaceutical composition in the form of a tablet with an enterically coated core or a pharmaceutical composition with a plurality of particles each of which is surrounded by an enteric coating.
• the core (or the particles) contains a therapeutically effective amount of a proton pump inhibitor.
• therapeutically effective indicates a sufficient amount of drug to alleviate a patient's symptoms by inhibiting acid production in the stomach, resulting in an increased median gastric pH, where median gastric pH is the median of gastric pH measurements taken at regular intervals over a 24 hour period.
• median gastric pH should be at least about 3.5 and, more preferably, at least 4.5.
• the enteric coating that surrounds the core or particles is designed to prevent the release of proton pump inhibitor until the surrounding pH is at least 3.5, with pH values greater than 5.5 being preferred.
• the elevated pH may not be obtained until the enterically coated drug reaches the patient's intestine, particularly the first time that a tablet is taken.
• the stomach should soon stabilize at a higher pH. hi these patients, the enterically coated component will rapidly release proton pump inhibitor into the stomach, preferably within 60 minutes after ingestion.
• a coating may be used which delays release of the proton pump inhibitor by some mechanism other than gastric pH e.g., in a time dependent manner.
• the dosage forms described above will include an outer coating containing a therapeutically effective amount of either a proton pump inhibitor or an H2 blocker.
• Drug in the outer coating is not enterically coated and should be released into a patient's stomach immediately after ingestion.
• the outer coating contains an acid labile proton pump inhibitor, it is recognized that a significant portion of the dosage delivered may be degraded in stomach acid before it can be absorbed into a patient's bloodstream. Nevertheless, sufficient inhibitor is taken up to provide for an alleviation of symptoms associated with GERD.
• enough drug i.e., proton pump inhibitor or H2 blocker, should be present to significantly suppress gastric acid secretion within six hours after ingestion by a patient.
• solid oral dosage forms will comprise an enterically coated core of proton pump inhibitor with non-enterically coated proton pump inhibitor or H2 blocker on the outside of the core in a film coat.
• This outer film coat should be thin to provide for essentially immediate drug release. Its thickness should generally be no more than 1,000 microns and preferably, it should be between 25 and 500 microns. Coatings with these characteristics can be obtained by spraying enterically coated cores with a film-forming solution containing drug.
• the outer coating may contain other agents such as stabilizers, buffers or alkaline substances. When buffers or alkaline substances are used, they should be designed to raise the pH of the stomach.
• Preferred proton pump inhibitors for use in both the outer coating and inner core of tablets include omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.
• AU of these drugs are commercially available or can be synthesized using techniques well known in the art. They should preferably be present at a dosage of 1-200 mg, and more preferably at 5-100 mg in the outer coating and at 5-600 mg in the inner core.
• Examples of preferred dosages for particular proton pump inhibitors in both the outer coating and inner core are: 5-50 mg omeprazole; 5-100 mg esomeprazole; 15-150 mg lansoprazole; 10-200 mg pantoprazole; and 5-100 mg rabeprazole.
• Other proton pump inhibitors may also be used, including pariprazole and leminoprazole.
• Preferred H2 blockers for use in the outer coating of tablets include: cimetidine; ranitidine; famotidine; ebrotidine; pabutidine; lafutidine; and nizatidine. These drugs should preferably be present at 1-300 mg and more preferably at 5-150 mg.
• the invention also includes methods of treating a patient for a disease or condition characterized by abnormal gastric acid production, gastric acid reflux, or damage to the gastrointestinal tract, by administering one or more of the tablets described above.
• Specific diseases or conditions that may be treated include: duodenal ulcers; gastric ulcers; gastroesophageal reflux disease; severe erosive esophagitis; poorly responsive systemic GERD; and Zollinger Ellison syndrome.
• the invention also includes methods for manufacturing unit dosage forms having the characteristics described above. These methods involve first forming a core comprising 5 to 600 nig of a proton pump inhibitor. A coating, preferably an enteric one that does not dissolve until the surrounding pH is at least 3.5, is then applied to the core.
• one or more additional layers are applied over the coating surrounding the core. These additional layers may contain drugs, excipients, buffers or alkaline agents.
• an outer coating that is applied by spraying. This outer coating is not enteric and contains 1- 200 mg of a proton pump inhibitor or 1-300 mg of a H2 blocker. Preferably, the outer coating is no more than 1,000 microns in diameter, and more preferably, it should be between 25 and 500 microns in diameter
• a stabilizer or a buffer designed to raise the pH of the stomach may be included in the outer coating or as a separate layer immediately below the coating.
• the most preferred proton pump inhibitors for use in tablets and the most preferred H2 blockers are those that are described above.
• Figure 1 Omeprazole Pellets: Figure 1 is a schematic drawing showing both uncoated pellets of omeprazole (A) and delayed release formulations in which a core pellet
• Example 1 The composition of the core pellet and of each of the outer layers is provided in Example 1.
• the pellets may be either compressed into a tablet or loaded into a capsule.
• Figure 2 Tablets Containing Immediate Release and Delayed Release Omeprazole Pellets: The figure shows a compressed tablet containing both uncoated omeprazole pellets (D), which release drug immediately upon exposure to gastric fluid, and enterically coated omeprazole pellets (E), that delay drug release until the pH of the surrounding medium is at least 3.5.
• the tablets may be coated with a non-enteric film that dissolves immediately after ingestion. The tablets are described in detail in Example 2.
• Figure 3 Bilayer Tablet: Figure 3 shows a bilayer tablet containing enterically coated, delayed release omeprazole pellets (F) and immediate release omeprazole granules (G).
• Figure 4 Multilayer Tablet Dosage Form: Figure 4 shows a tablet having a core layer (H) containing lansoprazole. This is surrounded by a barrier coating layer (I) that serves to protect the core.
• a third layer (J) is an enteric coating that does not dissolve until the surrounding medium is at a pH of 3.5 or higher.
• the outermost layer (K) is a film coating that contains a therapeutically effective amount of lansoprazole. This outer film is not enteric and releases the lansoprazole immediately after ingestion. The exact components present in each layer are described in Example 4.
• the present invention is directed to a dosage form that provides for both the quick release of an acid inhibitor to reduce anticipated reflux symptoms in a patient, as well as for the delayed release of a proton pump inhibitor to provide for longer term relief and to prevent the return of symptoms.
• active ingredients used in tablets i.e., proton pump inhibitors and H2 blockers, are well known in the art and the preferred agents described above are commercially available. If desired, drugs can also be manufactured using methodology well known in the art.
• the tablets of the present invention can be made in accordance with methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences. 16 th edition, A. Oslow, editor, Easton, PA (1980)).
• Drugs may be prepared in admixture with conventional excipients, carriers, buffers, flavoring agents, etc.
• Typical carriers include, but are not limited to: water; salt solutions; alcohols; gum arabic; vegetable oils; benzyl alcohols; polyethylene glycols; gelatin; carbohydrates, such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; paraffin; perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc.
• compositions can be sterilized and, if desired, mixed with auxiliary agents such as: lubricants; preservatives; disintegrants; stabilizers such as cyclodextrans; wetting agents; emulsifiers; salts; buffers; coloring agents; flavoring agents; or aromatic substances.
• auxiliary agents such as: lubricants; preservatives; disintegrants; stabilizers such as cyclodextrans; wetting agents; emulsifiers; salts; buffers; coloring agents; flavoring agents; or aromatic substances.
• buffers that can raise the pH of the stomach.
• bicarbonate buffers may be included in the outer coating or as a rapidly dissolving, separate layer immediately below the outer coating.
• the enteric coating surrounding the core may be applied using standard coating techniques.
• Materials used to form the enteric coating may be dissolved or dispersed in organic or aqueous solvents and may include one or more of the following: methacrylic acid copolymers; shellac; hydroxypropylmethylcellulose phthalate; polyvinyl acetate phthalate; hydroxypropylmethylcellulose trimellitate; carboxymethylcellulose; cellulose acetate phthalate; or other suitable enteric coating polymers.
• the pH at which the enteric coat will dissolve can be controlled by the polymer or combination of polymers selected and/or ratio of pendant groups. For example, dissolution characteristics of the coating can be altered by the ratio of free carboxyl groups to ester groups.
• Enteric coating layers may also contain pharmaceutical plasticizers such as: triethyl citrate; dibutyl phthalate; triacetin; polyethylene glycols; polysorbates; etc.
• additives such as dispersants, colorants, anti-adhering and anti- foaming agents may also be included.
• Tablets can be made using standard technology well known in the art.
• Drugs used in the core or the outer coating may be granulated by methods such as slugging, low-shear or high-shear granulation, wet granulation, or fluidized bed granulation.
• Outer coatings may be formed by preparing a mixture containing appropriate polymers and a sufficient amount of drug to produce a therapeutically effective dose. The solution may then be sprayed on preformed, enterically-coated cores to produce the final tablets. If desired, a buffer layer or layer containing other agents may be interspersed between the enterically coated core and the outer coating.
• compositions described above can be used to treat a patient for any disease or condition in which proton pump inhibitors are indicated.
• the most common condition will be GERD.
• Other conditions include duodenal ulcers, gastric ulcers, severe erosive esophagitis, and Zollinger Ellison syndrome
• a patient should be administered a sufficient daily dosage to eliminate the symptoms associated with excess gastric acid production.
• Typical daily dosages of all of the preferred agents are well known in the art.
• anywhere from 5-600 mg of proton pump inhibitor may be administered in the core of tablets and an additional 1-200 mg in the outer coating.
• an H2 blocker is used in the outer coating, it should generally be administered at a dosage of from 1 to 300 mg.
• the final dosages used will be selected by the attending physician based upon clinical conditions and using methods well known in the art. As a general rule, drugs will be designed to be taken once a day but other dosing regimens may also be used. In particular, under some conditions twice daily doses may be preferred. In general, it is desirable to administer the drugs before anticipated onset of symptoms due to eating, drinking, or any other provocative activity. Treatments should be continued even after symptoms associated with excess acid production have subsided and it is expected that patients will typically continue taking pharmaceutical compositions for many years.
• the present example is directed to a capsule that contains omeprazole pellets with (delayed release) and without (immediate release) an enteric coat (see Figure 1 for schematic of pellets).
• the omeprazole pellets contain sodium bicarbonate as an alkalizing excipient.
• Other soluble alkalizing agents that could be used include potassium bicarbonate, sodium carbonate, sodium hydroxide, and combinations of these agents.
• the alkalizing agent helps solubilize and protect omeprazole from degradation before it is absorbed.
• Sodium lauryl sulfate is present in pellets to help in the wetting of omeprazole.
• Other surfactants could be used to perform the same function.
• hydroxypropyhnethylcellulose is present to help in granule formation
• sodium starch glycolate is included as a disintegrant.
• Other excipients may also be used to perform these functions.
• the pellets are prepared by the wet massing technique and conventional extrusion and spheronization processes.
• Pellets for delayed release are first coated with a protective subcoating containing povidone.
• Other coating ingredients that could be used include Opaspray K-1-4210ATM and Opadry YS-I- 7006TM (trademarks of Colorcon, West Point, PA).
• Polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a subcoating suspension could also be used.
• Other ingredients that may be present in subcoatings include: plasticizers such as triethyl citrate or dibutyl phthalate; anti-adhering agents such as talc; lubricating ingredients such as magnesium stearate; and opacifiers such as titanium dioxide.
• the subcoated pellets are enteric coated using enteric coating polymers.
• the enteric coating polymer is methacrylic acid copolymer and the plasticizer is diethyl phthalate which is dissolved in a mixture of acetone and alcohol.
• the enteric film does not dissolve in the acidic pH normally found in the stomach but dissolves when the pH is above pH 4.5.
• Other materials that can be used in enteric coatings include: hydroxypropyl methylcellulose phthalate; ammoniomethacrylate copolymer; shellac; polyvinyl acetate phthalate; and cellulose acetate phthalate.
• Omeprazole, microcrystalline cellulose, sodium bicarbonate and sodium starch glycolate are dry mixed together and granulated with the granulating solution. The wet mass is mixed until a proper consistency is reached. It is then pressed through an extruder and spheronized to form pellets. The pellets are then dried and classified into suitable particle size ranges.
• Table 1 Composition of Omeprazole Pellets
• Enteric Coating Eudragit L-100 is dissolved in isopropanol and acetone and diethyl phthalate is then dissolved. The solution is sprayed on the subcoated pellet cores using film coating equipment. A sample of the pellets is tested for gastric resistance before stopping the coating process.
• Methacrylic Acid Copolymer NF 8.20 (Eudragit L-100) Diethyl Phthalate, NF 1.70
• Omeprazole immediate release pellets (uncoated) and delayed release pellets (enteric coated) are blended together and used to fill capsules to contain 20 mg delayed release omeprazole and 20 mg immediate release omeprazole per capsule.
• This tablet is compressed from a mixture of enteric coated omeprazole pellets and immediate release pellets and is illustrated in Figure 2.
• the formulation of omeprazole pellets contains 30 mg omeprazole and uses mannitol as a filler, hydroxypropylcellulose as a binder and microcrystalline cellulose as a disintegrant and filler. Delayed release pellets are coated with a subcoating followed by enteric coating with an aqueous dispersion of methacrylic acid copolymer.
• Omeprazole, mannitol, microcrystalline cellulose, hydroxypropylcellulose, sodium lauryl sulfate and dibasic sodium phosphate are dry mixed together and granulated with purified water. The wet mass is mixed until a proper consistency is reached. It is then pressed through an extruder and spheronized to form pellets. The resulting pellets are dried and classified into suitable particle size range. The composition of the pellets is shown in Table 4.
• Opadry clear is added slowly to purified water and the preparation is mixed until the Opadry is fully dispersed. The solution is sprayed on to half of the omeprazole pellets formed as described above until 1-2% of Opadry clear is deposited on the pellets.
• Eudragit L30D is dispersed in a purified water and simethicone emulsion. Talc and triethyl citrate are then dispersed. The suspension is sprayed on the pellet cores which contain the barrier film coat using film coating equipment. A sample of the pellets is tested for gastric resistance before stopping coating process.
• Omeprazole delayed release pellets and immediate release pellets are blended together with magnesium stearate and microcrystalline cellulose and compressed into a tablet containing 30 mg delayed release omeprazole and 30 mg immediate release omeprazole.
• the tablet can be film coated with pigmented Opadry or an equivalent containing typical film coating ingredients including hydroxypropyl methylcellulose, polyethylene glycol and colorant.
• Example 3 Bilayer Film Coated Tablet with Delayed Release Omeprazole and Immediate Release Omeprazole
• the bilayer tablet of the present example is compressed from enteric coated pellets and omeprazole granules and is illustrated in Figure 3.
• Enteric coated omeprazole pellets can be prepared as described in Example 1 or 2.
• Omeprazole granules are prepared using povidone as a binder, microcrystalline cellulose as a filler and disintegrant and mannitol as a filler.
• Omeprazole, microcrystalline cellulose, povidone, sodium lauryl sulfate, and dibasic sodium phosphate are mixed in a granulator. Water is added and mixed until a suitable granule is formed. The granules are dried in an oven and milled. The milled granules are blended with magnesium stearate and microcrystalline cellulose. Table 7: Composition of Omeprazole Granules
• the enteric coated pellets are mixed with microcrystalline cellulose and magnesium stearate.
• the blend consisting of enteric coated omeprazole pellets and the blend consisting of omeprazole granules are compressed into a bilayer tablet using a bilayer tablet press.
• the tablet can be film coated with pigmented Opadry or equivalent containing typical film coating ingredients including hydroxypropyl methylcellulose, polyethylene glycol and colorant.
• the first layer (H) is a core containing lansoprazole distributed throughout a matrix of pharmaceutically acceptable fillers, excipients, binding agents, disintegrants, and lubricants.
• the second layer (I) is a barrier layer which protects the first layer containing lansoprazole.
• the barrier film coat is applied by conventional pan coating technology and the weight of the barrier coat may vary from 1% to 3% of the core tablet weight.
• the core tablet is coated with coating ingredients such as
• Opaspray® K-1-4210A or Opadry® YS-1-7006 (Colorcon, West Point, PA).
• Polymer film coating ingredients such as hydroxypropylmethylcellulose 2910 and polyethylene glycol 8000 in a coating suspension may also be used.
• the third layer (J) is an enteric film coat.
• hydroxypropyl methylcellulose phthalate is the enteric coating ingredient
• cetyl alcohol is a plasticizer
• acetone and alcohol are solvents.
• Other materials for enteric coating are ammonio methacrylate copolymer, shellac, polyvinyl acetate phthalate, hydroxypropyl methylcellulose trimellitate and cellulose acetate phthalate.
• the fourth layer (K) is a film coating containing lansoprazole in an effective amount which is released from the dosage form as soon as the film coat dissolves.
• the film coat is applied by conventional pan coating technology and may vary from 4% to 8% of the core tablet weight, depending upon the amount of drug to be applied.
• Other ingredients are, plasticizers such as triethyl citrate, dibutyl phthalate, anti-adhering agents such as talc, lubricating ingredients such as magnesium stearate, opacif ⁇ ers such as, titanium dioxide, and ammonium hydroxide to adjust the pH of the dispersion.
• the film coating is thin and rapidly releases lansoprazole for absorption. Therefore, 10 mg lansoprazole releases first and then the core erodes and releases 15 mg lansoprazole.
• Lansoprazole, microcrystalline cellulose, lactose, povidone, sodium lauryl sulfate, and dibasic sodium phosphate are dry mixed and wet granulated in a granulator with sufficient purified water.
• the wet granules are dried, milled, and blended with microcrystalline cellulose and magnesium stearate. The final granule blend is compressed into tablets.
• Opadry clear is added slowly to purified water and mixing is continued until it is fully dispersed.
• the solution is sprayed on to the tablet cores in a conventional coating pan until the desired amount of Opadry clear is deposited on the tablets.
• Example 5 Treatment Example A patient is determined by his physician to be afflicted with GERD, which is provoked and aggravated by heavy meals before sleep.
• the patient is prescribed tablets as described in Example 4 to be taken each evening, 45 minutes before the evening meal. Untreated, the patient suffers from severe symptoms of esophageal reflux approximately 30 minutes after beginning dinner, and then throughout the night, requiring him to sleep seated in a recliner. After the patient takes the prescribed tablets the first evening, he experiences insignificant symptoms after dinner and is able to sleep lying in bed. On subsequent evenings, his GERD remains under control.

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• 2006
  • 2006-01-10 US US11/328,259 patent/US20060165797A1/en not_active Abandoned
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