Connect public, paid and private patent data with Google Patents Public Datasets

Delivery of drugs to mucosal surfaces

Download PDF

Info

Publication number
US20020197324A1
US20020197324A1 US10196590 US19659002A US2002197324A1 US 20020197324 A1 US20020197324 A1 US 20020197324A1 US 10196590 US10196590 US 10196590 US 19659002 A US19659002 A US 19659002A US 2002197324 A1 US2002197324 A1 US 2002197324A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
pectin
composition
surface
gel
therapeutic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10196590
Inventor
Peter Watts
Lisbeth Illum
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
West Pharmaceutical Services Drug Deliv and Clinical Res Cent Ltd
Original Assignee
West Pharmaceutical Services Drug Deliv and Clinical Res Cent Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0043Nose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/12Aerosols; Foams

Abstract

Liquid pharmaceutical compositions for administration to a mucosal surface, comprising a therapeutic agent and a pectin with a low degree of esterification are described. Such compositions gel, or can be adapted to gel, at the site of application in the absence of an extraneous source of divalent metal ions.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • [0001]
    This application is a continuation of U.S. patent application No. 09/402,976, filed Jan. 20, 2000, which was a §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 α-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.
  • [0023]
    U.S. Pat. No. 5,318,780 describes aqueous pharmaceutical vehicles containing two components, a film forming polymer (e.g., pectin) and an ionic polysaccharide, which are then gelled in situ by contacting the mixture with a counter-ion. Polygalacturonic acids such as pectin are mentioned in an extensive listing of representative useful polymers for application in the eye as corneal mastis protective corneal shields. No examples of the use of a pectin solution alone, nor of pectins with a low DE, or pectins that would gel in contact with the mucosa, are disclosed.
  • [0024]
    The preparation of pectin beads by ionotropic gelation has been described by Aydin and Akburfa (1996) Int. J. Pharm., 137, 133-136.
  • [0025]
    In summary, although it is known in the art that all pectins will form gels in the presence of calcium ions, for the pectins employed previously in pharmaceutical systems to be applied to mucosal surfaces, it has been hitherto understood that high levels of calcium are needed, which levels are well above physiological concentrations. This has necessitated the utilization of pectin systems which are applied either in the form of preformed gels, or before or after the addition of exogenous calcium in order to produce a gel in situ. That liquids (especially solutions) comprising low DE pectins may be applied as such, and may gel upon, or just after, application to mucosa is neither described nor suggested in any of the aforementioned prior art documents. Further, the importance of the DE of pectin upon such gelation properties is not mentioned in any of these prior art documents.
  • BRIEF SUMMARY OF THE INVENTION
  • [0026]
    The invention provides a single component liquid pharmaceutical composition for administration to a mucosal surface that includes (i) a therapeutic agent, (ii) a pectin with a low degree of esterification, (iii) and a aqueous carrier. The aqueous carrier gels or can be adapted to gel at the site of application.
  • [0027]
    The invention also provides a kit of parts that includes a liquid pharmaceutical composition for administration to a mucosal surface. The composition of the kit of parts includes a therapeutic agent, a pectin with a low degree of esterification, and an aqueous carrier. The composition gels or is adapted to gel at the site of application. Additionally, the kit does not include a solution of divalent metal ions to be added extraneously to the surface. The kit of parts of the invention may be packaged and presented with instructions to administer the composition to the mucosal surface in the absence of an extraneous source of divalent metal ions.
  • [0028]
    The invention is also directed to a pharmaceutical gel composition obtainable by applying a liquid composition, comprising a therapeutic agent, a pectin with a low degree of esterification, and an aqueous carrier for application to a mucosal surface of a mammalian patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
  • [0029]
    The invention also describes a method of treatment of a patient. The method comprises the administration of a liquid pharmaceutical composition. The composition includes a therapeutic agent, a pectin with a low degree of esterification, and an aqueous carrier. The composition gels or is adapted to gel at the site of application to a mucosal surface of the patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
  • [0030]
    Further described herein is a method of treatment of prophylaxis of a disease that comprises administration of a liquid pharmaceutical composition. The composition includes a therapeutic agent that is effective against the disease, a pectin with a low degree of esterification, and an aqueous carrier. The composition gels or is adapted to gel at the site of the application. The composition is applied to a mucosal surface of a patient in need of such treatment in the absence of extraneous application of a solution of divalent metal ions to the surface.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0031]
    The foregoing summary, as well as the following detailed description of preferred embodiments of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there is shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is illustrated, but in no way limited, by the following examples with reference to the figures in which:
  • [0032]
    [0032]FIG. 1 shows the effect of systemic uptake of salmon calcitonin when administered intranasally to sheep in formulations comprising low DE pectin.
  • [0033]
    [0033]FIG. 2 shows the cumulative release/diffusion of fexofenadine HCl from HP-β-CD and HP-β-CD/pectin 100 solutions to simulated nasal electrolyte solution.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0034]
    We have now found, surprisingly, that certain pectin materials, namely those with a low DE, may be administered in the form of single component, simple liquid formulations (i.e., in an aqueous carrier) which will gel, or can be readily adapted to gel, upon application to mucosa in the nasal, rectal, and vaginal cavities, in the eye, or at the back of the throat. We have also found, surprisingly, that gelation may occur at physiologically acceptable pH values in the presence of very much reduced calcium concentrations, i,e., those which can be found physiologically in the nasal secretions, as well as in the vaginal lumen, the rectal cavity, and the tear fluid of the eye.
  • [0035]
    According to a first aspect of the invention there is provided a single component liquid pharmaceutical composition for administration to a mucosal surface comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, that gels or can be adapted to gel at the site of application.
  • [0036]
    We have found, in particular, that such compositions gel, or can be adapted to gel, at the site of, and upon, or just after, application to a mucosal surface in the absence of an extraneously (i.e., separately and/or independently) applied (simultaneously or sequentially) solution of calcium (or other divalent metal) ions. There is thus provided a single component liquid pharmaceutical composition for application directly to a mucosal surface comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, which composition is adapted to gel at the site of application in the absence of an extraneous source (e.g., solution) of divalent metal ions applied to the same site.
  • [0037]
    According to a further aspect of the invention, there is provided a kit of parts comprising a liquid pharmaceutical composition for administration to a mucosal surface, comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, provided that the kit does not comprise a solution of divalent metal ions to be added extraneously to the surface.
  • [0038]
    In particular, there is provided a kit of parts comprising a liquid pharmaceutical composition for administration to a mucosal surface, which composition comprises a therapeutic agent, a pectin with a low DE and an aqueous carrier, and which kit of parts is packaged and presented with instructions to administer the composition to the surface in the absence of an extraneous source of divalent metal ions.
  • [0039]
    The liquid pharmaceutical compositions for administration to mucosal surfaces comprising therapeutic agent, low DE pectin and aqueous carrier, which are, or are to be, administered as a single component, and which gel, or are adapted to gel, in the absence of an extraneous source of divalent metal ions are referred to hereinafter as “the compositions of the invention”.
  • [0040]
    By “liquid” composition, we mean a composition which is in the form of a mobile fluid upon application to the mucosa. The compositions of the invention are in the form of an aqueous formulation comprising a solution, a suspension, or an emulsion, including pectin and therapeutic agent, in water. The compositions of the invention will gel, or may be adapted to gel, upon, or shortly (e.g., up to 5 minutes) after, application, to a form a solid or semi-solid gel material, which gel is suitable to provide a retaining effect at the site of administration.
  • [0041]
    By “degree of esterification (DE)”, it is meant the percentage of galacturonic acid units which are esterified, for example as described in the article by Walter in “The Chemistry and Technology of Pectin”, Academic Press, New York (1991), p. 192. By “low DE”, it is meant a pectin in which less than 50%, and more preferably less than 35%, of the galacturonic acid units are esterified.
  • [0042]
    The term “extraneous source” of divalent metal ions includes a separate and/or independent (i.e. exogenous) source of such ions. Ions which are present in a gel resulting from administration of a composition of the invention to a mucosa are not derived from either the composition, or from the bodily secretions of the patient to which the composition is to be applied (e.g., endogenous ions derived from nasal secretions, tear fluid, etc.). Divalent metal ions which may be mentioned include calcium ions.
  • [0043]
    According to a further aspect of the invention, there is provided a pharmaceutical gel composition obtainable by applying a liquid composition, comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, to a mucosal surface of a mammalian patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
  • [0044]
    The gels so formed upon contact with mucosal surfaces will contain only endogenous divalent metal ions (i.e., those derived directly from bodily secretions) and will not include exogenous divalent metal ions (i.e., those derived from an extraneous source). According to a further aspect of the invention there is provided a pharmaceutical gel composition, which gel comprises a therapeutic agent and a pectin with a low DE, which gel is obtainable by applying a liquid composition, comprising the therapeutic agent and pectin in an aqueous carrier, to a mucosal surface, and which gel is substantially free of divalent metal ions derived from an extraneous source applied to the mucosal surface before, or at the same time as, or after, the liquid composition is applied.
  • [0045]
    Because the compositions of the invention are not added in conjunction with an extraneous source of such ions, by “substantially free” of divalent metal ions, it is meant greater than 97%, preferably greater than 99%, more preferably greater than 99.9%, and especially greater than 99.99% free.
  • [0046]
    Pectins with a low DE can be obtained from known sources, or can be obtained via de-esterification of high DE pectins (which may be obtained from, for example, Sigma Fine Chemicals), in accordance with known techniques, such as those described in the article by Rollin in “Industrial Gums”, Academic Press, New York (1993) p. 257, or as described hereinbefore. Low DE pectin may, for example, be obtained from Copenhagen Pectin A/S as the commercial material known as Slendid Type 100 and Slendid Type 110. These pectins have been extracted from citrus peel and standardized by the addition of sucrose. The standardization process is as described by Rollin in the above-mentioned article. The DE is less than 50% for both pectins and of the order of 10% for type 100 and 35% for type 110. Further materials which may be employed include GENU pectin types LM 1912 CS and Pomosin pectin types LM 12 CG and LM 18 CG.
  • [0047]
    The compositions of the invention may be prepared by dissolving or dispersing the pectin of low DE and therapeutic agent in an aqueous system, to form a solution, a suspension or an emulsion in accordance with known techniques. For example, the therapeutic agent may be dissolved in a prior prepared aqueous solution of the pectin, or may be added as, or to form, a suspension in an aqueous system, where the drug particles are less than 100 microns in size, preferably between 1 and 20 microns. Alternatively, drug may be dissolved or suspended in a suitable oily vehicle such as a vegetable oil, and then dispersed into the aqueous pectin solution to form an emulsion. It will be appreciated by those skilled in the art that the type of aqueous formulation so developed will depend upon to mucosa to be treated, as well as the dose, and the physical characteristics and properties, of the drug (e.g., its solubility, basicity etc.).
  • [0048]
    The concentration of low DE pectin in compositions of the invention depends upon the nature of the pectin, the presence of other components, and other factors which influence gelation properties of the composition (see below), but may be from 1 g/L to 100 g/L, and is preferably from 1 g/L to 50 g/L, more preferably from 2 g/L to 10 g/L and especially from 5 g/L to 10 g/L.
  • [0049]
    Compositions of the invention may be used with a view to the prevention of a major problem in the delivery of drugs to the nose for local treatment, namely the rapid mucociliary clearance mechanism. This natural process, which removes deposited material from the front of the nose to the throat, can clear material from the nose with a half-time of about 10 to 20 minutes. Such clearance rates can be measured readily in man using the saccharin clearance test or by gamma scintigraphy (Aspden et al, J. Pharm. Sci., 86, 509 (1997); Illum et al, Int. J. Pharm., 39 (1987) 189-199).
  • [0050]
    Compositions of the invention may be employed to retain a therapeutic agent which is intended to act locally at a mucosal surface for a relatively long period when compared to mucosal delivery systems known in the art. If the therapeutic agent is easily absorbed, absorption may be retarded, thus keeping more of the drug at the site of application, where it is needed.
  • [0051]
    Therapeutic agents which may be employed in the compositions of the invention include, for nasal administration, drugs that are employed locally to treat conditions such as rhinitis, viral infections, as well as those which act as decongestants. The compositions of the invention may also be used as a way of improving the delivery of vaccines to the nose associated lymphoid tissue and for the better presentation of DNA for the transfection of nasal epithelial cells.
  • [0052]
    The following list of therapeutic agents are suitable for use in the compositions of the invention, for local treatment of a mucosal surface, is provided by way of illustration and is not meant to be exclusive: antiviral agents such as ICAM-1, pirovadir, acyclovir, bromovinyldeoxyuridine, α, β and γ-interferon, zidovudine; decongestants such as oxymetazaline; anti-allergic agents, such as sodium cromoglycate and budesonide; steroids, such as fluticazone; vaccines, such as DNA, influenza, pertussis, measles and diphtheria vaccines; antibacterial agents; antifungal agents, such as amphotericin, nystatin; contraceptive and/or spermicidal agents; antibodies especially for the treatment of RSV infection in children; prophylactic agents against HIV; antihistamines, such as diphenhydramine hydrochloride; and genes.
  • [0053]
    Combinations of the above-mentioned therapeutic agents may also be employed.
  • [0054]
    Compositions of the invention may also be employed to control the plasma level versus time profile for readily absorbable drugs which are intended to act systemically (i.e., to give a flatter profile), either by altering the rate of transport into the general circulation, or by retarding absorption of readily absorbable drugs. This can, for example, be of importance when side effects from high peak plasma levels are to be avoided.
  • [0055]
    The compositions of the invention may thus be used for the modification of the systemic absorption of mucosally administered drugs, including, but not limited to, apomorphine, nicotine, hyoscine hydrobromide, lignocaine, fentanyl, naratriptan, pheromones and propranolol.
  • [0056]
    Combinations of the above-mentioned therapeutic agents may also be employed.
  • [0057]
    The term “therapeutic agents” is intended herein to include agents which are suitable for use in the treatment, and in the prevention, of disease.
  • [0058]
    The compositions of the invention may be used to treat/prevent diseases/conditions in mammalian patients depending upon the therapeutic agent(s) which is/are employed. For the above, non-exhaustive lists of locally acting and systemic drugs, diseases/conditions which may be mentioned include those against which the therapeutic agent(s) in question are known to be effective, and include those specifically listed for the drugs in question in Martindale, “The Extra Pharmacopoeia”, 31st Edition, Royal Pharmaceutical Society (1996).
  • [0059]
    Preferred drugs include nicotine and apomorphine.
  • [0060]
    The amount of therapeutic agent which may be employed in the compositions of the invention will depend upon the agent which is used, and the disease to be treated, but may be in the range 0.01 to 40% w/w. However, it will be clear to the skilled person that suitable doses of therapeutic agents can be readily determined non-inventively. For example, estimates of dosage can be made from known injectable products assuming that from 0.1 to 90% of the dose is absorbed. Suitable single unit doses are in the range 10 μg to 500 mg depending upon the therapeutic agent(s) which is/are employed and the route of administration. Suitable daily doses are in the range 10 μg to 1 g/day depending upon the therapeutic agent(s) which is/are employed and the route of administration.
  • [0061]
    Most compositions comprising drug and a low DE pectin will gel upon application at the site of application, i.e., upon, or shortly (e.g., up to 5 minutes) after, contact with the relevant mucosal surface. However, in some formulations, the nature of the drug and/or the pectin which is/are employed may require that the composition is adapted such that it gels upon, or shortly (e.g., up to 1 minute) after, contact. This may be achieved readily via techniques which are well known to those skilled in the art:
  • [0062]
    For example, the concentration of pectin may be selected such that the aqueous formulation will gel once in contact with the mucosal surface.
  • [0063]
    Furthermore, the addition of monovalent ions to aid the gelling process may be required (for example, simple monovalent electrolytes, e.g., NaCl, may be added to adapt the liquid formulation to gel, as well as to provide isotonicity).
  • [0064]
    The quantity and nature of the drug in the aqueous formulation may also have an influence on the gelation properties. For example, the addition of a high level of a certain drugs, including those which are weak bases (such as nicotine), which are known to form reversible complexes with anionic materials such as pectin, may require a change in the ratio between drug and pectin, so that preferably 30%, more preferably 50%, and most preferably 60%, of the negative charges on the pectin molecule are uncomplexed.
  • [0065]
    Alternatively, sugars in the form of, for example, sucrose can be added to the formulation to aid gelation. Non-ionic polysaccharides (such as hydroxypropyl methyl cellulose) may also be used.
  • [0066]
    The pH of the composition has also been found to affect gelation properties. The pH of the compositions of the invention may be from 2 to 9, more preferably from 3 to 8 and most preferably from 4 to 7, taking into account the gelation properties of the composition and the properties of the therapeutic agent. For example, in general, we have found that the lower the DE of the pectin, the lower the pH at which the composition will gel. pH may be adjusted in accordance with techniques which will be well known to those skilled in the art, such as the addition of pharmaceutically acceptable buffering agents, especially those of low ionic strength. Axelos and Thibault in “The Chemistry and Technology of Pectin”, Academic Press, New York, pp. 109-118, (1991) describe how the gelation properties of low DE pectin solutions are somewhat sensitive to pH and ionic strength.
  • [0067]
    The above-mentioned techniques, which may be used to adapt the compositions of the invention to gel, may be investigated and determined in the normal course of routine experimentation by those skilled in the art. Combinations of these techniques may also be employed in order to affect gelation properties.
  • [0068]
    The compositions may also contain other additives in the form of pharmaceutical excipients, such as preservatives (e.g., low concentrations of materials such as sodium metabisulphate), stabilizers, flavoring agents, absorption enhancers such as bile salts, phospholipids, as well as agents which are known to interact with the drug, for example to form inclusion or salt-bridge complexes, and promote a controlled release in the nasal cavity from the formed gel, such as cyclodextrins and ion exchange resins.
  • [0069]
    Additional pharmaceutically acceptable excipients which may be added to the compositions of the invention include agents such as glycerol.
  • [0070]
    According to a further aspect of the invention there is provided a process for the preparation of a composition of the invention which comprises mixing together the therapeutic agent and the pectin in the aqueous carrier.
  • [0071]
    The compositions of the invention may be administered in suitable dosage forms, in accordance with techniques, and via delivery devices, all of which are known to those skilled in the art. For example, for nasal delivery, the compositions of the invention are preferably administered by way of a spray device, for example the Pfeiffer metered dose pump or the Valois metered dose pump, or via a liquid free flow system (such as nasal drops). For vaginal and rectal administration (infusion) a syringe-type applicator may be used, or plastics ampoules fitted with a suitable nozzle, where the contents of the ampoule can be delivered to the vaginal or rectal surface via the application of a slight pressure. Suitable systems for delivery of the compositions of the invention to the back of the throat include spray devices which are well known to those skilled in the art. Suitable systems for delivery of the compositions of the invention to eye include liquid free flow system which are well known to those skilled in the art (such as eye drops).
  • [0072]
    The compositions of the invention have the advantage that they may be readily administered to mucosal surfaces in the form of single component, simple liquid formulations, in the absence of an additional component comprising an extraneous source of divalent metal ions, using devices which are well known to those skilled in the art. The compositions of the invention also have the advantage that they gel upon, or shortly after, contact with mucosa, at physiologically acceptable pHs, in the presence of endogenous calcium (only) found physiologically in the nasal secretions, as well as in the vaginal lumen, the rectal cavity and the tear fluid of the eye.
  • [0073]
    Compositions of the invention also have the advantage that they may be used to retain a locally-acting drug at a mucosal surface, or to control drug absorption into the systemic circulation.
  • [0074]
    Compositions of the invention may also have the advantage that they may be well accepted by patients, and may comprise materials that are approved by regulatory authorities.
  • [0075]
    According to a further aspect of the invention there is provided a method of treatment of a patient which comprises the administration of a liquid pharmaceutical composition, comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, which composition gels or is adapted to gel at the site of application, to a mucosal surface of the patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
  • [0076]
    There is provided further a method of treatment or prophylaxis of a disease which comprises administration of a composition of the invention including a therapeutic agent which is effective against the disease to a mucosal surface of a patient in need of such treatment in the absence of extraneous application of a solution of divalent metal ions to the surface.
  • EXAMPLE 1
  • [0077]
    To Demonstrate that Pectins with Low DEs Gel Under Simulated Conditions of the Nasal Cavity while Pectins with Higher DEs Do Not
  • [0078]
    Materials:
  • [0079]
    Pectin, esterified, potassium salt (DE: 31%; lot 22H0548; Sigma)
  • [0080]
    Pectin, esterified, potassium salt (DE: 67%; lot 74H1093; Sigma)
  • [0081]
    Pectin, esterified (DE: 93%; lot 125H0123; Sigma).
  • [0082]
    Pectin, Slendid type 100 (lot 620970; Hercules; Denmark).
  • [0083]
    Pectin, Slendid type 110 (lot 626790; Hercules, Denmark).
  • [0084]
    Pectin, GENU type LM 12 CG (lot G 63481; Pomosin GmbH; Hercules;, Germany).
  • [0085]
    Pectin, GENU type LM 18 CG (lot G 63484; Pomosin GmbH; Hercules; Germany).
  • [0086]
    Sodium chloride (BDH).
  • [0087]
    Potassium chloride (BDH).
  • [0088]
    Calcium chloride dehydrate (Sigma).
  • [0089]
    A simulated nasal electrolyte (SNES) solution was prepared, composed of the following ingredients:
    Sodium chloride 8.77 g/L
    Potassium chloride 2.98 g/L
    Calcium chloride dehydrate 0.59 g/L
  • [0090]
    The SNES was prepared in double strength:
  • [0091]
    3.508 g of sodium chloride, 1.192 g of potassium chloride and 0.236 g of calcium chloride dehydrate were weighed into three weighing boats respectively, and
  • [0092]
    dissolved and transferred into a 200 mL volumetric flask.
  • [0093]
    The solution was stirred on a magnetic stirrer until the drug had dissolved.
  • [0094]
    Water was added to volume.
  • [0095]
    Preparation of 20 g/L pectin solutions
  • [0096]
    1 g of each type of pectin was weighed into a 100 mL bottle.
  • [0097]
    50 mL of ultrapure water was added to each bottle.
  • [0098]
    The content was stirred on a magnetic stirrer until pectin had dissolved, and
  • [0099]
    the pH of the solution was measured and adjusted to pH 4 or pH 6.5 with 0.1M sodium hydroxide solution.
  • [0100]
    Preparation of various formulations containing SNES and pectin with different concentrations (2 to 10 g/L)
  • [0101]
    Appropriate volumes of 20 g/L pectin solution, to obtain the final concentrations of 2, 3, 4, 5, 6, 7, 8, 9 and 10 g/L, were measured in a series of 10 mL screw capped glass tubes.
  • [0102]
    Appropriate volumes of water were added to obtain a total volume of 2.5 mL firstly, then 2.5 mL of the two fold concentration SNES was added.
  • [0103]
    The tubes were cooled in an ice water bath for 15 minutes.
  • [0104]
    The test tubes were tilted to check the phase state and flow property.
  • [0105]
    The tubes were vigorously shaken to check the phase state and flow property again.
  • [0106]
    Results
  • [0107]
    The results are shown in Table 1:
  • [0108]
    1. Pectin type 100 and 110 gelled with simulated nasal electrolyte solution when the final concentration of pectin was >2 g/L and formed a strong gel when the final concentration was >4 g/L at pH values of 4 and 6.5. The gel was transparent and homogeneous. The strength of gel increased with the increasing pectin concentration in system.
  • [0109]
    2. Pectin type LM 12 CG and LM 18 CG gelled at final pectin concentrations of 4 g/L and 6 g/L (pH 4) and 4 g/L (pH 6.5) respectively. These two pectin types only formed solid gels at pH 6.5 and at concentrations higher than 6 g/L and 8 g/L respectively.
  • [0110]
    3. Pectin with a DE of 31% (Sigma) gelled at a concentration of >2 g/L and formed a solid gel at concentrations >4 g/L. Pectin 67% and 93% did not form solid gels at concentrations up to 10 g/L at neither pH 4 nor at pH 6.5.
  • EXAMPLE 2
  • [0111]
    Nasal Drug Formulation Prepared from Pectins with Low Des
  • [0112]
    Formulations were prepared containing drugs in the form of nicotine (a weak base) and cromolyn sodium (sodium cromoglycate; a weak acid). Pectin formulations were prepared at a pectin concentration of 10 mg/mL using Slendid 100 and Slendid 110. The formulations were mixed with the simulated nasal electrolyte solution (the method of preparation of which was as in Example 1). The formulations were filled into a nasal delivery device (Pfeiffer metered dose pump) and the spray properties evaluated by visual examination.
  • [0113]
    The gelation of the formulation in the nasal electrolyte solution was evaluated as solution, gel or solid by visual observation and the flow properties before and after shaking. The results, which are set out in Table 2, show that when the formulation contained a weak acid (cromolyn sodium), gelation occurred in the nasal electrolyte solution. When the formulation contained a high level of a weak base (nicotine) then gelation did not occur.
  • [0114]
    It is believed that the reason for this difference is that the ionized nicotine may interact with the charged carboxyl groups on the pectin molecules and thereby influence the gelation characteristics of the low esterified pectin. Thus, with weakly basic drugs, a person skilled in the art is able to adjust the pectin concentration to take this interaction into account (see above).
  • EXAMPLE3
  • [0115]
    To Demonstrate that Nasal Formulations containing Low DE Pectin do not Enhance the Systemic Uptake of a Poorly Absorbed Drug
  • [0116]
    For the local delivery of drugs it is important to retain the drug at its site of action, namely the nasal, rectal and vaginal cavities. In such cases, the formulation should not enhance the absorption of the drug. It is known that some bioadhesive gelling formulations may increase systemic uptake. Therefore, experiments have been conducted in an animal model to demonstrate that pectins with low DE do not enhance the nasal uptake (systemically) of a model polar drug, salmon calcitonin (S-CT).
  • [0117]
    Sheep
  • [0118]
    Eight female, cross-bred sheep of known weight were used in this study. The average weight of the sheep was in the region of 60 kg. The sheep were weighed and labeled 1 to 8. An in-dwelling Secalon cannula fitted with a flowswitch was placed approximately 15 cm into one of the external jugular veins of each animal on the first day of the study. Whenever necessary, the cannula was kept patent by flushing it with heparinised (25 IU/mL) 0.9% saline solution. This cannula remained in-dwelling in the jugular vein of each animal for the duration of the study and was removed upon completion of the study.
  • [0119]
    Preparation of salmon calcitonin (S-CT) formulations
  • [0120]
    Two S-CT formulations were prepared. Each formulation contained 2000 IU/mL S-CT, which was sufficient material to administer a dose of 20 IU/kg in a volume of 0.01 mL/kg. The sheep were randomly divided into two groups of four animals and each group was dosed with a different S-CT formulation.
  • [0121]
    Summary of the dose groups
    S-CT Chitosan G210 Pectin Slendid 100
    Formulation (IU/kg) (mg/kg) (mg/kg)
    I 20
    II 20 0.1
  • [0122]
    Prior to dose administration the sheep were sedated with an intravenous dose of Ketamine Vetalar® (100 mg/mL injection) at 2.25 mg/kg. Intranasal doses were administered at 0.01 mL/kg. The dose was divided equally between each nostril. For dose administration, a blueline umbilical cannula was inserted into the nostril of the sheep to a depth of 10 cm, before the delivery of the appropriate volume of solution from a 1 mL syringe.
  • [0123]
    Blood sampling
  • [0124]
    Blood samples of 4 mL were collected from the cannulated jugular vein of the sheep at 15 and 5 minutes prior to S-CT administration and at 5, 15, 30, 45, 60, 90, 120, 150, 180, 240, 300, 360, 420 and 480 minutes post-administration. They were then mixed gently in 4 mL heparinised tubes and kept on crushed ice before plasma separation. Plasma was separated by centrifugation for 10 minutes at 4° C. approximately 3000 rpm. Each plasma sample was divided into two equal aliquots of approximately 1 mL and stored at −20° C. One set of plasma samples was used for calcium analysis.
  • [0125]
    Calcium analysis
  • [0126]
    Plasma calcium analysis was performed by the Clinical Chemistry Department, Queens Medical Centre, University of Nottingham. The results showed that for the formulation I and II the plasma calcium levels were very similar and that the presence of pectin in the formulation did not lead to an increase in the systemic bioavailability of the model drug.
  • EXAMPLE 4
  • [0127]
    Simulated Nasal Electrolyte Solution-Pectin Gelling System for Controlled Release of Fexofenadine Hydrochloride
  • [0128]
    Preparation of Formulations
  • [0129]
    Formulation 1-10 mg/mL fexofenadine HCl100 mg/mL HP-β-CD: 2 g of HP-β-CD was dissolved in 18-19 mL of water in a 20 mL volumetric flask. 200 mg of fexofenadine was added to the solution and stirred until the drug has dissolved. The pH of the solution was adjusted to 4.0, then the solution was made up to volume with water.
  • [0130]
    Formulation 2-10 mg/mL fexofenadine HCl/100 mg/mL HP-β-CD/10 mg/mL pectin 100:
  • [0131]
    50 mg of pectin 100 (SLENDID type 100, Hercules, Denmark) was dissolved in 5 mL of Formulation 1 in a 5 mL volumetric flask.
  • [0132]
    Release/Diffusion Testing
  • [0133]
    A Franz diffusion cell apparatus was set up in a closed loop arrangement and parameters were listed as follows:
  • [0134]
    Medium: Simulated nasal electrolyte solution
  • [0135]
    Temperature: 37° C.
  • [0136]
    Membrane: Cellulose nitrate, 0.45 Tm pore size
  • [0137]
    Volume of the closed loop arrangement: 8.8 mL
  • [0138]
    Stirring speed of a magnetic stirrer: 4
  • [0139]
    Peristaltic pump flow rate: 1 (The Cole-Parmer Masterflex peristaltic pump, Model 7518-60, fitted with Masterflex L/Sth 14 silicone tubing)
  • [0140]
    Sample volume: 0.4 mL (contained 4 mg of fexofenadine HCl, the maximum concentration of the drug in medium will be around 450 Tg/mL)
  • [0141]
    Wavelength: 260 nm
  • [0142]
    Results
  • [0143]
    The results are shown in FIG. 2. (Every point on the graphs represents a mean value of two points.)
  • [0144]
    The maximum UV absorbance of Formulation 1 (control) reached during the diffusion experiment was used as 100% release to calculate the percentage of release at each selected time point.
  • [0145]
    The results show a clear difference in release characteristics of the two formulations.
  • [0146]
    It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

Claims (39)

We claim:
1. A single component liquid pharmaceutical composition for administration to a mucosal surface comprising a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier, that gels or can be adapted to gel at the site of application.
2. A composition as claimed in claim 1, wherein the mucosal surface is the nasal cavity.
3. A composition as claimed in claim 1, wherein the mucosal surface is the vagina.
4. A composition as claimed in claim 1, wherein the mucosal surface is the rectum.
5. A composition as claimed in claim 1, wherein the mucosal surface is the back of the throat.
6. A composition as claimed in claim 1, where the mucosal surfaces is the eye.
7. A composition as claimed in claim 1, which is administered as a spray or a liquid free flowing system.
8. A composition as claimed in claim 1, wherein the degree of esterification is less than 50%.
9. A composition as claimed in claim 1, wherein the pectin concentration in the composition is from 1 to 100 g/L.
10. A composition as claimed in claim 1, wherein the pH of the composition is between 2 and 9.
11. A composition as claimed in claim 1, for use in the delivery of an antiviral agent to the nose or the vagina.
12. A composition as claimed in claim 1, for use in the delivery of a vaccine to the nose, the rectum or the vagina.
13. A composition as claimed in claims 1, for use in the delivery of a decongestant agent.
14. A composition as claimed in claims 1, for use in the delivery of a contraceptive agent.
15. A composition as claimed in claim 1, for use as a vaginal lubricating agent.
16. A composition as claimed in claim 1, for use in the delivery of an anti-allergic agent.
17. A pharmaceutical formulation in a form suitable for administration to a mucosal surface, which formulation comprises a composition according to claim 1 in a pharmaceutically acceptable dosage form.
18. A formulation as claimed in claim 17, which is in the form of a spray or a liquid free flowing system.
19. The use of a composition according to claim 1, as a means of delivery of therapeutic agents to the nose, the vagina, the rectum, the back of the throat or the eye.
20. A kit of parts comprising a liquid pharmaceutical composition for administration to a mucosal surface, comprising a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier, which composition gels or is adapted to gel at the site of application, provided that the kit does not comprise a solution of divalent metal ions to be added extraneously to the surface.
21. A kit of parts comprising a liquid pharmaceutical composition for administration to a mucosal surface, which composition comprises a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier, which composition gels or is adapted to gel at the site of application, and which kit of parts is packaged and presented with instructions to administer the composition to the surface in the absence of an extraneous source of divalent metal ions.
22. A kit of parts comprising a composition according to claim 1, which kit of parts is packaged and presented with instructions to administer the composition or formulation to a mucosal surface in the absence of an extraneous source of divalent metal ions.
23. A pharmaceutical gel composition obtainable by applying a liquid composition, comprising a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier, to a mucosal surface of a mammalian patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
24. A pharmaceutical gel composition comprising a therapeutic agent and a pectin with a low degree of esterification, which gel is obtainable by applying a liquid composition, comprising the therapeutic agent and pectin in an aqueous carrier, to a mucosal surface, and which gel is substantially free of divalent metal ions derived from an extraneous source applied to the mucosal surface before, or at the same time as, the liquid composition is applied.
25. A pharmaceutical gel composition obtainable by administering a composition according to claim 1, to a mucosal surface of a mammalian patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
26. A method of treatment of a patient which comprises the administration of a liquid pharmaceutical composition, comprising a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier, which composition gels or is adapted to gel at the site of application, to a mucosal surface of the patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
27. A method of treatment or prophylaxis of a disease which comprises administration of a liquid pharmaceutical composition, comprising a therapeutic agent which is effective against the disease, a pectin with a low degree of esterification and an aqueous carrier, which composition gels or is adapted to gel at the site of application, to a mucosal surface of a patient in need of such treatment, in the absence of extraneous application of a solution of divalent metal ions to the surface.
28. A method for delivering a therapeutic agent in a liquid formulation to the nose, eye, rectum, back of throat or vagina which comprises the delivery of the agent in a composition according to claim 1.
29. A method of treatment of a mammalian patient which comprises administration of a composition according to claim 1 to such a patient.
30. A method for the delivery of therapeutic agents to a mucosal surface in a mammal, which comprises administering a composition, as defined in claim 1 to the surface.
31. The use of a composition according to claim 1, as a means of delivery of therapeutic agents to the nose, vagina, rectum, back of the throat, or eye.
32. The use of a composition according to claim 1, in the manufacture of a medicament for the delivery of a therapeutic agent to the nose, vagina, rectum, back of the throat, or eye.
33. The use of a composition according to claim 1, in the manufacture of a medicament for the treatment or prophylaxis of a disease which comprises administration of the composition, including a therapeutic agent which is effective against the disease, to a mucosal surface of a patient in need of such treatment or prophylaxis, in the absence of extraneous application of a solution of divalent metal ions to the surface.
34. The use of a pectin with a low degree of esterification in the manufacture of a single component liquid composition for the delivery of therapeutic agents to mucosal surfaces.
35. The use of a composition according to claim 1, in the manufacture of a medicament for use in a method of treatment according to any one of claims 26 to 30.
36. A composition comprising a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier, which composition is packaged and presented for use in the treatment of a patient, which treatment comprises the administration of the composition to a mucosal surface of the patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
37. The use of a pectin with a low degree of esterification in the manufacture of an aqueous liquid pharmaceutical composition for the treatment of a patient comprising the administration of the composition to a mucosal surface of the patient in the absence of extraneous application of a solution of divalent metal ions to the surface.
38. A process for the preparation of a composition according to claim 1, which comprises mixing together the therapeutic agent and the pectin in the aqueous carrier.
39. A product obtainable by a process according to claim 38.
US10196590 1997-04-18 2002-07-15 Delivery of drugs to mucosal surfaces Abandoned US20020197324A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB9707934.7 1997-04-18
GB9707934A GB9707934D0 (en) 1997-04-18 1997-04-18 Improved delivery of drugs to mucosal surfaces
US09402976 US6432440B1 (en) 1997-04-18 1998-04-20 Pectin compositions and methods of use for improved delivery of drugs to mucosal surfaces
US10196590 US20020197324A1 (en) 1997-04-18 2002-07-15 Delivery of drugs to mucosal surfaces

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US10196590 US20020197324A1 (en) 1997-04-18 2002-07-15 Delivery of drugs to mucosal surfaces
US11562173 US20070092535A1 (en) 1997-04-18 2006-11-21 Delivery of drugs to mucosal surfaces
US11562002 US20070110677A1 (en) 1997-04-18 2006-11-21 Delivery of drugs to mucosal surfaces
US13078575 US20110182857A1 (en) 1997-04-18 2011-04-01 Delivery of Drugs to Mucosal Surfaces

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US09402976 Continuation US6432440B1 (en) 1997-04-18 1998-04-20 Pectin compositions and methods of use for improved delivery of drugs to mucosal surfaces
PCT/GB1998/001147 Continuation WO1998047535A1 (en) 1997-04-18 1998-04-20 Improved delivery of drugs to mucosal surfaces

Publications (1)

Publication Number Publication Date
US20020197324A1 true true US20020197324A1 (en) 2002-12-26

Family

ID=10811025

Family Applications (5)

Application Number Title Priority Date Filing Date
US09402976 Active US6432440B1 (en) 1997-04-18 1998-04-20 Pectin compositions and methods of use for improved delivery of drugs to mucosal surfaces
US10196590 Abandoned US20020197324A1 (en) 1997-04-18 2002-07-15 Delivery of drugs to mucosal surfaces
US11562173 Abandoned US20070092535A1 (en) 1997-04-18 2006-11-21 Delivery of drugs to mucosal surfaces
US11562002 Granted US20070110677A1 (en) 1997-04-18 2006-11-21 Delivery of drugs to mucosal surfaces
US13078575 Abandoned US20110182857A1 (en) 1997-04-18 2011-04-01 Delivery of Drugs to Mucosal Surfaces

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09402976 Active US6432440B1 (en) 1997-04-18 1998-04-20 Pectin compositions and methods of use for improved delivery of drugs to mucosal surfaces

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11562173 Abandoned US20070092535A1 (en) 1997-04-18 2006-11-21 Delivery of drugs to mucosal surfaces
US11562002 Granted US20070110677A1 (en) 1997-04-18 2006-11-21 Delivery of drugs to mucosal surfaces
US13078575 Abandoned US20110182857A1 (en) 1997-04-18 2011-04-01 Delivery of Drugs to Mucosal Surfaces

Country Status (9)

Country Link
US (5) US6432440B1 (en)
JP (3) JP2001524094A (en)
CA (1) CA2282506C (en)
DE (3) DE122011000009I1 (en)
DK (1) DK0975367T3 (en)
EP (1) EP0975367B1 (en)
ES (1) ES2221706T3 (en)
GB (2) GB9707934D0 (en)
WO (1) WO1998047535A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040115135A1 (en) * 2002-12-17 2004-06-17 Quay Steven C. Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity
US20040157777A1 (en) * 2002-12-17 2004-08-12 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US20040265377A1 (en) * 1997-10-27 2004-12-30 Harry Seager Solid dispersing vaccine composition for oral delivery
US20070161563A1 (en) * 2002-12-17 2007-07-12 Nastech Pharmaceutical Company Inc. A device for enhanced epithelial permeation of y2 receptor-binding peptides
US20070213270A1 (en) * 2004-06-16 2007-09-13 Costantino Henry R Peptide yy formulations having increased stability and resistance to microbial agents
US20070232537A1 (en) * 2005-12-19 2007-10-04 Nastech Pharmaceutical Company Inc. Intranasal pyy formulations with improved transmucosal pharmacokinetics
US20070231269A1 (en) * 2002-03-19 2007-10-04 Ionix Pharmaceuticals Limited Analgesics
US20080004218A1 (en) * 2002-12-17 2008-01-03 Nastech Pharmaceutical Company Inc. Methods for enhanced epithelial permeation of y2 receptor-binding peptides for treating and preventing obesity
US20080214664A1 (en) * 2007-03-02 2008-09-04 Combe Incorporated Anesthetic spray composition
US7691986B2 (en) 1998-05-13 2010-04-06 Nanotherapeutics, Inc. High molecular weight, low methoxyl pectins, and their production and uses
US20110171314A1 (en) * 2006-03-30 2011-07-14 Engene, Inc. Non-viral compositions and methods for transfecting gut cells in vivo
US8889176B2 (en) 2003-01-10 2014-11-18 Depomed, Inc. Method of managing or treating pain

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9707934D0 (en) * 1997-04-18 1997-06-04 Danbiosyst Uk Improved delivery of drugs to mucosal surfaces
DE69814086T2 (en) * 1997-08-26 2004-04-08 Aventis Pharmaceuticals Inc. Drugs for combination piperidinoalkanol decongestant
WO1999027905A1 (en) * 1997-12-02 1999-06-10 West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited Compositions for nasal administration
GB0000001D0 (en) * 2000-01-05 2000-02-23 Du Pont Uk Pharmaceutical compositions and their preparation
CN101181241A (en) 2000-07-31 2008-05-21 尼科梅德丹麦股份有限公司 Fentanyl composition for nasal administration
US7494669B2 (en) * 2001-02-28 2009-02-24 Carrington Laboratories, Inc. Delivery of physiological agents with in-situ gels comprising anionic polysaccharides
US6777000B2 (en) * 2001-02-28 2004-08-17 Carrington Laboratories, Inc. In-situ gel formation of pectin
CA2477044A1 (en) 2002-02-22 2003-09-04 Pharmacia Corporation Ophthalmic formulation with gum system
CA2487712A1 (en) * 2002-06-28 2004-01-08 Nastech Pharmaceutical Company Inc. Compositions and methods for modulating physiology of epithelial junctional adhesion molecules for enhanced mucosal delivery of therapeutic compounds
US8846075B2 (en) * 2003-01-24 2014-09-30 Magle Holding Ab Composition material for transmucosal delivery
US20060110517A1 (en) 2003-01-31 2006-05-25 Reinhold Carle Novel compositions comprising carotenoids
JP2006525354A (en) * 2003-05-01 2006-11-09 アルキメデス・ディヴェロップメント・リミテッドArchimedes Development Limited Lh-rh of analog leuprolide nasal administration
GB0315632D0 (en) * 2003-07-04 2003-08-13 West Pharm Serv Drug Res Ltd Pharmaceutical formulations
EP1530965B1 (en) 2003-11-11 2006-03-08 Mattern, Udo Controlled release delivery system of sexual hormones for nasal application
US8784869B2 (en) 2003-11-11 2014-07-22 Mattern Pharma Ag Controlled release delivery system for nasal applications and methods of treatment
US20050113730A1 (en) * 2003-11-24 2005-05-26 Sca Hygiene Products Ab Absorbent Article Containing A Skin Care Product
US20050129679A1 (en) 2003-12-15 2005-06-16 Nastech Pharmaceutical Company Inc. Method for opening tight junctions
CA2581896C (en) 2004-09-29 2015-11-10 Mount Sinai School Of Medicine Of New York University Fsh and fsh receptor modulator compositions and methods for inhibiting osteoclastic bone resorption and bone loss in osteoporosis
US7619008B2 (en) * 2004-11-12 2009-11-17 Kimberly-Clark Worldwide, Inc. Xylitol for treatment of vaginal infections
US20060140820A1 (en) 2004-12-28 2006-06-29 Udo Mattern Use of a container of an inorganic additive containing plastic material
US20060217443A1 (en) * 2005-03-28 2006-09-28 Kimberly-Clark Worldwide, Inc. Method for preventing and/or treating vaginal and vulval infections
US7786176B2 (en) 2005-07-29 2010-08-31 Kimberly-Clark Worldwide, Inc. Vaginal treatment composition containing xylitol
KR101495146B1 (en) 2006-03-16 2015-02-24 트리스 파마 인코포레이티드 Modified release formulations containing drug - ion exchange resin complexes
WO2008040488A1 (en) 2006-10-04 2008-04-10 M & P Patent Aktiengesellschaft Controlled release delivery system for nasal application of neurotransmitters
WO2008091592A1 (en) 2007-01-22 2008-07-31 Targacept, Inc. Intranasal, buccal, and sublingual administration of metanicotine analogs
CA2754677A1 (en) * 2009-03-26 2010-09-30 Pulmatrix, Inc. Methods for treating and preventing pneumonia and ventilator-associated tracheobronchitis
EP2845595A1 (en) * 2009-10-01 2015-03-11 Aptalis Pharmatech, Inc. Orally administered corticosteriod compositions
WO2011063774A3 (en) 2009-11-25 2012-01-19 Zentiva, K.S. Pectin complexes of steroids and pharmaceutical compositions based thereon
GB201013215D0 (en) * 2010-08-05 2010-09-22 Hera Pharmaceuticals Inc Expression of antibody or a fragment thereof in lactobacillus
GB2482536B (en) 2010-08-05 2013-07-24 Hera Pharmaceuticals Inc Expression of antibody or a fragment thereof in lactobacillus
CN105640925A (en) 2010-08-30 2016-06-08 普马特里克斯营业公司 Dry powder formula and method thereof for treating lung diseases
CA2812417A1 (en) 2010-09-29 2012-04-19 Pulmatrix, Inc. Cationic dry powders
US20130164338A1 (en) 2010-08-30 2013-06-27 Pulmatrix, Inc. Treatment of cystic fibrosis using calcium lactate, leucine and sodium chloride in a respiraple dry powder
CN103228273B (en) 2010-09-29 2017-04-05 普马特里克斯营业公司 Monovalent metal cations dry inhalation powder
US8623409B1 (en) 2010-10-20 2014-01-07 Tris Pharma Inc. Clonidine formulation
US8287903B2 (en) 2011-02-15 2012-10-16 Tris Pharma Inc Orally effective methylphenidate extended release powder and aqueous suspension product
US9757388B2 (en) 2011-05-13 2017-09-12 Acerus Pharmaceuticals Srl Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels
WO2014028610A1 (en) 2012-08-15 2014-02-20 Tris Pharma, Inc. Methylphenidate extended release chewable tablet
KR20150135328A (en) 2013-04-01 2015-12-02 풀매트릭스 인코퍼레이티드 Tiotropium dry powders
CN106659696A (en) * 2014-07-08 2017-05-10 费尔廷制药公司 Oral delivery system comprising two compartments

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2125212A (en) * 1938-05-03 1938-07-26 Vick Chemical Company Therapeutic composition
US2730483A (en) * 1952-08-12 1956-01-10 Nepera Chemical Co Inc Therapeutic compositions comprising neomycin, gramicidin and quaternary ammonium salt of thonzylamine
US4609640A (en) * 1981-11-17 1986-09-02 Toyo Jozo Company, Ltd. Preparation having excellent absorption property
US4613500A (en) * 1983-03-09 1986-09-23 Teijin Limited Powdery pharmaceutical composition for nasal administration
US4681887A (en) * 1985-06-21 1987-07-21 Richter Gedeon Vegyeszeti Gyar Rt. Pharmaceutical compositions with a neuroleptic action and process for preparing same
US4826683A (en) * 1987-01-09 1989-05-02 Bates Harry L Decongestant
US4915948A (en) * 1987-08-31 1990-04-10 Warner-Lambert Company Tablets having improved bioadhesion to mucous membranes
US4981875A (en) * 1987-08-12 1991-01-01 Bayer Aktiengesellschaft Medicaments for the region of the oral cavity
US4983385A (en) * 1985-11-22 1991-01-08 Sunstar Kabushiki Kaisha Ointment base
US5147648A (en) * 1986-01-16 1992-09-15 Christian Bannert Method of improving the adhesiveness of gels to mucosae
US5200180A (en) * 1987-06-26 1993-04-06 Christian Bannert Pharmaceutical composition for the treatment of the human eye
US5236714A (en) * 1988-11-01 1993-08-17 Alza Corporation Abusable substance dosage form having reduced abuse potential
US5238917A (en) * 1989-09-11 1993-08-24 Teikoku Seiyaku Kabushiki Kaisha High-absorbable transvaginal preparation containing biologically active polypeptide
US5318780A (en) * 1991-10-30 1994-06-07 Mediventures Inc. Medical uses of in situ formed gels
US5397771A (en) * 1990-05-10 1995-03-14 Bechgaard International Research And Development A/S Pharmaceutical preparation
US5457093A (en) * 1987-09-18 1995-10-10 Ethicon, Inc. Gel formulations containing growth factors
US5456745A (en) * 1988-08-13 1995-10-10 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Flexible, hydrophilic gel film, the process for its production and the use of it
US5707644A (en) * 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
US5955502A (en) * 1994-03-30 1999-09-21 Gs Development Ab Use of fatty acid esters as bioadhesive substances

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL135583C (en) * 1961-10-10
US4464378A (en) * 1981-04-28 1984-08-07 University Of Kentucky Research Foundation Method of administering narcotic antagonists and analgesics and novel dosage forms containing same
US4659696A (en) * 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4486423A (en) * 1983-04-21 1984-12-04 Janssen Pharmaceutica Inc. Stable fentanyl composition
US4806341A (en) * 1985-02-25 1989-02-21 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration
FR2588189B1 (en) * 1985-10-03 1988-12-02 Merck Sharp & Dohme pharmaceutical transition type has liquid-gel phase composition
JPS62236862A (en) 1986-04-09 1987-10-16 Nippon Kayaku Co Ltd Artificial mucus
US5346703A (en) * 1990-08-07 1994-09-13 Mediventures, Inc. Body cavity drug delivery with thermo-irreversible polyoxyalkylene and ionic polysaccharide gels
JPH0597706A (en) 1991-04-09 1993-04-20 Chemex Block Drug Jv Treatment of aphthous ulcer and other mucosal dermatosis
US5507277A (en) * 1993-01-29 1996-04-16 Aradigm Corporation Lockout device for controlled release of drug from patient-activateddispenser
US5543434A (en) * 1994-02-25 1996-08-06 Weg; Stuart L. Nasal administration of ketamine to manage pain
GB9406171D0 (en) * 1994-03-29 1994-05-18 Electrosols Ltd Dispensing device
DE69523301T2 (en) * 1994-05-13 2002-07-04 Aradigm Corp A narcotic aerosol formulation containing
GB9414966D0 (en) * 1994-07-26 1994-09-14 Danbiosyst Uk Pharmaceutical compositions for the nasal administration of antiviral agents
US6667279B1 (en) * 1996-11-13 2003-12-23 Wallace, Inc. Method and composition for forming water impermeable barrier
GB9707934D0 (en) * 1997-04-18 1997-06-04 Danbiosyst Uk Improved delivery of drugs to mucosal surfaces
US6541021B1 (en) * 1999-03-18 2003-04-01 Durect Corporation Devices and methods for pain management
US6663883B1 (en) * 1999-08-26 2003-12-16 Takeda Chemical Industries, Ltd. Matrix adhering to nasal mucosa
GB9924797D0 (en) * 1999-10-20 1999-12-22 West Pharm Serv Drug Res Ltd Compound

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2125212A (en) * 1938-05-03 1938-07-26 Vick Chemical Company Therapeutic composition
US2730483A (en) * 1952-08-12 1956-01-10 Nepera Chemical Co Inc Therapeutic compositions comprising neomycin, gramicidin and quaternary ammonium salt of thonzylamine
US4609640A (en) * 1981-11-17 1986-09-02 Toyo Jozo Company, Ltd. Preparation having excellent absorption property
US4613500A (en) * 1983-03-09 1986-09-23 Teijin Limited Powdery pharmaceutical composition for nasal administration
US4681887A (en) * 1985-06-21 1987-07-21 Richter Gedeon Vegyeszeti Gyar Rt. Pharmaceutical compositions with a neuroleptic action and process for preparing same
US4983385A (en) * 1985-11-22 1991-01-08 Sunstar Kabushiki Kaisha Ointment base
US5147648A (en) * 1986-01-16 1992-09-15 Christian Bannert Method of improving the adhesiveness of gels to mucosae
US4826683A (en) * 1987-01-09 1989-05-02 Bates Harry L Decongestant
US5200180A (en) * 1987-06-26 1993-04-06 Christian Bannert Pharmaceutical composition for the treatment of the human eye
US4981875A (en) * 1987-08-12 1991-01-01 Bayer Aktiengesellschaft Medicaments for the region of the oral cavity
US4915948A (en) * 1987-08-31 1990-04-10 Warner-Lambert Company Tablets having improved bioadhesion to mucous membranes
US5457093A (en) * 1987-09-18 1995-10-10 Ethicon, Inc. Gel formulations containing growth factors
US5456745A (en) * 1988-08-13 1995-10-10 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Flexible, hydrophilic gel film, the process for its production and the use of it
US5236714A (en) * 1988-11-01 1993-08-17 Alza Corporation Abusable substance dosage form having reduced abuse potential
US5238917A (en) * 1989-09-11 1993-08-24 Teikoku Seiyaku Kabushiki Kaisha High-absorbable transvaginal preparation containing biologically active polypeptide
US5707644A (en) * 1989-11-04 1998-01-13 Danbiosyst Uk Limited Small particle compositions for intranasal drug delivery
US5397771A (en) * 1990-05-10 1995-03-14 Bechgaard International Research And Development A/S Pharmaceutical preparation
US5318780A (en) * 1991-10-30 1994-06-07 Mediventures Inc. Medical uses of in situ formed gels
US5955502A (en) * 1994-03-30 1999-09-21 Gs Development Ab Use of fatty acid esters as bioadhesive substances

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100330183A1 (en) * 1997-10-27 2010-12-30 Harry Seager Solid dispersing vaccine composition for oral delivery
US20080014260A1 (en) * 1997-10-27 2008-01-17 Harry Seager Solid dispersing vaccine composition for oral delivery
US20040265377A1 (en) * 1997-10-27 2004-12-30 Harry Seager Solid dispersing vaccine composition for oral delivery
US7705135B2 (en) 1998-05-13 2010-04-27 Nanotherapeutics, Inc. Pharmaceutical compositions comprising aloe pectins, and methods for their production and use
US7691986B2 (en) 1998-05-13 2010-04-06 Nanotherapeutics, Inc. High molecular weight, low methoxyl pectins, and their production and uses
US20070231269A1 (en) * 2002-03-19 2007-10-04 Ionix Pharmaceuticals Limited Analgesics
US20110105551A1 (en) * 2002-03-19 2011-05-05 Vernalis (R&D) Limited Analgesics for nasal administration
US20070129299A1 (en) * 2002-12-17 2007-06-07 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of pyy peptide
US20070161563A1 (en) * 2002-12-17 2007-07-12 Nastech Pharmaceutical Company Inc. A device for enhanced epithelial permeation of y2 receptor-binding peptides
US7157426B2 (en) * 2002-12-17 2007-01-02 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US7863245B2 (en) * 2002-12-17 2011-01-04 Nastech Pharmaceutical Company, Inc. Compositions for enhanced epithelial permeation of neuropeptide Y for treating obesity
US7186691B2 (en) * 2002-12-17 2007-03-06 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US20070275893A1 (en) * 2002-12-17 2007-11-29 Nastech Pharmaceutical Company Inc. Compositions for enhanced epithelial permeation of peptide yy for treating obesity
US20080004218A1 (en) * 2002-12-17 2008-01-03 Nastech Pharmaceutical Company Inc. Methods for enhanced epithelial permeation of y2 receptor-binding peptides for treating and preventing obesity
US20040209807A1 (en) * 2002-12-17 2004-10-21 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US20040157777A1 (en) * 2002-12-17 2004-08-12 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity
US20090118158A1 (en) * 2002-12-17 2009-05-07 Nastech Pharmaceutical Company Inc. Compositions for enhanced epithelial permeation of peptide yy for treating obesity
US7166575B2 (en) * 2002-12-17 2007-01-23 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity
US20040115135A1 (en) * 2002-12-17 2004-06-17 Quay Steven C. Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity
US8889176B2 (en) 2003-01-10 2014-11-18 Depomed, Inc. Method of managing or treating pain
US9078814B2 (en) 2003-01-10 2015-07-14 Depomed, Inc. Intranasal spray device containing pharmaceutical composition
US9814705B2 (en) 2003-01-10 2017-11-14 Depomed, Inc. Intranasal spray device containing pharmaceutical composition
US20070213270A1 (en) * 2004-06-16 2007-09-13 Costantino Henry R Peptide yy formulations having increased stability and resistance to microbial agents
US20070232537A1 (en) * 2005-12-19 2007-10-04 Nastech Pharmaceutical Company Inc. Intranasal pyy formulations with improved transmucosal pharmacokinetics
US20110171314A1 (en) * 2006-03-30 2011-07-14 Engene, Inc. Non-viral compositions and methods for transfecting gut cells in vivo
US8846102B2 (en) 2006-03-30 2014-09-30 Engene, Inc. Non-viral compositions and methods for transfecting gut cells in vivo
US20100240749A9 (en) * 2007-03-02 2010-09-23 Combe Incorporated Anesthetic spray composition
US20080214664A1 (en) * 2007-03-02 2008-09-04 Combe Incorporated Anesthetic spray composition

Also Published As

Publication number Publication date Type
JP2001524094A (en) 2001-11-27 application
JP2009079052A (en) 2009-04-16 application
DK975367T3 (en) grant
ES2221706T3 (en) 2005-01-01 grant
JP2010280695A (en) 2010-12-16 application
JP4880657B2 (en) 2012-02-22 grant
US20110182857A1 (en) 2011-07-28 application
GB2340039A (en) 2000-02-16 application
DE122011000009I1 (en) 2011-06-16 grant
DK0975367T3 (en) 2004-07-26 grant
US6432440B1 (en) 2002-08-13 grant
US20070110677A1 (en) 2007-05-17 application
EP0975367B1 (en) 2004-03-31 grant
DE69822805D1 (en) 2004-05-06 grant
CA2282506A1 (en) 1998-10-29 application
GB2340039B (en) 2002-02-06 grant
WO1998047535A1 (en) 1998-10-29 application
GB9924123D0 (en) 1999-12-15 grant
EP0975367A1 (en) 2000-02-02 application
DE69822805T2 (en) 2005-02-17 grant
CA2282506C (en) 2008-12-30 grant
US20070092535A1 (en) 2007-04-26 application
GB9707934D0 (en) 1997-06-04 grant

Similar Documents

Publication Publication Date Title
Bakliwal et al. In-situ gel: new trends in controlled and sustained drug delivery system
US6465626B1 (en) Pharmaceutical compositions of chitosan with type-A gelatin
US5599534A (en) Reversible gel-forming composition for sustained delivery of bio-affecting substances, and method of use
US6316011B1 (en) End modified thermal responsive hydrogels
Andrews et al. Mucoadhesive polymeric platforms for controlled drug delivery
Marques et al. Simulated biological fluids with possible application in dissolution testing
US5110605A (en) Calcium polycarbophil-alginate controlled release composition and method
US6414033B1 (en) Drug dosage form based on the teorell-meyer gradient
US5747061A (en) Suspension of loteprednol etabonate for ear, eye, or nose treatment
Balasubramaniam et al. In vitro and in vivo evaluation of Gelrite® gellan gum-based ocular delivery system for indomethacin
Asane et al. Polymers for mucoadhesive drug delivery system: a current status
US20060013859A1 (en) Drug delivery system using subconjunctival depot
US6777000B2 (en) In-situ gel formation of pectin
US3711602A (en) Compositions for topical application for enhancing tissue penetration of physiologically active agents with dmso
US20090105336A1 (en) Beneficial Effects of Increasing Local Blood Flow
US6251436B1 (en) Drug preparations for treating sexual dysfunction
US20090123528A1 (en) Transdermal delivery of beneficial substances effected by a hostile biophysical environment
US6036977A (en) Drug preparations for treating sexual dysfunction
US7544348B2 (en) Liquid formulations for the prevention and treatment of mucosal diseases and disorders
Lee et al. Bioadhesive‐based dosage forms: The next generation
US5514673A (en) Pharmaceutical composition containing lipophilic drugs
Yu et al. Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies
US5215739A (en) Spray gel base and spray gel preparation using thereof
WO1997038698A1 (en) Methods for treating middle and inner ear disorders
Valenta The use of mucoadhesive polymers in vaginal delivery

Legal Events

Date Code Title Description
AS Assignment

Owner name: ARCHIMEDES DEVELOPMENT LIMITED, UNITED KINGDOM

Free format text: CHANGE OF NAME;ASSIGNOR:WEST PHARMACEUTICAL SERVICES DRUG DELIVERY & CLINICAL RESEARCH CENTRE LIMITED;REEL/FRAME:016700/0497

Effective date: 20050304

AS Assignment

Owner name: DEERFIELD PRIVATE DESIGN FUND III, L.P., NEW YORK

Free format text: SECURITY INTEREST;ASSIGNOR:DEPOMED, INC.;REEL/FRAME:035355/0039

Effective date: 20150402