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  Delivery of drugs to mucosal surfacesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Effervescent Or Pressurized Fluid Containing, Organic Pressurized FluidDelivery of drugs to mucosal surfaces description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070110677, Delivery of drugs to mucosal surfaces. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10/196,590, filed Jul. 15, 2002, which was a continuation of U.S. patent application Ser. No. 09/402,976, filed Jan. 20, 2000, now U.S. Pat. No. 6,432,440, issued Aug. 13, 2002, which was a .sctn.371 filing of International Application No. PCT/GB98/01147, filed Apr. 20, 1998, published in the English language on Oct. 29, 1998, under International Publication No. WO 98/47535, the contents of each of which are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] This invention relates to an improved system for the delivery of drugs to mucosal surfaces such as the nose, the eye, the vagina, the rectum and the back of the throat. [0003] Administration of therapeutic agents to mucosa is well known in the art. [0004] A variety of drugs may be administered to the nose, including those intended for the local treatment of nasal diseases, nasal vaccines, and those intended for systemic circulation. Because the nose has a reasonable surface area and a good blood supply, certain lipophilic drugs, such as nicotine and propranolol, can be absorbed rapidly into the blood, resulting in a bioavailability which is similar to that seen with intravenous injection. More polar drugs are less well absorbed, though absorption may be improved by the use of enhancing agents such as surfactants, powders such as microcrystalline cellulose, gelling microspheres (e.g., starch), and the bioadhesive polymer, chitosan. Examples of these systems are well known in the art and have been reviewed by Illum and Fisher in "Inhalation Delivery of Therapeutic Peptides and Proteins", Adjei and Gupta (eds.) Marcel Dekker Inc., New York (1997) 135-184. [0005] In a similar fashion, it is useful to deliver therapeutic agents, such as drugs and vaccines, to the vaginal cavity for a systemic effect or for the local treatment of diseases (particularly infectious diseases such as candidiasis and bacterial vaginitis) as well as for prophylaxis of diseases (e.g., HIV). Locally acting formulations may also be used to deliver contraceptive and spermicidal agents. [0006] Drugs may also be administered to mucosa in the eye and the rectum in order to achieve local effects or for systemic activity. [0007] Considerable advantages in terms of improved efficacy are expected to be gained if a nasally administered formulation were capable of retaining a drug, a vaccine, or DNA intended for local effect, in the nose for relatively long time periods. Previous workers have used a variety of strategies for this purpose. [0008] For example, Illum and others found that biodegradable microspheres based on materials such as starch could delay clearance to a period of hours as compared to a normal half life of clearance of about 10 to 15 minutes (Illum, et al., Int. J. Pharm., 39 (1986) 189-199). Surprisingly, such systems were also found to give an improved absorption by affecting the integrity of the tight junctions of the epithelial cells in the nasal cavity and are expected therefore to be best suited to drugs acting systemically. [0009] Similarly, Illum and others have shown that the bioadhesive material chitosan can modify mucociliary clearance with an increase in drug absorption (Illum, et al., Pharm Res., 11 (1994) 1186-1189). [0010] It would be most beneficial, due to ease of use and of administration, to have available a simple solution spray system that was suitable for the administration of drugs to the nose and, better still, for the drugs administered via such a system to have a long retention in the nasal cavity. The skilled person may envisage various strategies to this end, including the use of pharmacological agents that decrease mucociliary clearance by a direct effect on the action of cilia, such as cocaine, as well as formulation methods such as environmentally-responsive gels. [0011] Liquids that gel in response to a change in environment are known to those skilled in the art. The environmental change can be temperature, pH or ionic strength or a combination of these factors. Examples of all of these systems can be found in the prior art literature (see, for example, the smart hydrogel from Gelmed as described by Potts et al in Proceed. Intern. Symp. Control Rel., 24, 335 (1997)). However, the majority of these have been found to be unsuitable for nasal use in man because of factors such as irritation, discomfort (e.g., administration of cold solutions), mucosal damage, an unwanted enhancement of drug absorption into the systemic circulation, and many are unavailable due to lack of regulatory approval. [0012] In summary, it would present considerable advantages to provide a single component nasal delivery system, which was in the form of a liquid for ease of administration, and in particular one that gelled in the nose upon contact with the nasal tissues, which could be used to administer, and to modify absorption characteristics, of drugs (therapeutic agents) intended to act locally or systemically. It would also be desirable to provide a system which is well accepted by patients, does not enhance the absorption of drug intended for a local effect into the systemic circulation (as this could lead to side effects), and comprises materials that are approved by regulatory authorities. [0013] Those skilled in the art will appreciate that there are similar problems to be solved in respect of drug delivery for the improved treatment of conditions that affect the vaginal cavity, the rectum, the eye, and the back of the throat, as well as for the improved delivery of vaccines to the local lymphoid tissue, or for the improved delivery of DNA for the transfection of epithelial cells. [0014] For example, drugs intended for the treatment of vaginal infections, or drug free formulations intended to act as vaginal moisturizing agents (especially useful in post-menopausal conditions), should spread well in the vaginal cavity and be retained for long periods of time. However, it has been reported that so-called bioadhesive formulations that are intended to be retained in the vaginal cavity for days can be expelled rapidly, with more that 80% of the dose leaving the vagina in less than 2 hours (Brown, et al., 14, 1073 (1997)). Thus, it would be advantageous to provide a single component liquid composition that could be inserted into the vagina as a simple liquid and that gelled under the local environmental conditions to give good retention. [0015] For rectal enemas, it would be most beneficial if the liquid enema formed a gel once applied, ensuring close contact with the local environment and preventing early discharge. [0016] Similar problems may be identified in respect of administration to the eye, by virtue of the fact that liquid formulations are rapidly cleared from the eye through drainage down the naso-lacrymal duct. A single component liquid composition that gelled upon application to the eye would be advantageous for the treatment of conditions such as eye infections and inflammation. [0017] Pectins are materials which are found in the primary cell wall of all green land plants. They are heterogeneous materials, with a polysaccharide backbone that is uniform as .alpha.-1,4-linked polygalacturonic acid. Various neutral sugars have been identified in pectins such as xylose, galactose, rhamnose, and arabinose. [0018] A critical property of pectins which is known to affect their gelation properties, is the extent to which the galacturonic acid units are esterified. The degree of esterification (DE) of pectins found naturally can vary considerably (from 60 to 90%). The term DE is well understood by those skilled in the art and may be represented as the percentage of the total number of carboxyl groups which are esterified, or as the methoxyl content of the pectin. The respective theoretical maximum for each is 100% and 16% respectively. DE as used herein refers to the total number of carboxyl groups which are esterified. Low DE pectins (i.e., those having less than 50% esterification) are usually prepared by the de-esterification of extracted pectins, normally on a bench scale, by way of an enzymatic process, or, on an industrial scale, by the treatment with acid or ammonia in an alcoholic heterogeneous medium. For pectins with a low degree of methoxylation (DM; less than 45%) the gelation properties are known to depend on the DM and the molecular weight of the pectin. The chemistry of low methoxyl pectin gelation is described by Axelos and Thibault in "The Chemistry and Technology of Pectin", Academic Press, New York, pp. 109-118, (1991). [0019] Various prior art documents discuss the potential use of pectin as a bioadhesive and gelling material. Studies by Smart et al, J. Pharm. Pharmacol. 36, 295 (1984) in relation to the adhesiveness of various materials to mucus have shown that pectin is poorly adhesive in in vitro tests. A tablet capable of adhering to the mucus membrane containing pectin has been described in EP 306 454. Oechslein et al (Int. J. Pharm., 139, (1994), 25-32), have described the potential of various powder formulations to enhance the nasal absorption of the somatostatin analogue peptide octreotide. Pectin (type FPA) powder was used, and gave rise to an increase in the absolute bioavailability of the drug as compared to the drug administered in a saline solution. In none of these documents was the use of a solution formulation containing a pectin with a low DE, or a pectin that gels in contact with nasal secretions, described. [0020] Pectin has also been studied as a mucoadhesive ophthalmic material by Chetoni et al (Bull. Chem. Farm., 135, 147 (1996)). Salt complexes of drugs with pectin for administration to the oral mucosa as patches have been described by Burgalassi et al, World Meet. Pharm. Biopharm. Pharm. Technol., (1995), p. 839, APGI, Paris. Popovici and Szasz (in "Buccal and Nasal Administration as Alternatives to Parenteral Administration", Minutes of a European Symposium (1992), Duchene, D., Ed., Sante, Paris, France. p. 292-6) have described mucoadhesive hydrogels containing cellulose and pectin and a bivalent cation in the form of magnesium. The use of a low DE pectin as a solution that would gel in contact with mucosal surfaces was not described in any of these documents. [0021] U.S. Pat. No. 4,826,683 describes a nasal decongestant containing vegetable oil, aloe vera, zinc, vitamin C, vitamin A, vitamin E, vitamin B6, biotin, and fruit pectin. The content of fruit pectin was to a maximum of 2 g per liter. The solubilized fruit pectin supplied by General Foods under the trade name "Certo" was preferred. JP 62236862 describes an artificial mucus composed of a mixture of a spinnable water soluble polymer and a polysaccharide, protein or vinyl polymer. Pectin is listed as a suitable polysaccharide, though the type of pectin is not specified. [0022] U.S. Pat. No. 5,147,648 (EP 289 512) describes a pharmaceutical formulation made from at least two components which, when added separately, can form a gel for treating a mucosa. The two components are applied separately to the same area of a mucous membrane. The components may be added simultaneously or sequentially. One of the gel forming solution components includes a calcium salt (e.g., calcium gluconate) and the other may include a pectin. There is no suggestion in this prior art document that a solution comprising pectin may be administered as a single component, in the absence of a separately applied solution of calcium ions, which will gel once in contact with the mucosa. Continue reading about Delivery of drugs to mucosal surfaces... 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