Title:  Opioid agonist in a fast dispersing dosage form

United States Patent:  6,680,071

Issued:  January 20, 2004

Inventors:  Johnson; Edward Stewart (Ruscombe, GB); Lacy; Jon (Genthod, CH)

Assignee:  R. P. Scherer Technologies, Inc. (Paradise Valley, NV)

Appl. No.:  936060

Filed:  January 14, 2002

PCT Filed:  March 2, 2000

PCT NO:  PCT/US00/05531

PCT PUB.NO.:  WO00/51539

PCT PUB. Date:  September 8, 2000

Abstract

This invention relates to a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid (.mu.receptor) agonist, such as fentanyl, or a salt thereof, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity. A process for preparing such a composition and the use of such a composition as an analgesic, for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication, for the induction of anesthesia, as a sedative and/or for the treatment of anxiety are also provided.

SUMMARY OF THE INVENTION

The term "fast-dispersing dosage form", as used herein and in the claims, refers to compositions which disintegrate/disperse within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, of being placed in the oral cavity. It therefore encompasses all the types of dosage forms described in the preceding paragraphs as well as any other equivalent dosage form. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water-dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.

In the case of the preferred type of fast-dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components. Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes.

Other matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalarnine.

One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.

Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable coloring agents include red, black and yellow iron oxides and FD&C dyes such as FD&C Blue No. 2 and FD&C Red No. 40 available from Ellis & Everard. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Suitable sweeteners include aspartame, acesulfame K and thaumatic. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.

The compositions of the invention comprise an opioid (.mu. receptor) agonist as an active ingredient. Representative drugs within this class include, but are not limited to, alfentanil, codeine, diamorphine, dihydrocodeine, fentanyl, hydromorphine, methadone, morphine, morphine-6-glucoronide, oxymorphine, pethidine, sufentanil and tramadol and salts of these compounds. Such drugs are commercially available and their routes of administration and dosage rates are reported in the literature.

Thus, there is disclosed a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid agonist characterized in that the composition is in the form of a fast dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.

A preferred active ingredient for use in the invention is fentanyl or a salt thereof. If a salt is used, it is preferred that the salt is an acid-addition salt of fentanyl, especially the citrate salt. However, since it is known that the un-ionized form of fentanyl penetrates mucosal membranes better than the ionized form, the composition of the invention may be buffered to a suitable pH range typically 7 to 7.5 by addition of an acid or alkaline substance.

The active ingredient is generally present in the composition in an amount from 0.2 to 95%, normally 1 to 20%, by weight of the composition of dried dosage form. Generally the active ingredient is present in an amount from 0.1 to 200 mg, normally 0.2 to 20 mg per dose depending upon the particular drug.

When the active ingredient is fentanyl it is preferably incorporated in the composition in an amount of from 0.5 to 10% by weight of the dried dosage form.

According to another aspect of the invention there is provided a process for preparing a pharmaceutical composition as previously defined which comprises bringing a carrier into association with the active ingredient.

In a further aspect, the invention provides the use of a fast-dispersing dosage form designed to release active ingredient rapidly in the oral cavity to deliver an opioid (.mu. receptor) agonist, such as fentanyl, or a salt thereof. A method of administering an opioid (.mu. receptor) agonist, such as fentanyl, or a salt thereof to a patient which comprises introducing into the oral cavity of the patient a composition as previously defined is also provided.

The invention also provides, in another aspect, a composition as defined above for use as an analgesic. The composition is particularly useful for the treatment of chronic pain, especially in a patient already receiving opioid therapy. In this respect, it is envisaged that the composition of the invention could provide the possibility of more individual titration of dose when required when the pain is most severe, especially during the night.

It is estimated that about 29% of patients with cancer continue to experience moderate to severe pain despite analgesic therapy and this can occur as intermittent breakthrough pain, often due to increases in a patient's activity level. Attempts to counteract this type of pain by increasing the dose of long-acting formulations of analgesics often produce slow onset of analgesia and unwanted side-effects of sedation, constipation or nausea and vomiting. However, the composition of the invention provides a rapidly acting, potent analgesic which would reduce the pain for the required time and then wear off fairly quickly thereby minimizing the side-effects of the active ingredient. Accordingly, the invention also provides a composition for use in the treatment of breakthrough pain in a patient experiencing chronic pain.

The composition of the invention is easier and quicker to administer than any of the existing dosage forms of fentanyl and other opioid (.mu. receptor) agonists. Thus, it is also suitable for administration in situations where an anesthetic, sedative or anxiolytic effect is required and the patient is conscious. The invention therefore also provides a composition for use as an anesthetic premedication, for the induction of anesthesia, for use as a sedative and/or for the treatment of anxiety.

According to a further aspect of the invention there is also provided the use of a composition as defined above for the manufacture of a medicament for use as an analgesic, for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication, for the induction of anesthesia, as a sedative and/or for the treatment of anxiety.

A method of treating pain, especially chronic pain or breakthrough pain, or anxiety is also provided which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition as previously defined.

The invention also provides a method of inducing an anesthetic effect or a sedative effect in a patient which comprises introducing into the oral cavity of the patient a pre-determined amount of a composition as previously defined calculated to induce anesthesia or sedation respectively in the patient.

DETAILED DESCRIPTION OF THE INVENTION

This invention is further illustrated by the following Examples.

EXAMPLE 1

Preparation of a Fast-dispersing Dosage Form Containing Fentanyl Citrate

(a) Preparation of Fentanyl 0.126% Dispersion

Gelatin (765 g) and mannitol (540 g) were dispersed in a portion of purified water (16 kg) by mixing thoroughly in the bowl of a vacuum mixer. The mix was then heated to 40^oC.+2^oC. and homogenised for ten minutes to allow complete dissolution of the solids. The mix was cooled down to room temperature (20-24^oC.). When cooled, the fentanyl citrate (22.68 g), the aspartame (90 g), and mint flavour (90 g) were added sequentially to the mix. The mix was then homogenized to ensure complete dissolution of the solids. The remaining water (492 g) was added to the mixer and the bulk mix homogenized to ensure dissolution was complete.

(b) Preparation of Fentanyl 0.2 mg (as the Base) Units.

250 mg of fentanyl 0.126% dispersion formed in (a) above was dosed into each of one of a series of pre-formed blister pockets having a pocket diameter of about 12 mm. The blister laminate comprised 200 .mu.m PVC (polyvinyl chloride) coated with 40 gsm PVdC (polyvinyl dichloride). The product was frozen immediately in a liquid nitrogen freeze tunnel. The frozen product was then stored below -20^oC. for a minimum of 12 hours prior to freeze-drying in a freeze drier using a drying temperature of +10^oC. and a chamber pressure of 0.5 mbar. The freeze dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20 .mu.m aluminium).

Each blister was then coded with a batch number and overwrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely. Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.

EXAMPLES 2 TO 4

The following formulations were prepared by analogous methods to Example 1.

EXAMPLE 2

EXAMPLE 3

EXAMPLE 4

Examples 1 to 4 using fentanyl citrate correspond to 200, 400, 800 and 1000 .mu.g of fentanyl base respectively.

Industrial Applicability

A need exists in the medical community for improved pain management. The present invention provides a dosage form that can be efficiently and economically used by patients for the management of their breakthrough pain. This is benefit to the patients and to the caregivers.

While the invention has been described through the use of specific embodiments, one skilled in the art will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention claimed herein.

Claim 1 of 12 Claims

What is claimed is:

1. A pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, an opioid agonist characterized in that said composition is in the form of a solid fast-dispersing dosage form comprising a network of said active ingredient and a water-soluble or water-dispersible carrier which is inert towards said active ingredient and wherein, said dosage form disintegrates within 1-30 seconds of being placed in the oral cavity.

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