Effervescent tablet for the sublingual, buccal and gingival administration of fentanyl

ES 2 324 908 T3

DESCRIPTION

Tablet for buccal, sublingual or gingival administration, comprising an effervescent pair.

Technical field

The present invention relates to pharmaceutical compositions and more particularly to pharmaceutical compositions for the oral administration of a drug, which contain an effervescent agent to enhance the absorption of the drug by the oral route through the buccal, sublingual and gingival mucosa.

Previous technique

Effervescent agents 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 explained in this text, and as commonly used, an effervescent tablet dissolves in water to provide a fizzy or frothy liquid beverage. See also Schaeffer US Patent Nos. 5,102,665 and 5,468,504. In such a beverage the effervescent agent helps mask the taste of the drugs.

Effervescent compositions have also been employed for use as taste masking agents in dosage forms that do not dissolve in water prior to administration. For example, US Patent No. 4,639,368 describes a chewing gum that contains a medicament that can be absorbed through the oral cavity and that contains an amount of an effervescent agent that masks the taste.

More recently effervescent agents have been used to obtain a rapid dispersion and / or dissolution of the drug in the oral cavity. See US Patent Nos. 5,178,878 and 5,223,264. The effervescent agent tends to stimulate saliva production thereby providing additional water to aid in further effervescent action. These dosage forms provide a pleasant drug presentation, particularly for patients who have difficulty swallowing capsules or tablets. PCT application WO 97/06786 describes the pregastric absorption of certain drugs using rapid release dosage forms.

Various approaches have been suggested for the administration through the oral mucosa of various drugs. When drugs are absorbed from the oral mucosa, they prevent the process of hepatic and gastrointestinal metabolism. This can lead to a faster onset of action and / or improved bioavailability of a drug. However, many compounds do not penetrate the oral mucosa quickly. See, for example, Christina Graffner, Clinical Experience with Novel Buccal and Sublingual Administration; NOVEL DRUG DELIVERY AND ITS THERAPEUTIC APPLICATION, edited by LF Prescott and WS 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 MJ Rathbone. Compounds that can be absorbed well 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 does not offer as large a surface area as the small intestine.

Despite these and other efforts to increase the penetration of drugs through the oral mucosa, there have been unmet needs for improved methods of delivering drugs through the oral mucosa.

Summary of the invention

The pharmaceutical compositions according to the present invention comprise a drug that can be administered orally in combination with an effervescent agent used as a penetration enhancer to influence the permeability of the drug through the buccal, sublingual and gingival mucosa.

Detailed description of the invention

The present invention relates to a tablet according to independent claim 1. Additional preferred embodiments of the invention are defined in the dependent claims.

One aspect of this invention is to use effervescent agents as penetration enhancers to influence oral absorption of the drug. Effervescent agents can be used alone or in combination with other penetration enhancers, leading to an increase in the rate and extent of absorption of an active drug. It is believed that such an increase may be due to one or all of the following mechanisms:

1. reduction of the viscosity and / or thickness of the mucous layer;

2. tight junction disorder;

ES 2 324 908 T3

3. induction of a change in the structure of the cell membrane; and

Four. increased hydrophobic environment within the cell membrane.

The present dosage forms must include an amount of an effervescent agent effective to aid penetration of the drug through the oral mucosa. The effervescent agent is provided in an amount of between 5% and 80% by weight, based on the weight of the finished tablet, and more preferably in an amount of between 30% and 80% by weight. It is particularly preferred that sufficient effervescent material is provided so that the evolved gas is greater than about 5 cm³ but less than about 3 cm³, after 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 that evolve gas. Preferred effervescent agents evolve gas through a chemical reaction that occurs upon exposure of the effervescent agent (an effervescent pair) to water and / or saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source and a carbon dioxide source such as bicarbonate or alkali carbonate. The reaction of these two general compounds produces carbon dioxide gas upon contact with water or saliva. Materials of this type activated by water must be kept in a generally anhydrous state with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the tablet. Acid sources can be any that are safe for human consumption and can generally include Hydrite food acids, acids and antacids such as, for example: citric, tartaric, malic, fumaric, adipic and succinic. 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. Also included are reagents that give off oxygen or other gases and are safe for human consumption.

The effervescent agent (s) of the present invention are not always based on a reaction that forms carbon dioxide. Reagents that give off oxygen or other gases that are safe for human consumption are also considered in scope. When the effervescent agent includes two mutually reactive components, such as an acid source and a carbonate source, it is preferred that both components fully react. Therefore, an equivalent ratio of components that provides equal equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a monoreactive carbonate base or an equal amount of a bireactive base must be used for complete neutralization to occur. However, in other embodiments of the present invention, the amount of the acid or carbonate source may exceed the amount of the other component. This can be useful to enhance the taste and / or action of a tablet containing an excess of any of the components. In this case, it is acceptable that the additional amount of any of the components can remain unreacted.

The present dosage forms also include a pH adjusting substance in amounts in addition to that required for effervescence. For drugs that are weakly acidic or weakly basic, the pH of the aqueous environment can influence the relative concentrations of the ionized and non-ionized forms of the drug present in solution according to the Henderson-Hasselbach equation. PH solutions in which an effervescent couple has dissolved are slightly acidic due to the evolution of carbon dioxide. The pH of the local environment, for example saliva in direct contact with the tablet and any drugs that may have dissolved therefrom, can be adjusted by incorporating a pH-adjusting substance into the tablet to control the relative parts of the ionized forms. and non-ionized of the drug. In this way, the present dosage forms can be optimized for each specific drug. If the non-ionized 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 tolerable limits for the subject) to a level that favors the non-ionized form. ionized drug. On the contrary, if the ionized form dissolves more easily, the local environment should favor ionization.

The effervescent agent and the pH adjusting substance should preferably not compromise the aqueous solubility of the drug, so that the dosage forms allow a sufficient concentration of the drug to be present in the non-ionized form. Therefore, the percentage of the pH adjusting substance and / or the effervescent agent must be adjusted depending on the drug.

Suitable pH adjusting substances for use in the present invention include any weak acids or weak bases in amounts in addition to those required for effervescence. Suitable pH adjusting substances 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 is a systemically distributable pharmaceutical drug that can be absorbed by the body through the oral mucosa. Although the dosage forms can be used with a wide range of drugs, as discussed below, they are especially suitable for drugs and other pharmaceutical components that experience significant loss of activity in the lumen of the gastrointestinal tract or in the tissues of the gastrointestinal tract. during the process of

ES 2 324 908 T3 absorption or after 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, thus reducing the loss of activity after passage through the liver.

Pharmaceutical components may include, without limitation, analgesics, anti-inflammatories, antipyretics, antibiotics, antimicrobials, laxatives, anorectics, antihistamines, antiasthmatics, antidiuretics, antiflatulents, antimigraine agents, antispasmodics, sedatives, antideractivity agents, antihypertensive agents, antihypertensive agents, antihypertensive agents, antihypertensive agents, antihypertensive agents. ; peptides, proteins, oligonucleotides and other substances of biological origin, and combinations thereof. The terms "active ingredient (s)", "pharmaceutical component (s) ^)" and "active agents" are also encompassed by the drugs and pharmaceutically active components described in Mantelle, US Patent No. 5,234,957, at columns 18-21. Alternatively or additionally, the active ingredient may include drugs and other pharmaceutical ingredients, vitamins, minerals, and dietary supplements as defined in US Patent No. 5,178,878.

The dosage form preferably includes an effervescent couple, in combination with the other components to enhance the absorption of the pharmaceutical component through the oral mucosa and to improve the disintegration profile and 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, for example, Mechanistic Studies on Effervescent - Induced Permeability Enhancement by Jonathan Eichman (1997). Effervescence, due to its mucus-separating properties, will also enhance the residence time of the bioadhesive, thereby increasing the residence time for 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 effervescent-producing agents, a dosage form according to the present invention may also include suitable non-effervescent disintegration agents. Non-limiting examples of non-effervescent disintegrating agents include: microcrystalline cellulose, croscarmellose sodium, crospovidone, starches, cornstarch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, alginates, gums such as agar, guar, carob flour, karaya, pectin and tragacanth. Disintegrators can comprise up to about 20 percent by weight and preferably between about 2 and about 10% of the total weight of the composition.

In addition to the particles according to the present invention, the dosage forms can also include gliding, lubricating, binding, sweetening, flavoring and coloring components. Any conventional sweetening or flavoring component can be used. Combinations of sweetening, flavoring components, or sweetening and flavoring components can likewise be used.

Examples of binders that can be used include acacia, tragacanth, gelatin, starch, cellulose materials such as sodium methylcellulose and carboxymethylcellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites , sugars, invert sugars and the like. The binders can be used in an amount of up to 60 percent by weight and preferably from about 10 to about 40 percent by weight of the total composition.

Coloring agents may include titanium dioxide, and suitable food coloring such as those known as FDC colorants and natural coloring agents such as grape skin extract, red beet powder, beta-carotene, annatto, carmine, turmeric, paprika. , etc. The amount of coloring agent used can range from about 0.1 to about 3.5 percent by weight of the total composition.

The flavors incorporated in the composition can be selected from synthetic flavor oils and natural and / or aromatic flavor oils, extracts of plants, leaves, flowers, fruits, etc., and combinations thereof. These may include cinnamon oil, wintergreen oil, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, nutmeg oil, sage oil, oil of bitter almonds and cassia oil. They are also useful as aromas vanilla, citrus oil , including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of flavoring can depend on several factors, including the desired organoleptic effect. The flavors can be present in an amount ranging from about 0.05 to about 3 percent by weight based on the weight of the composition. Grape and cherry flavors and citrus flavors such as orange are particularly preferred flavors.

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 tablet formation. The filler will also desirably aid 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.

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Manufacturing method

Tablets can be made by direct compression, wet granulation, or any other tableting technique. See, for example, US Patent Nos. 5,178,878 and 5,223,264. The tablet can be a layered tablet consisting of a layer of the active ingredient placed between a bioadhesive layer and an effervescence layer. Other layered forms include the components discussed above in layers of various compositions.

<td>Effervescence level:</td><td>between 5% and 95%</td>

<td>Tablet size:</td><td>between 3/16 "- 5/8"</td>

<td>Tablet hardness:</td><td>between 5 N and 80 N</td>

<td>Route of administration:</td><td>sublingual, buccal, gingival</td>

The dosage form can 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, adjacent to a cheek (for buccal administration), under the tongue (for sublingual administration), and between the upper lip and the gingiva (for gingival administration). The dosage form begins to disintegrate spontaneously due to moisture in the mouth. Disintegration, and particularly effervescence, stimulates additional salivation, which further enhances disintegration.

Example 1

The dosage form should include fentanyl, an effervescent agent, and a substance that adjusts the pH 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 soluble drug will not be unduly compromised, and will allow a sufficient concentration of the drug to be present in the non-ionized form.

Two fentanyl formulations were produced, each containing 36% effervescence. These tablets were compressed using concave punches with a depth of half an inch.

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Component

<td>FORMULATION</td><td>COMPONENT</td><td>QUANTITY (MG)</td>

<td>WEATHER</td><td>Fentanyl, citrate, USP</td><td> 1,57</td>

<td>OF DISGREGATION</td><td>Lactose monohydrate</td><td> 119,47</td>

<td>SHORT</td><td>Microcrystalline cellulose, silified</td><td> 119,47</td>

<td></td><td>Anhydrous sodium carbonate</td><td> 46, 99</td>

<td></td><td>Sodium bicarbonate</td><td> 105</td>

<td></td><td>Citric acid, anhydrous</td><td> 75</td>

<td></td><td>Polyvinylpyrrolidone, cross-linked</td><td> 25</td>

<td></td><td>Magnesium stearate</td><td> 5</td>

<td></td><td>Silicon dioxide colloidal</td><td> 2,5</td>

<td></td><td></td><td></td>

<td></td><td>Total tablet mass</td><td> 500</td>

<td></td><td></td><td></td>

<td></td><td></td><td></td>

<td>WEATHER</td><td>Fentanyl, citrate, USP</td><td> 1,57</td>

<td>OF DISGREGATION</td><td>Lactose monohydrate</td><td> 270,93</td>

<td>LENGTH</td><td>Sodium carbonate, anhydrous</td><td> 40,00</td>

<td></td><td>Sodium bicarbonate</td><td> 105</td>

<td></td><td>Citric acid, anhydrous</td><td> 75</td>

<td></td><td>Magnesium stearate</td><td> 5</td>

<td></td><td>Silicon dioxide colloidal</td><td> 2,5</td>

<td></td><td></td><td></td>

<td></td><td>Total tablet mass</td><td> 500</td>

Example 2

The dosage form included prochlorperazine (pKa = 8.1), an effervescent agent, and a pH adjusting substance such that a slightly higher pH is produced to facilitate penetration enhancement.

With regard to prochlorperazine, an antiemetic drug, two formulations were developed, buccal and sublingual. The buccal tablets were compressed as quarter inch diameter biconvex tablets, while the sublingual tablets were three-eighths inch diameter biconvex tablets. Those dimensions were chosen to provide a comfortable fit in the respective part of the oral cavity for which they were designed. The formulas for these tablets are as follows:

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<td>FORMULATION</td><td>COMPONENT NAME</td><td>QUANTITY (MG)</td>

<td>ORAL</td><td>Prochlorperazine</td><td> 5, 00</td>

<td></td><td>Sodium bicarbonate</td><td> 15,52</td>

<td></td><td>Citric acid, anhydrous</td><td> 11,08</td>

<td></td><td>Sodium bicarbonate</td><td> 45,78</td>

<td></td><td>HPMC K4M Prem</td><td> 5, 00</td>

<td></td><td>Dicalcium phosphate dihydrated</td><td> 5,00</td>

<td></td><td>Mannitol</td><td> 11,67</td>

<td></td><td>Magnesium stearate</td><td> 0,95</td>

<td></td><td></td><td></td>

<td></td><td>Total</td><td> 100,00</td>

<td></td><td></td><td></td>

<td></td><td></td><td></td>

<td>SUBLINGUAL</td><td>Prochlorperazine</td><td> 5,00</td>

<td></td><td>Sodium bicarbonate</td><td> 61,25</td>

<td></td><td>Citric acid, anhydrous</td><td> 43,75</td>

<td></td><td>Sodium bicarbonate</td><td> 95</td>

<td></td><td>Sodium carbonate</td><td> 91,25</td>

<td></td><td>HPMC Methocel K4M Prem</td><td> 40</td>

<td></td><td>Mannitol</td><td> 60</td>

<td></td><td>Magnesium stearate</td><td> 3,75</td>

<td></td><td>Total</td><td> 400</td>

Applicability