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

Procedure for the manufacture of tablets painkillers that comprise an effervescent pair for your administration through the oral mucosa.

Technical field

The present invention relates to methods of manufacture of pharmaceutical compositions and more particularly to methods of manufacturing pharmaceutical compositions for oral administration of a medicine, containing an agent effervescent to enhance oral drug absorption at through the oral, sublingual and gingival mucosa.

Prior art

Effervescent agents have been shown They are useful and advantageous for oral administration. See<i>Pharmaceutical Dosage Forms: Tablets</i> volume I, second edition. A. Lieberman. Ed. 1989, Marcel Dekker, Inc. How to explains in this text, and as commonly used, a Effervescent tablet dissolves in water to provide a gaseous or foamy liquid drink. See also patents U.S. 5,102,665 and 5,468,504 to Schaeffer. In a drink of this type the effervescent agent helps to mask the taste of medications

Compositions have also been used effervescent for use as taste masking agents in Dosage forms that do not dissolve in water before administration. For example, U.S. Patent No. 4,639,368 describes a gum that contains a medicine that can be absorbed through the oral cavity and it contains an amount of a Effervescent agent that masks the taste.

More recently agents have been employed effervescent to obtain a rapid dispersion and / or dissolution of the medication in the oral cavity. See US patents No. 5,178,878 and 5,223,264. The effervescent agent tends to stimulate saliva production thereby providing additional water to help in the additional effervescent action. These forms of Dosage provide a pleasant presentation of the drug, particularly for patients who have difficulty swallowing capsules or tablets PCT application WO 97/06786 describes the Astral absorption of certain drugs using forms of Quick release dosage.

Several proposals for the administration through the oral mucosa of various drugs. When drugs are absorbed from the oral mucosa, they avoid the process of hepatic and gastrointestinal metabolism. This can lead to a faster onset of action and / or bioavailability Enhanced drug. However, many compounds do not penetrate quickly in the oral mucosa. 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 &amp; 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 well absorbed orally (a through the gastrointestinal tract) may not be well absorbed at through the mucosa of the mouth because the oral mucosa is less permeable than the intestinal mucosa and does not offer a surface area as big as the small intestine.

Despite these and other efforts to increase medication penetration through the mucosa orally, there have been unmet needs for improved methods of administration of medications through the oral mucosa.

Summary of the invention

Pharmaceutical compositions manufactured according to the present invention comprise an analgesic medicament that can be administered orally in combination with an agent effervescent used as a penetration enhancer to influence in the permeability of the medication through the oral mucosa, sublingual and gingival.

Detailed description of the invention

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

An aspect of this invention is to use agents effervescent as penetration enhancers to influence Oral absorption of the drug. Effervescent agents can be used alone or in combination with other enhancers of the penetration, which leads to an increase in speed and extent of absorption of an active drug. It is believed that a This type of increase may be due to one or all of the following mechanisms:

<dl><dt>1.</dt><dd>viscosity reduction and / or thickness of the mucous layer;</dd></dl>

<dl><dt>2.</dt><dd>binding disorder narrow;</dd></dl>

<dl><dt>3.</dt><dd>induction of a change in structure of the cell membrane; and</dd></dl>

<dl><dt>4.</dt><dd>increased hydrophobic environment within of the cell membrane.</dd></dl>

The present dosage forms should include an amount of an effervescent agent effective to help in the penetration of the drug through the oral mucosa. The agent Effervescent is provided in an amount between 5% and 80% by weight, based on the weight of the finished tablet, and more preferably in an amount between 30% and 80% by weight. It is particularly preferred that effervescent material be provided enough so that the gas released is more than about 5 cm3 but less than about 3 cm3, after exposure of the tablet to an aqueous environment. Without However, the amount of effervescent agent must be optimized to Each specific drug.

The term "effervescent agent" includes compounds that give off gas. Preferred effervescent agents they release gas through a chemical reaction that takes place after exposure of the effervescent agent (an effervescent pair) to water and / or saliva in the mouth. This reaction is most of the times result of the reaction of a source of soluble acid and a source of carbon dioxide such as bicarbonate or carbonate alkaline. The reaction of these two general compounds produces gas of carbon dioxide after contact with water or saliva. The water-activated materials of this type should be kept in a generally anhydrous state and little or no moisture absorbed or in a stable hydrated form, since exposure to water will break up the tablet prematurely. Acid sources can be whatever is safe for human consumption and can generally include food acids, acids and antacids Hydrite such as, for example: citric, tartaric, malic, fumaric, adipic and succinic. Carbonate sources include salt of bicarbonate and dry solid carbonate such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. I also know include reagents that give off oxygen or other gases and that are safe for human consumption.

The effervescent agent (s) of the present invention is not always based on a reaction that forms carbon dioxide. The reagents they give off oxygen or other gases that are safe for human consumption They are also considered within reach. When the agent Effervescent includes two mutually reactive components, such as a source of acid and a source of carbonate, it is preferred that Both components react completely. Therefore, it prefer an equivalent ratio of components that you provide Equivalent equivalents For example, if the acid used is diprotic, then double the amount of a base of monoreactive carbonate or an equal amount of a base bi-reactive so that complete neutralization is carried out. Without However, in other embodiments of the present invention, the amount of the source of acid or carbonate can exceed the quantity of the other component. This can be useful to enhance the taste and / or action of a tablet that contains an excess of Any of the components. In this case, it is acceptable that the additional amount of any of the components may be left without react.

The present dosage forms also included in additional quantities to that required for the Effervescence substance that adjusts the pH. For drugs that are weakly acidic or weakly basic, the pH of the aqueous environment may influence the relative concentrations of the forms ionized and non-ionized drug present in the solution according to the Henderson-Hasselbach equation. The pH solutions in which an effervescent pair has dissolved they are slightly acidic due to the evolution of carbon. The pH of the local environment, for example, saliva on contact direct with the tablet and any drug that may have been dissolved from it, can be adjusted by incorporating compressed a substance that adjusts the pH to control relative parts of the ionized and non-ionized forms of the drug. In this way, the present forms of Dosage for each specific drug. If known or suspected that the non-ionized drug is absorbed through the membrane cellular (transcellular absorption), it would be preferable to alter the pH from the local environment (within the tolerable limits for the subject) to a level that favors the non-ionized form of the drug. By on the contrary, if the ionized form dissolves more easily, the Local environment should favor ionization.

The effervescent agent and the substance that adjusts pH should not preferably compromise aqueous solubility of the drug, so that the dosage forms allow a sufficient concentration of the drug is present in the form no ionized Therefore, the percentage of the substance that adjusts the pH and the effervescent agent should be adjusted depending on the drug.

Substances that adjust the pH suitable for its use in the present invention include any weak acid or weak base in additional quantities to those required for the effervescence or, preferably, any buffer system that Do not damage the oral mucosa. Substances that adjust the appropriate pH for use in the present invention include, but are not limited to a, any of the acids or bases mentioned previously as effervescent compounds, hydrogen hydrogen phosphate disodium, sodium dihydrogen phosphate and potassium salt equivalent.

The active ingredient suitable for use in present dosage forms is an analgesic medication that can be distributed systemically that can be absorbed by the organism through the oral mucosa. Dosage forms They are especially suitable for drugs and other components pharmacists experiencing a significant loss of activity in the lumen of the gastrointestinal tract or in the tissues of the gastrointestinal tract during the absorption process or after It passed through the liver after absorption in the intestinal tract. The Absorption through the oral mucosa allows the drug to enter systemic circulation without first passing through the liver, and so reduces the loss of activity after passing through the liver.

The dosage form includes a pair effervescent, in combination with the other components for enhance the absorption of the pharmaceutical component through the oral mucosa and to improve the profile of disintegration and Organoleptic properties of the dosage form. For example, the area of ​​contact between the dosage form and the mucosa oral, and 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 separation properties will also enhance the residence time of the bioadhesive, thereby increasing the residence time for drug absorption. Examples no Limitations 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 producing agents of Effervescence, a dosage form manufactured according to the present invention may also include non-disintegrating agents suitable effervescent. Non-limiting examples of agents of Non-effervescent disintegration 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, carob flour, karaya, pectin and tragacanth The disintegrants can comprise up to approximately 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, dosage forms may also include sliding components, lubricants, binders, sweeteners, flavoring and coloring. Any component can be used conventional sweetener or flavoring. In the same way they can combinations of sweetening, flavoring components, or sweetening and flavoring components.

Examples of binders that can be used include gum arabic, tragacanth, gelatin, starch, materials cellulose such as methyl cellulose and sodium carboxymethyl cellulose, alginic acids and salts thereof, magnesium silicate and aluminum, 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 approximately 40 percent by weight of the composition total.

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

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

An aspect of the invention provides the manufacture of a solid oral tablet dosage form, suitable for sublingual, oral and gingival administration. They can loads of excipients be used to facilitate the formation of compressed. Loading will also help desirably in the rapid dissolution of the dosage form in the mouth. Examples Non-limiting suitable loads include: mannitol, dextrose, lactose, sucrose and calcium carbonate.

Manufacturing method

The tablets can be manufactured by compression direct, wet granulation or any other technique of tablet manufacturing See, for example, patents U.S. 5,178,878 and 5,223,264. The tablet can be a stratified tablet consisting of a layer of the principle active placed between a bioadhesive layer and a layer of effervescence. Other stratified forms include the components exposed above in layers of various compositions.

<dl><dt><u>Level of effervescence</u>:</dt><dd>between 5% and 95%</dd></dl>

<dl><dt><u>Size compressed</u>:</dt><dd>between 3/16 '' - 5/8 ''</dd></dl>

<dl><dt><u>Hardness compressed</u>:</dt><dd>between 5 N and 80 N</dd></dl>

<dl><dt><u>Way of administration</u>:</dt><dd>sublingual, buccal, gingival</dd></dl>

The dosage form can be administered to a human being or another mammalian subject placing the form of dosing in the subject's mouth and keeping it in the mouth, adjacent to a cheek (for oral administration), below the tongue (for sublingual administration) and between the upper lip and the gum (for gingival administration). The dosage form begins to disintegrate spontaneously due to the humidity of the mouth. Disintegration, and particularly effervescence, stimulate additional salivation, which further enhances the disintegration

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Example 1

The dosage form must 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 little water soluble drug will not compromise excessively, and allow a sufficient concentration of the drug to be present in the non-ionized form.

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

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Component

<figref>1</figref>

<figref>2</figref>

Industrial applicability

The invention relates to industries pharmaceutical and medical and the production of forms of dosage.