Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-05-14
2003-03-11
Dees, Jose′ G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S045000, C424S434000, C424S435000, C424S489000, C514S004300, C514S009100, C128S200140
Reexamination Certificate
active
06531112
ABSTRACT:
1. Field of the Invention
The present invention relates to formulations for non-invasive delivery of calcitonin across mucous membranes by oral or inhalant routes to patients and to processes for preparing the formulations.
2. Description of the Prior Art
Effective, convenient, and comfortable delivery of calcitonin to patients is an area of major concern. A conventional mode of delivery for many drugs is by oral ingestion of pills or tablets that disintegrate into primary particles, and release the drug for absorption into the patient's bloodstream from the stomach and gastrointestinal (GI) tract. However, calcitonin is not suitable for conventional modes of delivery such as oral delivery, as it is susceptible to enzymatic degradation, and its large size and hydrophilic nature makes it ill suited for absorption through the GI tract. Saliva and/or gastrointestinal compounds tend to degrade or digest the calcitonin, rendering it ineffective.
Efforts have recently been made to develop more effective routes for administering calcitonin. See, e.g., U.S. Pat. No. 5,726,154, “Stabilization and Oral Delivery of Calcitonin”; U.S. Pat. No. 5,441,933, “Pharmaceutical Compositions and Dosage Forms for the Oral Delivery of Calcitonin”; and U.S. Pat. No. 5,281,580, “Calcitonin-containing Emulsion for Nasal Administration,” each of which is incorporated herein. However, issues such as compositional stability, patient convenience, and difficulty in fabrication (e.g., cost) often need to be considered as the formulations and delivery methods are developed. There remains a need for a relatively simple process and formulation for conveniently and effectively administering calcitonin, particularly methods that are applicable for oral mucosal administration and provide a more efficient and reliable bioavailability.
DESCRIPTION OF THE INVENTION
This invention provides a formulation useful for conveniently delivering calcitonin to a targeted area. One aspect of the present invention is a stabilized form of calcitonin resistant to chemical and enzymatic degradation. The solid particles are less exposed to potential deleterious components of the formulation. In another aspect of the invention, a formulation is provided that is adapted for oral (buccal) delivery of calcitonin. In this formulation, an effective amount of calcitonin is mixed with an “oral absorption enhancer” in a carrier solvent, preferably also in the presence of a surfactant. The oral cavity presents a large exposed mucous membrane through which the calcitonin can be absorbed. Incorporating the permeation enhancer into the particle or onto the surface of the solid particles increases the effective concentration of the permeation enhancer at the uptake site. This reduces the concentration required in the bulk solvent which decreases the likelihood of nonspecific irritation. Thus the formulation is optimized for oral absorption directly through the buccal mucosa of the oral cavity. The carrier solvent preferably is non-aqueous which further limits the exposure of the solid calictonin particles to hydrolytic degradation.
For example, an exemplary formulation adapted for oral mucosal delivery according to this aspect of the invention includes at least three components: (1) an effective amount of calcitonin; (2) an oral absorption enhancer for disrupting or modifying the absorptive surface of the targeted site (such as wetting) to improve absorption across the membrane; (3) an optional formulation surfactant for increasing the miscibility of the formulation ingredients or reducing the size of the calcitonin to droplet size suitable for intra-oral delivery ( e.g., 5-200 &mgr;m); and (4) a carrier solvent.
The term “alkyl group” as used herein means a saturated, monovalent, unbranched or branched hydrocarbon chain. Examples of alkyl groups include, but are not limited to, C
6
—C
20
alkyl groups, such as hexyl, heptyl, and octyl, decyl, dodecyl tetradecyl, hexadecyl, octadecyl. An alkyl group can be unsubstituted or substituted/with one or two suitable substituents.
The term “alkenyl group” as used herein means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. The double bond can be E or Z isomers. Suitable alkenyl groups include, but are not limited to C
6
—C
20
alkenyl groups, such as hexenyl, hexadienyl, (Z)-octadec-12-enyl, (E)-octadec-12-enyl, (Z)-tetradec-10-enyl. An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
Orally-acceptable absorption enhancers include surfactants such as sodium lauryl sulfate, palmitoyl carnitine, Laureth-9, phosphatidylcholine, cyclodextrin and derivatives thereof; bile salts such as sodium deoxycholate, sodium taurocholate, sodium glycochlate, and sodium fusidate; chelating agents including EDTA, citric acid and salicylates; and fatty acids (e.g., oleic acid, lauric acid, acylcarnitines, mono- and diglycerides). Other oral absorption enhancers include benzalkonium chloride, benzethonium chloride, CHAPS (3-(3-cholamidopropyl)-dimethylammonio-1-propanesulfonate), Big-CHAPS (N, N-bis(3-D-gluconamidopropyl)-cholamide), chlorobutanol, octoxynol-9, benzyl alcohol, phenols, cresols, and alkyl alcohols. Preferred oral absorption enhancers for the present invention include sulfates, RSO
4
−
M
+
, wherein R is selected from a group consisting of C
6
—C
20
alkyl and C
6
—C
20
alkenyl and M is an alkali metal cation. An especially preferred oral absorption enhancer for the present invention is sodium lauryl sulfate.
The formulation surfactant may be selected from surfactants such as benzalkonium chloride, benzethonium chloride, polysorbate 80, sodium lauryl sulfate, Brij surfactants (e.g., polyoxy(n)-oleoethers, wherein n is from 1 to 100), Tween surfactants (e.g., sorbitan monooleate {Span 80} and sorbitan monolaurate {Span 20}), Pluronic surfactants (e.g., Pluronic F77), lecithin, oleic acid, polyoxyethylene, and dioctyl sodium sulfosuccinate (Aerosol OT).
The carrier solvent preferably is a non-aqueous carrier solvent selected from ethanol, glycerol, propylene glycol, polyethylene glycol, sorbitol, vitamin E and derivatives of vitamin E, and polyvinylpyrrolidone.
According to another aspect of the invention, a formulation adapted for non-invasive transmucosal delivery is comprised of solid phase particles suspended in a delivery medium. With this formulation, dehydrated solid-phase particles are composed of calcitonin containing with at least one of a surfactant and a permeation enhancer, and suspended in a suspension medium such as a pharmaceutically acceptable carrier or propellant system. The suspension medium is preferably a non-aqueous carrier solvent as described above. The formulation may be applied to the buccal cavity by intraoral administration, or by inhalation to the pulmonary or nasal region. The delivery device transports the suspended particles contained in droplets aerosolized from the device, where the surfactant and/or permeation enhancer enable the absorption of the calcitonin through the buccal, pulmonary or nasal epithelial membrane. The permeation enhancers increase membrane permeability and facilitate drug transport through the biological membranes, thereby enhancing the bioavailablity of the delivered calcitonin. Suitable permeation enhancers and surfactants may be selected from the compounds referenced above. The calcitonin is then transported through the buccal epithelial membrane at the area where the peptide was deposited and reaches the systemic blood circulation. With this invention, the formulation may be delivered via an atomized spray or liquid, thereby avoiding the pains and discomfort encountered with invasive modes of delivery by injection.
Applying the inventive concepts described herein, each dose of calcitonin may be separately included within a container, such that single doses of calcitonin can be conveniently administered. Also, the calcitonin may be p
Libbey, III Miles A.
McCoy Randall E.
Williams, III Robert O.
Dees Jose′ G.
DelRx Pharmaceutical Corporation
Haghighatian M.
Mathews, Collins Shepherd & McKay, P.A.
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