US20050064030A1 - Sublingual buccal effervescent - Google Patents
Sublingual buccal effervescent Download PDFInfo
- Publication number
- US20050064030A1 US20050064030A1 US10/977,029 US97702904A US2005064030A1 US 20050064030 A1 US20050064030 A1 US 20050064030A1 US 97702904 A US97702904 A US 97702904A US 2005064030 A1 US2005064030 A1 US 2005064030A1
- Authority
- US
- United States
- Prior art keywords
- amount
- effervescent
- weight
- medicament
- selecting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
Definitions
- the present invention relates to pharmaceutical compositions, and more particularly to pharmaceutical compositions for oral administration of a medicament, which contain an effervescent agent for enhancing oral drug absorption across the buccal, sublingual, and gingival mucosa.
- Effervescents have been shown to be useful and advantageous for oral administration. See Pharmaceutical Dosage Forms: Tablets Volume I, Second Edition. A. Lieberman. ed. 1989, Marcel Dekker, Inc. As discussed in this text, and as commonly employed, an effervescent tablet is dissolved in water to provide a carbonated or sparkling liquid drink. See also U.S. Pat. Nos. 5,102,665 and 5,468,504 to Schaeffer, herein incorporated by reference. In such a drink, the effervescent helps to mask the taste of medicaments.
- Effervescent compositions have also been employed for use as taste masking agents in dosage forms which are not dissolved in water prior to administration.
- U.S. Pat. No. 4,639,368 describes a chewing gum containing a medicament capable of absorption through the buccal cavity and containing a taste masking amount of an effervescent.
- J. Rathbone which are herein incorporated by reference.
- the compounds which may be well absorbed per-orally may not be well absorbed through the mucosa of the mouth because the oral mucosa is less permeable than the intestinal mucosa and it does not offer as big a surface area as the small intestine.
- compositions of the present invention comprise an orally administrable medicament in combination with an effervescent agent used as penetration enhancer to influence the permeability of the medicament across the buccal, sublingual, and gingival mucosa.
- One aspect of this invention is to use effervescent as penetration enhancers for influencing oral drug absorption.
- Effervescent agents can be used alone or in combination with other penetration enhancers, which leads to an increase in the rate and extent of absorption of an active drug. It is believed that such increase can rise from one or all of the following mechanisms:
- the present dosage forms should include an amount of an effervescent agent effective to aid in penetration of the drug across the oral mucosa.
- the effervescent is provided in an amount of between about 5% and about 95% by weight, based on the weight of the finished tablet, and more preferably in an amount of between about 30% and about 80% by weight. It is particularly preferred that sufficient effervescent material be provided such that the evolved gas is more than about 5 cm 3 but less than about 30 cm 3 , upon exposure of the tablet to an aqueous environment.
- the amount of effervescent agent must be optimized for each specific drug.
- effervescent agent includes compounds which evolve gas.
- the preferred effervescent agents evolve gas by means of a chemical reaction which takes place upon exposure of the effervescent agent (an effervescent couple) to water and/or to saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source and a source of carbon dioxide such as an alkaline carbonate or bicarbonate. The reaction of these two general compounds produces carbon dioxide gas upon contact with water or saliva.
- Such water-activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the tablet.
- the acid sources may be any which are safe for human consumption and may generally include food acids, acid and hydrite antacids such as, for example: citric, tartaric, amalic, fumeric, adipic, and succinics.
- Carbonate sources include dry solid carbonate and bicarbonate salt such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. Reactants which evolve oxygen or other gasses and which are safe for human consumption are also included.
- the effervescent agent(s) of the present invention is not always based upon a reaction which forms carbon dioxide. Reactants which evolve oxygen or other gasses which are safe for human consumption are also considered within the scope. Where the effervescent agent includes two mutually reactive components, such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, an equivalent ratio of components which provides for equal equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono-reactive carbonate base, or an equal amount of a di-reactive base should be used for complete neutralization to be realized. However, in other embodiments of the present invention, the amount of either acid or carbonate source may exceed the amount of the other component. This may be useful to enhance taste and/or performance of a tablet containing an overage of either component. In this case, it is acceptable that the additional amount of either component may remain unreacted.
- the present dosage forms may also include in amounts additional to that required for effervescence a pH adjusting substance.
- a pH adjusting substance For drugs that are weakly acidic or weakly basic, the pH of the aqueous environment can influence the relative concentrations of the ionized and unionized forms of the drug present in solution according to the Henderson-Hasselbach equation.
- the pH solutions in which an effervescent couple has dissolved is slightly acidic due to the evolution of carbon dioxide.
- the pH of the local environment e.g., saliva in immediate contact with the tablet and any drug that may have dissolved from it, may be adjusted by incorporating in the tablet a pH adjusting substances which permit the relative portions of the ionized and unionized forms of the drug to be controlled. In this way, the present dosage forms can be optimized for each specific drug.
- the unionized drug is known or suspected to be absorbed through the cell membrane (transcellular absorption) it would be preferable to alter the pH of the local environment (within the limits tolerable to the subject) to a level that favors the unionized form of the drug. Conversely, if the ionized form is more readily dissolved the local environment should favor ionization.
- the aqueous solubility of the drug should preferably not be compromised by the effervescent and pH adjusting substance, such that the dosage forms permit a sufficient concentration of the drug to be present in the unionized form.
- the percentage of the pH adjusting substance and/or effervescent should therefore be adjusted depending on the drug.
- Suitable pH adjusting substance for use in the present invention include any weak acid or weak base in amounts additional to that required for the effervescence or, preferably, any buffer system that is not harmful to the oral mucosa.
- Suitable pH adjusting substance for use in the present invention include, but are not limited to, any of the acids or bases previously mentioned as effervescent compounds, disodium hydrogen phosphate, sodium dihydrogen phosphate and the equivalent potassium salt.
- the active ingredient suitable for use in the present dosage forms can include systematically distributable pharmaceutical ingredients, vitamins, minerals, dietary supplements, as well as non-systematically distributable drugs.
- the active ingredient is a systemically active pharmaceutical ingredient which is absorbable by the body through the oral mucosa.
- the dosage forms can be employed with a wide range of drugs, as discussed below, it is especially suitable for drugs and other pharmaceutical ingredients which suffer significant loss of activity in the lumen of the gastrointestinal tract or in the tissues of the gastrointestinal tract during absorption process or upon passage through the liver after absorption in the intestinal tract. Absorption through the oral mucosa allows the drug to enter the systemic circulation without first passing through the liver, and thus alleviates the loss of activity upon passage through the liver.
- Pharmaceutical ingredients may include, without limitation, analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatulents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers; peptides, proteins, oligonucleotides and other substances of biological origin, and combinations thereof.
- active ingredient(s) “pharmaceutical ingredient(s)” and “active agents” are the drugs and pharmaceutically active ingredients described in Mantelle, U.S. Pat. No.
- the active ingredient can include drugs and other pharmaceutical ingredients, vitamins, minerals and dietary supplements as the same are defined in U.S. Pat. No. 5,178,878, the disclosure of which is also incorporated by reference herein.
- the dosage form preferably includes an effervescent couple, in combination with the other ingredients to enhance the absorption of the pharmaceutical ingredient across the oral mucosa and to improve the disintegration profile and the organoleptic properties of the dosage form.
- the area of contact between the dosage form and the oral mucosa, and the residence time of the dosage form in the oral cavity can be improved by including a bioadhesive polymer in this drug delivery system. See, e.g., Mechanistic Studies on Effervescent-Induced Permeability Enhancement by Jonathan Eichman (1997), which is incorporated by reference herein.
- bioadhesives used in the present invention include, for example, Carbopol 934 P, Na CMC, Methocel, Polycarbophil (Noveon AA-1), HPMC, Na alginate, Na Hyaluronate and other natural or synthetic bioadhesives.
- a dosage form according to the present invention may also include suitable non-effervescent disintegration agents.
- suitable non-effervescent disintegration agents include: microcrystalline, cellulose, croscarmellose sodium, crospovidone, starches, corn starch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, alginates, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth.
- Disintegrants may comprise up to about 20 weight percent and preferably between about 2 and about 10% of the total weight of the composition.
- the dosage forms may also include glidants, lubricants, binders, sweeteners, flavoring and coloring components. Any conventional sweetener or flavoring component may be used. Combinations of sweeteners, flavoring components, or sweeteners and flavoring components may likewise be used.
- binders which can be used include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, invert sugars and the like. Binders may be used in an amount of up to 60 weight percent and preferably about 10 to about 40 weight percent of the total composition.
- Coloring agents may include titanium dioxide, and dyes suitable for food such as those known as F.D.&C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc.
- the amount of coloring used may range from about 0.1 to about 3.5 weight percent of the total composition.
- Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
- Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof.
- the amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors may be present in an amount ranging from about 0.05 to about 3 percent by weight based upon the weight of the composition.
- Particularly preferred flavors are the grape and cherry flavors and citrus flavors such as orange.
- One aspect of the invention provides a solid, oral tablet dosage form suitable for sublingual, buccal, and gingival administration.
- Excipient fillers can be used to facilitate tableting.
- the filler desirably will also assist in the rapid dissolution of the dosage form in the mouth.
- suitable fillers include: mannitol, dextrose, lactose, sucrose, and calcium carbonate.
- Tablets can either be manufactured by direct compression, wet granulation or any other tablet manufacturing technique. See, e.g., U.S. Pat. Nos. 5,178,878 and 5,223,264, which are incorporated by reference herein.
- the tablet may be a layered tablet consisting of a layer of the active ingredient sandwiched between a bioadhesive layer and an effervescence layer.
- Other layered forms which include the ingredients set forth above in layers of diverse compositions.
- the dosage form may be administered to a human or other mammalian subject by placing the dosage form in the subject's mouth and holding it in the mouth, either adjacent a cheek (for buccal administration), beneath the tongue (for sublingual administration) and between the upper lip and gum (for gingival administration).
- the dosage form spontaneously begins to disintegrate due to the moisture in the mouth.
- the disintegration, and particularly the effervescence, stimulates additional salivation which further enhances disintegration.
- the dosage form should include Fentanyl, an effervescent and pH adjusting substance so that the pH is adjusted to neutral (or slightly higher) since the pKa of fentanyl is 7.3. At this pH, the aqueous solubility of this poorly water-soluble drug would not be compromised unduly, and would permit a sufficient concentration of the drug to be present in the unionized form.
Abstract
A pharmaceutical dosage form adapted to supply a medicament to the oral cavity for buccal, sublingual or gingival absorption of the medicament which contains an orally administrable medicament in combination with an effervescent for use in promoting absorption of the medicament in the oral cavity. The use of an additional pH adjusting substance in combination with the effervescent for promoting the absorption drugs is also disclosed.
Description
- The present application is a continuation application of U.S. patent application Ser. No. 10/269,669 filed Oct. 11, 2002, which is a divisional application of U.S. patent application Ser. No. 09/661,693, filed Sep. 14, 2000, which is a continuation application of U.S. patent application Ser. No. 09/327,814 filed Jun. 8, 1999, which is a continuation application of U.S. patent application Ser. No. 09/277,424, filed Mar. 26, 1999, which claims the benefit of U.S. Provisional Application No. 60/079,652 filed on Mar. 27, 1998, the benefit of which is claimed under 35 U.S.C. § 120 and the disclosure of which is incorporated by reference herein.
- The present invention relates to pharmaceutical compositions, and more particularly to pharmaceutical compositions for oral administration of a medicament, which contain an effervescent agent for enhancing oral drug absorption across the buccal, sublingual, and gingival mucosa.
- Effervescents have been shown to be useful and advantageous for oral administration. See Pharmaceutical Dosage Forms: Tablets Volume I, Second Edition. A. Lieberman. ed. 1989, Marcel Dekker, Inc. As discussed in this text, and as commonly employed, an effervescent tablet is dissolved in water to provide a carbonated or sparkling liquid drink. See also U.S. Pat. Nos. 5,102,665 and 5,468,504 to Schaeffer, herein incorporated by reference. In such a drink, the effervescent helps to mask the taste of medicaments.
- Effervescent compositions have also been employed for use as taste masking agents in dosage forms which are not dissolved in water prior to administration. For example, U.S. Pat. No. 4,639,368 describes a chewing gum containing a medicament capable of absorption through the buccal cavity and containing a taste masking amount of an effervescent.
- More recently effervescents have been employed to obtain rapid dissolution and/or dispersion of the medicament in the oral cavity. See U.S. Pat. Nos. 5,178,878 and 5,223,264. The effervescent tends to stimulate saliva production thereby providing additional water to aid in further effervescent to a faster onset of action and/or improved bioavailability action. These dosage forms give an agreeable presentation of the drug, particularly for patients who have difficulty in swallowing tablets or capsules. PCT application WO 97/06786 describes pre-gastric absorption of certain drugs using rapidly-disbursing dosage forms.
- Various proposals have been advanced for oral mucosal administration of various drugs. When drugs are absorbed from the oral mucosa, they bypass the gastrointestinal and hepatic metabolism process. This can lead of a drug. However, many compounds do not rapidly penetrate the oral mucosa. See, e.g., Christina Graffner, Clinical Experience with Novel Buccal and Sublingual Administration; NOVEL DRUG DELIVERY AND ITS THERAPEUTIC APPLICATION, edited by L. F. Prescott and W. S. Nimmo (1989); David Harris & Joseph R. Robinson, Drug Delivery via the Mucous Membranes of the Oral Cavity; JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 81 (January 1992); Oral Mucosal Delivery, edited by M. J. Rathbone, which are herein incorporated by reference. The compounds which may be well absorbed per-orally (through the gastrointestinal tract) may not be well absorbed through the mucosa of the mouth because the oral mucosa is less permeable than the intestinal mucosa and it does not offer as big a surface area as the small intestine.
- Despite these and other efforts toward increasing the permeation of medicaments across the oral mucosa, there have been unmet needs for improved methods of administrating medicaments across the oral mucosa.
- The pharmaceutical compositions of the present invention comprise an orally administrable medicament in combination with an effervescent agent used as penetration enhancer to influence the permeability of the medicament across the buccal, sublingual, and gingival mucosa.
- One aspect of this invention is to use effervescent as penetration enhancers for influencing oral drug absorption. Effervescent agents can be used alone or in combination with other penetration enhancers, which leads to an increase in the rate and extent of absorption of an active drug. It is believed that such increase can rise from one or all of the following mechanisms:
-
- 1. reducing the mucosal layer thickness and/or viscosity;
- 2. tight junction alteration;
- 3. inducing a change in the cell membrane structure; and
- 4. increasing the hydrophobic environment within the cellular membrane.
- The present dosage forms should include an amount of an effervescent agent effective to aid in penetration of the drug across the oral mucosa. Preferably, the effervescent is provided in an amount of between about 5% and about 95% by weight, based on the weight of the finished tablet, and more preferably in an amount of between about 30% and about 80% by weight. It is particularly preferred that sufficient effervescent material be provided such that the evolved gas is more than about 5 cm3 but less than about 30 cm3, upon exposure of the tablet to an aqueous environment. However, the amount of effervescent agent must be optimized for each specific drug.
- The term “effervescent agent” includes compounds which evolve gas. The preferred effervescent agents evolve gas by means of a chemical reaction which takes place upon exposure of the effervescent agent (an effervescent couple) to water and/or to saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source and a source of carbon dioxide such as an alkaline carbonate or bicarbonate. The reaction of these two general compounds produces carbon dioxide gas upon contact with water or saliva. Such water-activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the tablet. The acid sources may be any which are safe for human consumption and may generally include food acids, acid and hydrite antacids such as, for example: citric, tartaric, amalic, fumeric, adipic, and succinics. Carbonate sources include dry solid carbonate and bicarbonate salt such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. Reactants which evolve oxygen or other gasses and which are safe for human consumption are also included.
- The effervescent agent(s) of the present invention is not always based upon a reaction which forms carbon dioxide. Reactants which evolve oxygen or other gasses which are safe for human consumption are also considered within the scope. Where the effervescent agent includes two mutually reactive components, such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, an equivalent ratio of components which provides for equal equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono-reactive carbonate base, or an equal amount of a di-reactive base should be used for complete neutralization to be realized. However, in other embodiments of the present invention, the amount of either acid or carbonate source may exceed the amount of the other component. This may be useful to enhance taste and/or performance of a tablet containing an overage of either component. In this case, it is acceptable that the additional amount of either component may remain unreacted.
- The present dosage forms may also include in amounts additional to that required for effervescence a pH adjusting substance. For drugs that are weakly acidic or weakly basic, the pH of the aqueous environment can influence the relative concentrations of the ionized and unionized forms of the drug present in solution according to the Henderson-Hasselbach equation. The pH solutions in which an effervescent couple has dissolved is slightly acidic due to the evolution of carbon dioxide. The pH of the local environment, e.g., saliva in immediate contact with the tablet and any drug that may have dissolved from it, may be adjusted by incorporating in the tablet a pH adjusting substances which permit the relative portions of the ionized and unionized forms of the drug to be controlled. In this way, the present dosage forms can be optimized for each specific drug. If the unionized drug is known or suspected to be absorbed through the cell membrane (transcellular absorption) it would be preferable to alter the pH of the local environment (within the limits tolerable to the subject) to a level that favors the unionized form of the drug. Conversely, if the ionized form is more readily dissolved the local environment should favor ionization.
- The aqueous solubility of the drug should preferably not be compromised by the effervescent and pH adjusting substance, such that the dosage forms permit a sufficient concentration of the drug to be present in the unionized form. The percentage of the pH adjusting substance and/or effervescent should therefore be adjusted depending on the drug.
- Suitable pH adjusting substance for use in the present invention include any weak acid or weak base in amounts additional to that required for the effervescence or, preferably, any buffer system that is not harmful to the oral mucosa. Suitable pH adjusting substance for use in the present invention include, but are not limited to, any of the acids or bases previously mentioned as effervescent compounds, disodium hydrogen phosphate, sodium dihydrogen phosphate and the equivalent potassium salt.
- The active ingredient suitable for use in the present dosage forms can include systematically distributable pharmaceutical ingredients, vitamins, minerals, dietary supplements, as well as non-systematically distributable drugs. Preferably, the active ingredient is a systemically active pharmaceutical ingredient which is absorbable by the body through the oral mucosa. Although the dosage forms can be employed with a wide range of drugs, as discussed below, it is especially suitable for drugs and other pharmaceutical ingredients which suffer significant loss of activity in the lumen of the gastrointestinal tract or in the tissues of the gastrointestinal tract during absorption process or upon passage through the liver after absorption in the intestinal tract. Absorption through the oral mucosa allows the drug to enter the systemic circulation without first passing through the liver, and thus alleviates the loss of activity upon passage through the liver.
- Pharmaceutical ingredients may include, without limitation, analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatulents, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, beta blockers; peptides, proteins, oligonucleotides and other substances of biological origin, and combinations thereof. Also encompassed by the terms “active ingredient(s)”, “pharmaceutical ingredient(s)” and “active agents” are the drugs and pharmaceutically active ingredients described in Mantelle, U.S. Pat. No. 5,234,957, in columns 18 through 21. That text of Mantelle is hereby incorporated by reference. Alternatively or additionally, the active ingredient can include drugs and other pharmaceutical ingredients, vitamins, minerals and dietary supplements as the same are defined in U.S. Pat. No. 5,178,878, the disclosure of which is also incorporated by reference herein.
- The dosage form preferably includes an effervescent couple, in combination with the other ingredients to enhance the absorption of the pharmaceutical ingredient across the oral mucosa and to improve the disintegration profile and the organoleptic properties of the dosage form. For example, the area of contact between the dosage form and the oral mucosa, and the residence time of the dosage form in the oral cavity can be improved by including a bioadhesive polymer in this drug delivery system. See, e.g., Mechanistic Studies on Effervescent-Induced Permeability Enhancement by Jonathan Eichman (1997), which is incorporated by reference herein. Effervescence, due to its mucus stripping properties, would also enhance the residence time of the bioadhesive, thereby increasing the residence time for the drug absorption. Non-limiting examples of bioadhesives used in the present invention include, for example, Carbopol 934 P, Na CMC, Methocel, Polycarbophil (Noveon AA-1), HPMC, Na alginate, Na Hyaluronate and other natural or synthetic bioadhesives.
- In addition to the effervescence-producing agents, a dosage form according to the present invention may also include suitable non-effervescent disintegration agents. Non-limiting examples of non-effervescent disintegration agents include: microcrystalline, cellulose, croscarmellose sodium, crospovidone, starches, corn starch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, alginates, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth. Disintegrants may comprise up to about 20 weight percent and preferably between about 2 and about 10% of the total weight of the composition.
- In addition to the particles in accordance with the present invention, the dosage forms may also include glidants, lubricants, binders, sweeteners, flavoring and coloring components. Any conventional sweetener or flavoring component may be used. Combinations of sweeteners, flavoring components, or sweeteners and flavoring components may likewise be used.
- Examples of binders which can be used include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, invert sugars and the like. Binders may be used in an amount of up to 60 weight percent and preferably about 10 to about 40 weight percent of the total composition.
- Coloring agents may include titanium dioxide, and dyes suitable for food such as those known as F.D.&C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc. The amount of coloring used may range from about 0.1 to about 3.5 weight percent of the total composition.
- Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors may be present in an amount ranging from about 0.05 to about 3 percent by weight based upon the weight of the composition. Particularly preferred flavors are the grape and cherry flavors and citrus flavors such as orange.
- One aspect of the invention provides a solid, oral tablet dosage form suitable for sublingual, buccal, and gingival administration. Excipient fillers can be used to facilitate tableting. The filler desirably will also assist in the rapid dissolution of the dosage form in the mouth. Non-limiting examples of suitable fillers include: mannitol, dextrose, lactose, sucrose, and calcium carbonate.
- Method of Manufacture
- Tablets can either be manufactured by direct compression, wet granulation or any other tablet manufacturing technique. See, e.g., U.S. Pat. Nos. 5,178,878 and 5,223,264, which are incorporated by reference herein. The tablet may be a layered tablet consisting of a layer of the active ingredient sandwiched between a bioadhesive layer and an effervescence layer. Other layered forms which include the ingredients set forth above in layers of diverse compositions.
-
- Effervescence Level: Between 5%-95%
- Tablet size: Between {fraction (3/16)}″-⅝″
- Tablet hardness: Between 5N and 80N
- Route of administration: Sublingual, Buccal, Gingival
- The dosage form may be administered to a human or other mammalian subject by placing the dosage form in the subject's mouth and holding it in the mouth, either adjacent a cheek (for buccal administration), beneath the tongue (for sublingual administration) and between the upper lip and gum (for gingival administration). The dosage form spontaneously begins to disintegrate due to the moisture in the mouth. The disintegration, and particularly the effervescence, stimulates additional salivation which further enhances disintegration.
- The dosage form should include Fentanyl, an effervescent and pH adjusting substance so that the pH is adjusted to neutral (or slightly higher) since the pKa of fentanyl is 7.3. At this pH, the aqueous solubility of this poorly water-soluble drug would not be compromised unduly, and would permit a sufficient concentration of the drug to be present in the unionized form.
- Two fentanyl formulations, each containing 36% effervescence, were produced. These tablets were compressed using half-inch shallow concave punches.
QUANTITY FORMULATION COMPONENT (MG) SHORT Fentanyl, citrate, USP 1.57 DISINTEGRATION Lactose monohydrate 119.47 TIME Microcrystalline 119.47 Cellulose, Silicified Sodium carbonate, 46.99 anhydrous Sodium bicarbonate 105 Citric acid, anhydrous 75 Polyvinylphrrolidone, 25 cross-linked Magnesium stearate 5 Colloidal silicon dioxide 2.5 Total tablet mass 500 LONG Fentanyl citrate, USP 1.57 DISINTEGRATION Lactose monohydrate 270.93 TIME Sodium carbonate, 40.00 anhydrous Sodium bicarbonate 105 Citric acid, anhydrous 75 Magnesium stearate 5 Colloidal silicon dioxide 2.5 Total tablet mass 500 - The dosage form included prochlorperazine (pKa=8.1), an effervescent and pH adjusting substance so that a slightly higher pH is produced to facilitate the permeation enhancement.
- With respect to prochlorperazine, an anti-emetic drug, two formulations, buccal and sublingual, were developed. The buccal tablets were compressed as quarter inch diameter biconvex tablets, whereas the sublingual tablets were three-eighths inch diameter biconvex tablets. These dimensions were chosen to give a comfortable fit in the respective part of the oral cavity for which they were designed. The formulae for these tablets are as follows:
QUANTITY FORMULATION COMPONENT NAME (MG) BUCCAL Prochlorperazine 5.00 Sodium Bicarbonate 15.52 Citric Acid, Anhydrous 11.08 Sodium Bicarbonate 45.78 HPMC K4M Prem 5.00 Dicalcium phosphate 5.00 dihydrate Mannitol 11.67 Magnesium Stearate 0.95 Total 100.00 SUBLINGUAL Prochlorperazine 5.00 Sodium Bicarbonate 61.25 Citric Acid, Anhydrous 43.75 Sodium Bicarbonate 95 Sodium carbonate 91.25 HPMC Methocel K4M Prem 40 Mannitol 60 Magnesium Stearate 3.75 Total 400
Claims (18)
1. A method of manufacturing a tablet suitable for direct oral administration across the oral mucosa, said method comprising the steps of:
a) selecting a pharmaceutically effective amount of an orally administrable medicament;
b) selecting at least one saliva activated effervescent couple and determining what amount of same will be necessary to provide for both tablet disintegration and an increase in either the rate or extent of absorption of said orally administrable medicament across the oral mucosa, wherein said amount of said at least one effervescent couple ranges from about 5% by weight to about 80% by weight;
c) producing a mixture from said medicament and said saliva activated effervescent couple; and
d) compressing at least a portion of said mixture so as to form at least one tablet.
2. The method of claim 1 , further comprising the step of selecting a bioadhesive and producing said mixture including same.
3. The method of claim 1 , further comprising the step of: selecting a non-effervescent disintegration agent and producing said mixture including same.
4. The method of claim 1 , further comprising the step of: selecting one or more glidants, lubricants, binders, sweeteners, flavoring and coloring components and producing said mixture including same.
5. The method of claim 1 , wherein said orally administrable medicament is selected from the group consisting of analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatulents, anti-emetics, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, and beta blockers.
6. The method of claim 1 , wherein said orally administrable medicament is selected from the group consisting of peptides, proteins and oligonucleotides.
7. The method of claim 1 , wherein said at least one saliva activated effervescent agent is present in an amount between about 20% by weight and 80% by weight.
8. A method of manufacturing a tablet suitable for direct oral administration across the oral mucosa, said method comprising the steps of:
a) selecting at least one orally administrable medicament capable of existing in an ionized form and a unionized form in aqueous environment and determining a pharmaceutically effective amount of same;
b) selecting at least one saliva activated effervescent couple and determining what amount of same will be necessary to provide for both tablet disintegration and an increase in either the rate or extent of absorption of said orally administrable medicament across the oral mucosa;
c) selecting a pH adjusting substance and determining what amount of same is sufficient to change the pH of a local environment of said tablet at a site of absorption in the mouth to favor said unionized form of said medicament;
d) producing a mixture from said medicament, said selected saliva activated effervescent couple and said pH adjusting substance, in said predetermined amounts; and
e) compressing at least a portion of said mixture so as to form at least one tablet.
9. The method of claim 8 , further comprising the step of: selecting one or more glidants, lubricants, binders, sweeteners, flavoring and coloring components and producing said mixture including same.
10. The method of claim 8 , wherein said orally administrable medicament is selected from the group consisting of analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorexics, antihistamines, antiasthmatics, antidiuretics, antiflatulents, anti-emetics, antimigraine agents, antispasmodics, sedatives, antihyperactives, antihypertensives, tranquilizers, decongestants, and beta blockers.
11. The method of claim 8 , wherein said orally administrable medicament is selected from the group consisting of peptides, proteins and oligonucleotides.
12. The method according to claim 8 , wherein said at least one effervescent agent is present in an amount between about 5% by weight and 95% by weight.
13. The method according to claim 8 , wherein said at least one effervescent agent is present in an amount between about 5% by weight and 80% by weight.
14. The method according to claim 13 , wherein said at least one effervescent agent is present in an amount between about 20% by weight and 80% by weight.
15. The method according to claim 8 , wherein said at least one effervescent agent is present in an amount sufficient to evolve a gas in an amount between about 5 cm3 to about 30 cm3.
16. The method according to claim 8 , wherein said pH adjusting substance is a base.
17. The method according to claim 16 , wherein said base is selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.
18. The method according to claim 8 , wherein said pH adjusting substance is an acid.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/977,029 US20050064030A1 (en) | 1998-03-27 | 2004-10-29 | Sublingual buccal effervescent |
US11/511,098 US8802130B2 (en) | 1998-03-27 | 2006-08-28 | Sublingual buccal effervescent |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7965298P | 1998-03-27 | 1998-03-27 | |
US27742499A | 1999-03-26 | 1999-03-26 | |
US09/327,814 US6200604B1 (en) | 1998-03-27 | 1999-06-08 | Sublingual buccal effervescent |
US66169300A | 2000-09-14 | 2000-09-14 | |
US10/269,669 US20030091629A1 (en) | 1998-03-27 | 2002-10-11 | Sublingual buccal effervescent |
US10/977,029 US20050064030A1 (en) | 1998-03-27 | 2004-10-29 | Sublingual buccal effervescent |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/269,669 Continuation US20030091629A1 (en) | 1998-03-27 | 2002-10-11 | Sublingual buccal effervescent |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/511,098 Continuation US8802130B2 (en) | 1998-03-27 | 2006-08-28 | Sublingual buccal effervescent |
Publications (1)
Publication Number | Publication Date |
---|---|
US20050064030A1 true US20050064030A1 (en) | 2005-03-24 |
Family
ID=46281346
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/269,669 Abandoned US20030091629A1 (en) | 1998-03-27 | 2002-10-11 | Sublingual buccal effervescent |
US10/977,029 Abandoned US20050064030A1 (en) | 1998-03-27 | 2004-10-29 | Sublingual buccal effervescent |
US11/511,098 Expired - Lifetime US8802130B2 (en) | 1998-03-27 | 2006-08-28 | Sublingual buccal effervescent |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/269,669 Abandoned US20030091629A1 (en) | 1998-03-27 | 2002-10-11 | Sublingual buccal effervescent |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/511,098 Expired - Lifetime US8802130B2 (en) | 1998-03-27 | 2006-08-28 | Sublingual buccal effervescent |
Country Status (1)
Country | Link |
---|---|
US (3) | US20030091629A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070207207A1 (en) * | 2006-01-06 | 2007-09-06 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US20070260491A1 (en) * | 2006-05-08 | 2007-11-08 | Pamela Palmer | System for delivery and monitoring of administration of controlled substances |
US20070299687A1 (en) * | 2006-06-23 | 2007-12-27 | Pamela Palmer | Inpatient system for patient-controlled delivery of oral transmucosal medications dosed as needed |
US20080131508A1 (en) * | 2006-12-01 | 2008-06-05 | Cephalon, Inc | Oral transmucosal nicotine dosage form |
US20080147044A1 (en) * | 2006-01-06 | 2008-06-19 | Acelrx Pharmaceuticals, Inc. | Methods for administering small volume oral transmucosal dosage forms using a dispensing device |
US20080164275A1 (en) * | 2007-01-05 | 2008-07-10 | Acelrx Pharmaceuticals, Inc. | Storage and dispensing devices for administration of oral transmucosal dosage forms |
US20090131479A1 (en) * | 2006-01-06 | 2009-05-21 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage |
US20090214442A1 (en) * | 2006-12-01 | 2009-08-27 | Cephalon, Inc. | Oral Transmucosal Nicotine Dosage Form |
US20090263476A1 (en) * | 2008-04-16 | 2009-10-22 | Jobdevairakkam Christopher N | Composition of Rapid Disintegrating Direct Compression Buccal Tablet |
US8252329B2 (en) | 2007-01-05 | 2012-08-28 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US8357114B2 (en) | 2006-01-06 | 2013-01-22 | Acelrx Pharmaceuticals, Inc. | Drug dispensing device with flexible push rod |
US8535714B2 (en) | 2006-01-06 | 2013-09-17 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8865743B2 (en) | 2006-01-06 | 2014-10-21 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8945592B2 (en) | 2008-11-21 | 2015-02-03 | Acelrx Pharmaceuticals, Inc. | Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6974590B2 (en) | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US20030118645A1 (en) * | 1998-04-29 | 2003-06-26 | Pather S. Indiran | Pharmaceutical compositions for rectal and vaginal administration |
US20030091629A1 (en) | 1998-03-27 | 2003-05-15 | Cima Labs Inc. | Sublingual buccal effervescent |
US7799342B2 (en) * | 2000-12-06 | 2010-09-21 | Wyeth Llc | Fast dissolving tablet |
US20030068356A1 (en) * | 2001-07-10 | 2003-04-10 | Pather S. Indiran | Sequential drug delivery systems |
DE10207394B4 (en) * | 2002-02-21 | 2007-03-29 | Lts Lohmann Therapie-Systeme Ag | Taste-masked oblate medicinal preparation |
US20080213363A1 (en) * | 2003-01-23 | 2008-09-04 | Singh Nikhilesh N | Methods and compositions for delivering 5-HT3 antagonists across the oral mucosa |
BRPI0418228B8 (en) | 2003-12-31 | 2021-05-25 | Cima Labs Inc | dosage form, and method of preparing a tablet for buccal, gingival or sublingual administration of fentanyl |
EP1708685B1 (en) | 2003-12-31 | 2011-03-09 | Cima Labs Inc. | Effervescent oral opiate dosage forms and methods of administering oxycodone |
WO2005065317A2 (en) * | 2003-12-31 | 2005-07-21 | Cima Labs Inc. | Effervescent oral fentanyl dosage form |
KR20130006523A (en) * | 2004-02-17 | 2013-01-16 | 트랜스셉트 파마슈티칼스, 인코포레이티드 | Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof |
KR20080031208A (en) * | 2005-05-25 | 2008-04-08 | 트랜스셉트 파마슈티칼스, 인코포레이티드 | Solid compositions and methods for treating middle-of-the night insomnia |
US20070225322A1 (en) * | 2005-05-25 | 2007-09-27 | Transoral Pharmaceuticals, Inc. | Compositions and methods for treating middle-of-the night insomnia |
US20070287740A1 (en) * | 2005-05-25 | 2007-12-13 | Transcept Pharmaceuticals, Inc. | Compositions and methods of treating middle-of-the night insomnia |
CN110913853A (en) | 2017-06-20 | 2020-03-24 | 医师印章有限责任公司 | Orally dissolving melatonin formulations with acidulants that render melatonin soluble in saliva |
Citations (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1262888A (en) * | 1917-02-20 | 1918-04-16 | Albert Westlake | Mouth-tablet. |
US1263888A (en) * | 1918-01-10 | 1918-04-23 | J T Vail | Wave-motor. |
US3131123A (en) * | 1959-03-13 | 1964-04-28 | Lab Francais De Therapeutique | Enteric tablets and manufacture thereof |
US3577490A (en) * | 1967-10-02 | 1971-05-04 | Miles Lab | Effervescent tablet and process for making same |
US3888976A (en) * | 1972-09-21 | 1975-06-10 | William P Mlkvy | Zinc and strontium ion containing effervescent mouthwash tablet |
US3961041A (en) * | 1974-11-14 | 1976-06-01 | Interx Research Corporation | Effervescent enteric coated L-dopa formulation and method of using the same |
US3972995A (en) * | 1975-04-14 | 1976-08-03 | American Home Products Corporation | Dosage form |
US4147768A (en) * | 1976-09-13 | 1979-04-03 | Interx Research Corporation | Enteric coated digoxin and therapeutic use thereof |
US4187286A (en) * | 1979-01-02 | 1980-02-05 | G&W Laboratories, Inc. | Contraceptive suppository |
US4289751A (en) * | 1979-06-29 | 1981-09-15 | Merck & Co., Inc. | Effervescent enteric-coated formulation of soluble form of erythromycin and therapeutic use thereof |
US4493848A (en) * | 1983-07-14 | 1985-01-15 | The Procter & Gamble Company | Compositions and methods useful for producing analgesia |
US4503031A (en) * | 1982-12-17 | 1985-03-05 | Glassman Jacob A | Super-fast-starting-sustained release tablet |
US4599342A (en) * | 1984-01-16 | 1986-07-08 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
US4639368A (en) * | 1984-08-23 | 1987-01-27 | Farmacon Research Corporation | Chewing gum containing a medicament and taste maskers |
US4671953A (en) * | 1985-05-01 | 1987-06-09 | University Of Utah Research Foundation | Methods and compositions for noninvasive administration of sedatives, analgesics, and anesthetics |
US4756710A (en) * | 1985-04-05 | 1988-07-12 | Merck & Co., Inc. | pH-Mediated drug delivery system |
US4853211A (en) * | 1982-03-05 | 1989-08-01 | Eisai Co., Ltd. | Stable, effervescent vaginal suppositories |
US5002771A (en) * | 1989-02-06 | 1991-03-26 | Rorer Pharmaceutical Corp. | Calcitonin suppository formulations |
US5028411A (en) * | 1984-04-19 | 1991-07-02 | National Research Development Corporation | Pharmaceutical compositions |
US5053396A (en) * | 1985-08-27 | 1991-10-01 | Blass David H | Therapeutic composition |
US5073374A (en) * | 1988-11-30 | 1991-12-17 | Schering Corporation | Fast dissolving buccal tablet |
US5135752A (en) * | 1988-10-14 | 1992-08-04 | Zetachron, Inc. | Buccal dosage form |
US5178878A (en) * | 1989-10-02 | 1993-01-12 | Cima Labs, Inc. | Effervescent dosage form with microparticles |
US5223264A (en) * | 1989-10-02 | 1993-06-29 | Cima Labs, Inc. | Pediatric effervescent dosage form |
US5458879A (en) * | 1994-03-03 | 1995-10-17 | The Procter & Gamble Company | Oral vehicle compositions |
US5468504A (en) * | 1990-12-21 | 1995-11-21 | Laboratoires Glaxo S.A. | Effervescent pharmaceutical compositions |
US5503846A (en) * | 1993-03-17 | 1996-04-02 | Cima Labs, Inc. | Base coated acid particles and effervescent formulation incorporating same |
US5559096A (en) * | 1991-04-15 | 1996-09-24 | Applied Microbiology, Inc. | Pharmaceutical compositions against gastric disorders |
US5607697A (en) * | 1995-06-07 | 1997-03-04 | Cima Labs, Incorporated | Taste masking microparticles for oral dosage forms |
US5624687A (en) * | 1991-04-15 | 1997-04-29 | Yamanouchi Pharmaceutical Co., Ltd. | Quick-dissolution solid preparation |
US5626866A (en) * | 1994-03-07 | 1997-05-06 | Theratech, Inc. | Drug-containing adhesive composite transdermal delivery device |
US5646151A (en) * | 1996-03-08 | 1997-07-08 | Adolor Corporation | Kappa agonist compounds and pharmaceutical formulations thereof |
US5656284A (en) * | 1995-04-24 | 1997-08-12 | Balkin; Michael S. | Oral transmucosal delivery tablet and method of making it |
US5853748A (en) * | 1994-08-31 | 1998-12-29 | Cortecs (Uk) Limited | Pharmaceutical compositions |
US5900252A (en) * | 1990-04-17 | 1999-05-04 | Eurand International S.P.A. | Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon |
US5952004A (en) * | 1994-03-18 | 1999-09-14 | Shire Laboratories Inc. | Emulsified drug delivery systems |
US5958455A (en) * | 1996-02-09 | 1999-09-28 | Quadrant Holdings Cambridge Ltd | Oral solid dosage forms, methods of making same and compositions thereof |
US5958458A (en) * | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
US6034085A (en) * | 1994-11-02 | 2000-03-07 | Bristol-Myers Squibb Co. | Salt form of nefazodone for use in extended release formulations |
US6068853A (en) * | 1994-04-13 | 2000-05-30 | Novartis Corporation | Temporally controlled drug delivery systems |
US6071539A (en) * | 1996-09-20 | 2000-06-06 | Ethypharm, Sa | Effervescent granules and methods for their preparation |
US6117912A (en) * | 1995-11-06 | 2000-09-12 | Somerset Pharmaceuticals, Inc. | Sublingual and buccal administration of selegiline for treating certain selegiline-responsive diseases and conditions |
US6129906A (en) * | 1995-11-11 | 2000-10-10 | The Procter & Gamble Company | Silicone containing powders |
US6200604B1 (en) * | 1998-03-27 | 2001-03-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US6264981B1 (en) * | 1999-10-27 | 2001-07-24 | Anesta Corporation | Oral transmucosal drug dosage using solid solution |
US6326384B1 (en) * | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
US6326360B1 (en) * | 1998-03-11 | 2001-12-04 | Grelan Pharmaceuticals Co., Ltd. | Bubbling enteric coated preparations |
US6342002B1 (en) * | 2000-07-14 | 2002-01-29 | Double Dynasty Co., Ltd. | Structure of a wax-polishing machine |
US6350470B1 (en) * | 1998-04-29 | 2002-02-26 | Cima Labs Inc. | Effervescent drug delivery system for oral administration |
US6488961B1 (en) * | 1996-09-20 | 2002-12-03 | Ethypharm, Inc. | Effervescent granules and methods for their preparation |
US6576250B1 (en) * | 1998-03-27 | 2003-06-10 | Cima Labs Inc. | Pharmaceutical compositions for rectal and vaginal administration |
Family Cites Families (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2887437A (en) * | 1956-08-22 | 1959-05-19 | Pfizer & Co C | Palatable vitamin tablet containing an amino acid |
US3042531A (en) * | 1959-12-09 | 1962-07-03 | Leslie Salt Company | Method of making a compressed tablet |
GB1212704A (en) | 1967-11-21 | 1970-11-18 | Prodotti Antibiotici Spa | Vaginal suppositories |
NL7302521A (en) | 1973-02-23 | 1974-08-27 | Foaming, effervescent capsules - contg. therapeutic agents for rectal and vaginal use | |
US3962417A (en) * | 1974-03-27 | 1976-06-08 | Howell Charles J | Dentifrice |
US4370160A (en) * | 1978-06-27 | 1983-01-25 | Dow Corning Corporation | Process for preparing silicone microparticles |
US4443428A (en) * | 1982-06-21 | 1984-04-17 | Euroceltique, S.A. | Extended action controlled release compositions |
US4613497A (en) * | 1984-02-29 | 1986-09-23 | Health Products Development, Inc. | Dry, water-foamable pharmaceutical compositions |
US4725427A (en) * | 1984-03-13 | 1988-02-16 | Albion International, Inc. | Effervescent vitamin-mineral granule preparation |
US4863737A (en) * | 1985-05-01 | 1989-09-05 | University Of Utah | Compositions and methods of manufacture of compressed powder medicaments |
GB8421226D0 (en) * | 1984-08-21 | 1984-09-26 | Int Conferences Ab | Tooth cleaning tablet |
GB8426152D0 (en) * | 1984-10-16 | 1984-11-21 | Reckitt & Colmann Prod Ltd | Medicinal compositions |
IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
US5785989A (en) * | 1985-05-01 | 1998-07-28 | University Utah Research Foundation | Compositions and methods of manufacturing of oral dissolvable medicaments |
US5288497A (en) * | 1985-05-01 | 1994-02-22 | The University Of Utah | Compositions of oral dissolvable medicaments |
US4687662A (en) * | 1985-08-30 | 1987-08-18 | Warner-Lambert Company | Therapeutic effervescent composition |
US4764375A (en) | 1985-09-11 | 1988-08-16 | Kv Pharmaceutical Company | Sachet drug delivery system |
IT1209667B (en) * | 1985-11-12 | 1989-08-30 | Zambon Spa | EFFEVERSCENT COMPOSITION ANALGESIC ADAPTITY. |
US4876039A (en) | 1986-11-04 | 1989-10-24 | Dow Corning Corporation | Process for preparing silicone microparticles cured by a Michael addition reaction |
IE873172L (en) | 1986-12-29 | 1988-06-29 | Harvard College | Continuous process for producing a comestible tablet |
GB8724763D0 (en) | 1987-10-22 | 1987-11-25 | Aps Research Ltd | Sustained-release formulations |
US5234957A (en) * | 1991-02-27 | 1993-08-10 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
FR2633181B1 (en) * | 1988-06-24 | 1992-01-10 | Glaxo Lab Sa | RANITIDINE-BASED PHARMACEUTICAL COMPOSITION AND PROCESS FOR PREPARING THE SAME |
GB8820327D0 (en) * | 1988-08-26 | 1988-09-28 | May & Baker Ltd | New compositions of matter |
US5004601A (en) * | 1988-10-14 | 1991-04-02 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
DE3838431A1 (en) | 1988-11-12 | 1990-05-17 | Bayer Ag | IBUPROFEN SHOWER PREPARATIONS |
GB8909793D0 (en) | 1989-04-28 | 1989-06-14 | Beecham Group Plc | Pharmaceutical formulation |
US5219574A (en) * | 1989-09-15 | 1993-06-15 | Cima Labs. Inc. | Magnesium carbonate and oil tableting aid and flavoring additive |
DK0494972T3 (en) | 1989-10-02 | 1997-05-12 | Cima Labs Inc | Shower dose form and method of administration thereof |
US5102666A (en) * | 1990-09-11 | 1992-04-07 | Oramed, Inc. | Calcium polycarbophil controlled release composition and method |
US5464632C1 (en) | 1991-07-22 | 2001-02-20 | Prographarm Lab | Rapidly disintegratable multiparticular tablet |
DE4139883A1 (en) | 1991-11-29 | 1993-06-03 | Michael Prof Dr Dittgen | Prodn. of bio-adhesive medicament, e.g. oral or vaginal tablet - comprises mixing drug with swellable, bio-adhesive polymer, dispersant and opt. binder |
IT1253711B (en) * | 1991-12-17 | 1995-08-23 | Alfa Wassermann Spa | VAGINAL PHARMACEUTICAL FORMULATIONS CONTAINING RIFAXIMIN AND THEIR USE IN THE TREATMENT OF VAGINAL INFECTIONS |
EP0553777B1 (en) * | 1992-01-29 | 2002-04-24 | Takeda Chemical Industries, Ltd. | Fast dissolving tablet and its production |
US5851553A (en) | 1993-09-10 | 1998-12-22 | Fuisz Technologies, Ltd. | Process and apparatus for making rapidly dissolving dosage units and product therefrom |
US5635210A (en) * | 1994-02-03 | 1997-06-03 | The Board Of Regents Of The University Of Oklahoma | Method of making a rapidly dissolving tablet |
US5550861A (en) * | 1994-09-27 | 1996-08-27 | Novalink Technologies, Inc. | Modular PCMCIA modem and pager |
FR2729858B1 (en) | 1995-01-30 | 1997-04-18 | Mission Soc Civ | EFFERVESCENT COMPOSITION BASED ON IODIZED POLYVINYLPYRROLIDONE AND USE FOR DISINFECTION |
FR2732217B1 (en) | 1995-03-29 | 1997-06-06 | Hesnard Xavier | SOLID ADMINISTRATION FORM FOR ORAL USE |
GB9510830D0 (en) | 1995-05-27 | 1995-07-19 | Zeneca Ltd | Proteins |
US5948389A (en) * | 1995-06-07 | 1999-09-07 | El Khoury & Stein, Ltd. | Method of enhancing the analgesic efficacy of locally and topically administered opioids and other local anesthetics |
CA2218370C (en) | 1995-07-31 | 2006-10-03 | Gerhard Gergely | Chewable tablet with effervescent action |
GB9517062D0 (en) | 1995-08-18 | 1995-10-25 | Scherer Ltd R P | Pharmaceutical compositions |
GB2307857B (en) | 1995-12-04 | 1999-01-27 | Euro Celtique Sa | An effervescent formulation |
DE19606151C2 (en) * | 1996-02-20 | 1999-05-12 | Losan Pharma Gmbh | Effervescent ibuprofen preparation and process for making the same |
DE19618543C2 (en) * | 1996-05-08 | 1998-07-02 | Ivoclar Ag | Polymerizer |
JP2000511178A (en) | 1996-05-17 | 2000-08-29 | メルク エンド カンパニー インコーポレーテッド | Effervescent bisphosphonate preparation |
US5853759A (en) | 1996-05-17 | 1998-12-29 | Merck & Co.. Inc. | Effervescent alendronate formulation |
US20010006677A1 (en) * | 1996-10-29 | 2001-07-05 | Mcginity James W. | Effervescence polymeric film drug delivery system |
EP0839526A3 (en) | 1996-10-31 | 1999-01-07 | Takeda Chemical Industries, Ltd. | Solid pharmaceutical preparation with fast buccal disintegration or dissolution |
US5948787A (en) * | 1997-02-28 | 1999-09-07 | Alza Corporation | Compositions containing opiate analgesics |
ES2296331T3 (en) | 1997-04-01 | 2008-04-16 | Cima Labs Inc. | BLISTER TYPE AND COMPRESSED PACKAGING. |
FR2766089B1 (en) * | 1997-07-21 | 2000-06-02 | Prographarm Lab | IMPROVED MULTIPARTICULAR TABLET WITH RAPID DELIVERY |
ES2173364T5 (en) * | 1997-10-27 | 2005-04-16 | DR. GERGELY & CO. | EFERVESCENT COMPOSITION WITH VEGETABLE EXTRACT. |
US20030091629A1 (en) | 1998-03-27 | 2003-05-15 | Cima Labs Inc. | Sublingual buccal effervescent |
US6974590B2 (en) * | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US20030118645A1 (en) * | 1998-04-29 | 2003-06-26 | Pather S. Indiran | Pharmaceutical compositions for rectal and vaginal administration |
DE19814257A1 (en) | 1998-03-31 | 1999-10-07 | Asta Medica Ag | effervescent formulations |
US6368625B1 (en) * | 1998-08-12 | 2002-04-09 | Cima Labs Inc. | Orally disintegrable tablet forming a viscous slurry |
SE9803239D0 (en) * | 1998-09-24 | 1998-09-24 | Diabact Ab | Composition for the treatment of acute pain |
SE9803240D0 (en) * | 1998-09-24 | 1998-09-24 | Diabact Ab | A pharmaceutical composition having a rapid action |
US6294192B1 (en) | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US6680071B1 (en) * | 1999-03-03 | 2004-01-20 | R. P. Scherer Technologies, Inc. | Opioid agonist in a fast dispersing dosage form |
US6835194B2 (en) | 1999-03-18 | 2004-12-28 | Durect Corporation | Implantable devices and methods for treatment of pain by delivery of fentanyl and fentanyl congeners |
US6383471B1 (en) * | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
US6262062B1 (en) * | 2000-08-15 | 2001-07-17 | Cpd, Llc | Method of treating the syndrome of coronary heart disease risk factors in humans |
WO2002045713A2 (en) | 2000-12-04 | 2002-06-13 | Sepracor, Inc. | Orally-bioavailable formulations of fentanyl and congeners thereof |
US20030035839A1 (en) * | 2001-05-15 | 2003-02-20 | Peirce Management, Llc | Pharmaceutical composition for both intraoral and oral administration |
FR2832311B1 (en) * | 2001-11-21 | 2004-04-16 | Besins Int Belgique | FILM-FORMING POWDER, COMPOSITIONS COMPRISING SAME, PREPARATION METHODS AND USES THEREOF |
FR2834212B1 (en) * | 2001-12-27 | 2004-07-09 | Besins Int Belgique | USE OF IMMEDIATE RELEASE POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS |
US6713470B2 (en) * | 2002-01-22 | 2004-03-30 | Ml Laboratories Plc | Method of treatment |
ES2270335T7 (en) | 2003-01-31 | 2012-03-16 | Orexo Ab | PHARMACEUTICAL EFFECT COMPOSITION. |
US20050042281A1 (en) * | 2003-08-21 | 2005-02-24 | Singh Nikhilesh N. | Compositions for delivering therapeutic agents across the oral mucosa |
WO2005065317A2 (en) * | 2003-12-31 | 2005-07-21 | Cima Labs Inc. | Effervescent oral fentanyl dosage form |
BRPI0418228B8 (en) * | 2003-12-31 | 2021-05-25 | Cima Labs Inc | dosage form, and method of preparing a tablet for buccal, gingival or sublingual administration of fentanyl |
US20070036853A1 (en) * | 2003-12-31 | 2007-02-15 | Cima Labs Inc. | Generally linear effervescent oral fentanyl dosage form and methods of administering |
EP1708685B1 (en) * | 2003-12-31 | 2011-03-09 | Cima Labs Inc. | Effervescent oral opiate dosage forms and methods of administering oxycodone |
TWI354551B (en) | 2004-10-04 | 2011-12-21 | Cima Labs Inc | Effervescent oral opiate dosage forms and uses the |
TWI387466B (en) | 2004-10-04 | 2013-03-01 | Cima Labs Inc | Generally linear effervescent oral fentanyl dosage form and methods of administering |
JP2010511611A (en) * | 2006-12-01 | 2010-04-15 | シマ ラブス インク. | Oral transmucosal nicotine dosage form |
US20090214442A1 (en) * | 2006-12-01 | 2009-08-27 | Cephalon, Inc. | Oral Transmucosal Nicotine Dosage Form |
-
2002
- 2002-10-11 US US10/269,669 patent/US20030091629A1/en not_active Abandoned
-
2004
- 2004-10-29 US US10/977,029 patent/US20050064030A1/en not_active Abandoned
-
2006
- 2006-08-28 US US11/511,098 patent/US8802130B2/en not_active Expired - Lifetime
Patent Citations (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1262888A (en) * | 1917-02-20 | 1918-04-16 | Albert Westlake | Mouth-tablet. |
US1263888A (en) * | 1918-01-10 | 1918-04-23 | J T Vail | Wave-motor. |
US3131123A (en) * | 1959-03-13 | 1964-04-28 | Lab Francais De Therapeutique | Enteric tablets and manufacture thereof |
US3577490A (en) * | 1967-10-02 | 1971-05-04 | Miles Lab | Effervescent tablet and process for making same |
US3888976A (en) * | 1972-09-21 | 1975-06-10 | William P Mlkvy | Zinc and strontium ion containing effervescent mouthwash tablet |
US3961041A (en) * | 1974-11-14 | 1976-06-01 | Interx Research Corporation | Effervescent enteric coated L-dopa formulation and method of using the same |
US3972995A (en) * | 1975-04-14 | 1976-08-03 | American Home Products Corporation | Dosage form |
US4147768A (en) * | 1976-09-13 | 1979-04-03 | Interx Research Corporation | Enteric coated digoxin and therapeutic use thereof |
US4187286A (en) * | 1979-01-02 | 1980-02-05 | G&W Laboratories, Inc. | Contraceptive suppository |
US4289751A (en) * | 1979-06-29 | 1981-09-15 | Merck & Co., Inc. | Effervescent enteric-coated formulation of soluble form of erythromycin and therapeutic use thereof |
US4853211A (en) * | 1982-03-05 | 1989-08-01 | Eisai Co., Ltd. | Stable, effervescent vaginal suppositories |
US4503031A (en) * | 1982-12-17 | 1985-03-05 | Glassman Jacob A | Super-fast-starting-sustained release tablet |
US4493848A (en) * | 1983-07-14 | 1985-01-15 | The Procter & Gamble Company | Compositions and methods useful for producing analgesia |
US4599342A (en) * | 1984-01-16 | 1986-07-08 | The Procter & Gamble Company | Pharmaceutical products providing enhanced analgesia |
US5028411A (en) * | 1984-04-19 | 1991-07-02 | National Research Development Corporation | Pharmaceutical compositions |
US4639368A (en) * | 1984-08-23 | 1987-01-27 | Farmacon Research Corporation | Chewing gum containing a medicament and taste maskers |
US4756710A (en) * | 1985-04-05 | 1988-07-12 | Merck & Co., Inc. | pH-Mediated drug delivery system |
US4671953A (en) * | 1985-05-01 | 1987-06-09 | University Of Utah Research Foundation | Methods and compositions for noninvasive administration of sedatives, analgesics, and anesthetics |
US5053396A (en) * | 1985-08-27 | 1991-10-01 | Blass David H | Therapeutic composition |
US5135752A (en) * | 1988-10-14 | 1992-08-04 | Zetachron, Inc. | Buccal dosage form |
US5073374A (en) * | 1988-11-30 | 1991-12-17 | Schering Corporation | Fast dissolving buccal tablet |
US5002771A (en) * | 1989-02-06 | 1991-03-26 | Rorer Pharmaceutical Corp. | Calcitonin suppository formulations |
US5178878A (en) * | 1989-10-02 | 1993-01-12 | Cima Labs, Inc. | Effervescent dosage form with microparticles |
US5223264A (en) * | 1989-10-02 | 1993-06-29 | Cima Labs, Inc. | Pediatric effervescent dosage form |
US5900252A (en) * | 1990-04-17 | 1999-05-04 | Eurand International S.P.A. | Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon |
US5468504A (en) * | 1990-12-21 | 1995-11-21 | Laboratoires Glaxo S.A. | Effervescent pharmaceutical compositions |
US5559096A (en) * | 1991-04-15 | 1996-09-24 | Applied Microbiology, Inc. | Pharmaceutical compositions against gastric disorders |
US5624687A (en) * | 1991-04-15 | 1997-04-29 | Yamanouchi Pharmaceutical Co., Ltd. | Quick-dissolution solid preparation |
US5503846A (en) * | 1993-03-17 | 1996-04-02 | Cima Labs, Inc. | Base coated acid particles and effervescent formulation incorporating same |
US5458879A (en) * | 1994-03-03 | 1995-10-17 | The Procter & Gamble Company | Oral vehicle compositions |
US5626866A (en) * | 1994-03-07 | 1997-05-06 | Theratech, Inc. | Drug-containing adhesive composite transdermal delivery device |
US5952004A (en) * | 1994-03-18 | 1999-09-14 | Shire Laboratories Inc. | Emulsified drug delivery systems |
US6068853A (en) * | 1994-04-13 | 2000-05-30 | Novartis Corporation | Temporally controlled drug delivery systems |
US5958458A (en) * | 1994-06-15 | 1999-09-28 | Dumex-Alpharma A/S | Pharmaceutical multiple unit particulate formulation in the form of coated cores |
US5853748A (en) * | 1994-08-31 | 1998-12-29 | Cortecs (Uk) Limited | Pharmaceutical compositions |
US6034085A (en) * | 1994-11-02 | 2000-03-07 | Bristol-Myers Squibb Co. | Salt form of nefazodone for use in extended release formulations |
US5656284A (en) * | 1995-04-24 | 1997-08-12 | Balkin; Michael S. | Oral transmucosal delivery tablet and method of making it |
US5607697A (en) * | 1995-06-07 | 1997-03-04 | Cima Labs, Incorporated | Taste masking microparticles for oral dosage forms |
US6117912A (en) * | 1995-11-06 | 2000-09-12 | Somerset Pharmaceuticals, Inc. | Sublingual and buccal administration of selegiline for treating certain selegiline-responsive diseases and conditions |
US6129906A (en) * | 1995-11-11 | 2000-10-10 | The Procter & Gamble Company | Silicone containing powders |
US5958455A (en) * | 1996-02-09 | 1999-09-28 | Quadrant Holdings Cambridge Ltd | Oral solid dosage forms, methods of making same and compositions thereof |
US5646151A (en) * | 1996-03-08 | 1997-07-08 | Adolor Corporation | Kappa agonist compounds and pharmaceutical formulations thereof |
US6071539A (en) * | 1996-09-20 | 2000-06-06 | Ethypharm, Sa | Effervescent granules and methods for their preparation |
US6488961B1 (en) * | 1996-09-20 | 2002-12-03 | Ethypharm, Inc. | Effervescent granules and methods for their preparation |
US6326360B1 (en) * | 1998-03-11 | 2001-12-04 | Grelan Pharmaceuticals Co., Ltd. | Bubbling enteric coated preparations |
US6200604B1 (en) * | 1998-03-27 | 2001-03-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US6576250B1 (en) * | 1998-03-27 | 2003-06-10 | Cima Labs Inc. | Pharmaceutical compositions for rectal and vaginal administration |
US6350470B1 (en) * | 1998-04-29 | 2002-02-26 | Cima Labs Inc. | Effervescent drug delivery system for oral administration |
US6391335B1 (en) * | 1998-04-29 | 2002-05-21 | Cima Labs Inc. | Effervescent drug delivery system for oral administration |
US6509036B2 (en) * | 1998-04-29 | 2003-01-21 | Cima Labs Inc. | Effervescent drug delivery system for oral administration |
US6326384B1 (en) * | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
US6264981B1 (en) * | 1999-10-27 | 2001-07-24 | Anesta Corporation | Oral transmucosal drug dosage using solid solution |
US6342002B1 (en) * | 2000-07-14 | 2002-01-29 | Double Dynasty Co., Ltd. | Structure of a wax-polishing machine |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8202535B2 (en) | 2006-01-06 | 2012-06-19 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage forms |
US8778394B2 (en) | 2006-01-06 | 2014-07-15 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage forms |
US10245228B2 (en) | 2006-01-06 | 2019-04-02 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US10507180B2 (en) | 2006-01-06 | 2019-12-17 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US20080147044A1 (en) * | 2006-01-06 | 2008-06-19 | Acelrx Pharmaceuticals, Inc. | Methods for administering small volume oral transmucosal dosage forms using a dispensing device |
US10342762B2 (en) | 2006-01-06 | 2019-07-09 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage forms |
US20090131479A1 (en) * | 2006-01-06 | 2009-05-21 | Acelrx Pharmaceuticals, Inc. | Small-volume oral transmucosal dosage |
US9289583B2 (en) | 2006-01-06 | 2016-03-22 | Acelrx Pharmaceuticals, Inc. | Methods for administering small volume oral transmucosal dosage forms using a dispensing device |
US8865743B2 (en) | 2006-01-06 | 2014-10-21 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8865211B2 (en) | 2006-01-06 | 2014-10-21 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US20070207207A1 (en) * | 2006-01-06 | 2007-09-06 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US8231900B2 (en) | 2006-01-06 | 2012-07-31 | Acelrx Pharmaceutical, Inc. | Small-volume oral transmucosal dosage |
US9320710B2 (en) | 2006-01-06 | 2016-04-26 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8252328B2 (en) | 2006-01-06 | 2012-08-28 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US8357114B2 (en) | 2006-01-06 | 2013-01-22 | Acelrx Pharmaceuticals, Inc. | Drug dispensing device with flexible push rod |
US8535714B2 (en) | 2006-01-06 | 2013-09-17 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US8778393B2 (en) | 2006-01-06 | 2014-07-15 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US9744129B2 (en) | 2006-01-06 | 2017-08-29 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
US20070260491A1 (en) * | 2006-05-08 | 2007-11-08 | Pamela Palmer | System for delivery and monitoring of administration of controlled substances |
US20070299687A1 (en) * | 2006-06-23 | 2007-12-27 | Pamela Palmer | Inpatient system for patient-controlled delivery of oral transmucosal medications dosed as needed |
US20090214442A1 (en) * | 2006-12-01 | 2009-08-27 | Cephalon, Inc. | Oral Transmucosal Nicotine Dosage Form |
US20110206621A1 (en) * | 2006-12-01 | 2011-08-25 | Cephalon, Inc. | Oral transmucosal nicotine dosage form |
US20080131508A1 (en) * | 2006-12-01 | 2008-06-05 | Cephalon, Inc | Oral transmucosal nicotine dosage form |
US9066847B2 (en) | 2007-01-05 | 2015-06-30 | Aceirx Pharmaceuticals, Inc. | Storage and dispensing devices for administration of oral transmucosal dosage forms |
US8252329B2 (en) | 2007-01-05 | 2012-08-28 | Acelrx Pharmaceuticals, Inc. | Bioadhesive drug formulations for oral transmucosal delivery |
US20080164275A1 (en) * | 2007-01-05 | 2008-07-10 | Acelrx Pharmaceuticals, Inc. | Storage and dispensing devices for administration of oral transmucosal dosage forms |
US20090263476A1 (en) * | 2008-04-16 | 2009-10-22 | Jobdevairakkam Christopher N | Composition of Rapid Disintegrating Direct Compression Buccal Tablet |
US8945592B2 (en) | 2008-11-21 | 2015-02-03 | Acelrx Pharmaceuticals, Inc. | Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same |
Also Published As
Publication number | Publication date |
---|---|
US20030091629A1 (en) | 2003-05-15 |
US8802130B2 (en) | 2014-08-12 |
US20060292219A1 (en) | 2006-12-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8802130B2 (en) | Sublingual buccal effervescent | |
US8728441B2 (en) | Sublingual buccal effervescent | |
US6200604B1 (en) | Sublingual buccal effervescent | |
EP0396335A1 (en) | Pharmaceutical formulation | |
CA2515025A1 (en) | Sugar-free oral transmucosal solid dosage forms and uses thereof | |
KR20150038745A (en) | Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof | |
US20080254101A1 (en) | Pilocarpine compositions and methods of use thereof | |
HU227477B1 (en) | Solid, quick dissolving pharmaceutical compositions containing cetrizine | |
AU2004242477B2 (en) | Sublingual buccal effervescent | |
AU2007203233B2 (en) | Sublingual buccal effervescent | |
US20080187589A1 (en) | Multi-modal delivery via transmucosal and gastro-intestinal absorption of antihistamines and symptom relief | |
ES2383478T3 (en) | Tablet for oral, sublingual or gingival administration comprising an effervescent additive | |
JP2005272401A (en) | Chewable tablet | |
KR20160105935A (en) | Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: CIMA LABS INC., MINNESOTA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PATHER, S. INDIRAN;KHANKARI, RAJENDRA K.;EICHMAN, JONATHAN D.;AND OTHERS;REEL/FRAME:015391/0672;SIGNING DATES FROM 19990628 TO 19990819 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |