WO1997038698A1 - Methods for treating middle and inner ear disorders - Google Patents

Methods for treating middle and inner ear disorders Download PDF

Info

Publication number
WO1997038698A1
WO1997038698A1 PCT/US1997/006507 US9706507W WO9738698A1 WO 1997038698 A1 WO1997038698 A1 WO 1997038698A1 US 9706507 W US9706507 W US 9706507W WO 9738698 A1 WO9738698 A1 WO 9738698A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
substance
materials
biological
pharmacological activity
middle
Prior art date
Application number
PCT/US1997/006507
Other languages
French (fr)
Inventor
Mark C. Manning
Eli Shefter
Michael J. Hart
Original Assignee
University Technology Corporation
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

Links

Classifications

    • 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
    • A61K9/0046Ear
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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

Abstract

Provided are methods to deliver drugs to the middle or inner ear of a mammal in need of such drug comprising inserting a composition comprising a biocompatible polymer and at least one pharmacologically active agent. More particularly, the invention relates to a method for treating Meniere's disease using a composition of hyaluronic acid and gentamicin.

Description

METHODS FOR TREATING MIDDLE AND INNER EAR DISORDERS

FIELD OF THE INVENTION The present invention provides methods for treating middle and inner ear disorders. The methods involve administering a composition comprising hyaluronic acid, or other suitable biocompatible polymer, and at least one pharmacologically active substance useful for treating such disorders.

BACKGROUND OF THE INVENTION To treat various ear disorders, it is often necessary to deliver therapeutic agents to inner and middle ear tissues. A variety of structures have been developed that can deliver/administer therapeutic agents into the external auditory canal ofthe outer ear including those disclosed in U.S. Pat. Nos. 4,034,759, 3,528,419, 4,159,719 and 2,642,065.

However, the delivery of therapeutic agents in a controlled and effective manner to tissue structures ofthe middle, and particularly, the inner ear (e.g., those portions of the ear contained within the temporal bone which is the most dense bone tissue in the human body) is considerably more difficult. Inner ear tissue structures of primary importance include the cochlea, the endolymphatic sac/duct, the vestibular labyrinth and all ofthe compartments which include these components. Access to the inner ear tissue regions is typically through a variety of structures including the round window membrane, the oval window/stapes footplate and the annular ligament. For the purposes of this invention, the structures tnrough which access to the inner ear may be accomplished shall be considered middle-inner ear interface tissue structures. In addition, the middle ear is defined as the physiological air-containing tissue zone behind the tympanic membrane (i.e., the ear drum) and ahead of the inner ear. Note also that access to the inner ear may be had through the endolymphatic sac/endolymphatic duct and the otic capsule.

The foregoing inner ear tissues are of minimal size and, in the past, only readily accessible through microsurgical procedures. In order to treat various diseases and conditions associated with these and other inner ear tissues, the delivery of medicines is important. Exemplary medicines, or substances having biological or pharmacological activity, that are typically used to treat inner ear tissues include urea, mannitol, sorbitol, glycerol, xylocaine, epinephrine, immunoglobulins, sodium chloride, steroids, heparin, hyaluronidase, aminoglycoside antibiotics (e.g., streptomycin/gentamicin), and other drugs, biological materials, pharmaceutical compositions and therapeutic agents suitable for treating tissues ofthe human body. The effectiveness of therapies for the middle and inner ears is hampered by the routes of administration currently available. For example, typically antibiotics are systemically administered to treat infections ofthe middle ear. Systemic administration of antibiotics to combat middle ear infection generally results in a prolonged lag time to achieve therapeutic levels in the middle ear, and requires high initial doses in order to achieve such levels. These drawbacks complicate the ability to obtain therapeutic levels and may preclude the use of some antibiotics altogether. Systemic administration is most often effective when the infection has reached advanced stages, but at this point permanent damage may already have been done to the middle ear and inner ear structure. Drugs also can be administered by injection or lavage to the middle ear, but such administration cannot generally be used to achieve prolonged therapeutic levels. Similarly, ear drops can be used to apply antibiotics to the ear canal, but the ability of antibiotics to reach the middle ear when applied in this manner is difficult to predict or control, and poses difficulties, e.g., regarding the possible ototoxic effects of penetration enhancers that may be used. Middle ear drug delivery is further complicated by the fact that the ciliary action ofthe cells lining the mucous membrane clears the middle ear of medications that do arrive.

Delivery of drugs to the inner ear is even more problematical. For example, in the case of Meniere's disease, patients with a unilateral functional lesion at the level of the vestibular labyrinth component ofthe inner ear experience intense episodes of vertigo, usually with nausea and vomiting. They may also experience continuous disorientation in space. All of these symptoms can be incapacitating. Meniere's disease is caused by a variety of histopathological states, all of which can be termed vestibulopathies. The current primary therapy for Meniere's patients, if change in diet and administration of antibiotics does not alleviate the symptoms, is a vestibular nerve section. By sectioning the vestibular nerve, vestibular function is irreversibly lost on one side and allows the patient to reorient over a period of time. The success rate is high, yet significant risks are involved. This is a major intracranial operation with hospital stays averaging five days. Even though the procedure is straightforward, it presents the risk of intracranial infection, cerebrospinal fluid (CSF) leak, and complications due to general anaesthetics. In addition, there is severe postoperative vertigo for two to three days.

An alternative therapy is to inhibit vestibular function with an ototoxic therapeutic agent. Aminoglycoside antibiotics, such as gentamicin sulfate (GS), are known to be ototoxic, causing loss of hearing and vestibular function. However, with the appropriate dose, it should be possible to inhibit vestibular function without affecting hearing. If the drug is placed in the middle ear, which is accessible from the outside, the drug can diffuse through the round membrane and into the inner ear, which is very difficult to access. It is essential that drug remain in contact with the round membrane for all ofthe dose to be delivered.

Clinical studies for treating Meniere's disease have been performed using GS, with some success. (See, e.g., Nedzelski, J.M., et al., "Treatment of Meniere's Disease with Topical Gentamicin: A Preliminary Report," J. Otolaryngology, Vol. 21, pp. 95-101 (1992) and Paines, L.S. and Duneen, R., "Irritative Spontaneous Nystagmus Following Intratympanic Gentamicin for Meniere's Disease," Laryngoscope, Vol. 103. pp. 745-49 (1993).) However, these studies used GS solutions, which do not reliably remain in the middle ear, either due to leakage around the eardrum or via percolation back through the eardrum, if administered intertympanically. These problems lead to variation in dose, often requiring additional treatments, which increase the chance of hearing loss. Consequently, GS treatment to treat Meniere's disease has met with limited acceptance. Development of a dosage form which could reliably deliver a fixed dose and remain in contact with the round membrane would be highly advantageous for solving this and other problems relating to delivering drugs to the middle and inner ears. Clearly what is needed is a method to deliver therapeutically effective levels of drug to sufferers of diseases and other conditions ofthe middle or inner ear, in a fashion that is prompt, responsive, prolonged, effective, and safe.

SUMMARY OF THE INVENTION The present invention provides a composition incorporating one or more pharmacologically active agents, the composition being particularly useful in a method for treating middle or inner ear diseases and other conditions capable of being treated by such an agent. The composition comprises a biocompatible polymer support incoφorating a therapeutically effective releasable amount of at least one such active agent, the characteristics ofthe composition being such that, upon insertion into the middle ear, the composition is capable of maintaining its position in order to provide a surface that substantially contacts the round membrane of the middle ear and providing extended release of active agent to the inner ear. Preferably, the biocompatible polymer is biodegradable as well. More specifically, the present invention provides a gel composition system and methods for delivering a drug or other therapeutic, e.g., GS, to the middle or inner ear in a more controlled fashion. The GS is administered in an amount of about 5-360 mg per patient, more specifically about 20 to 200 mg per patient and, even more specifically, about 40 mg per patient. If the doses are greater than 200 mg, the patient should be dosed more than once. Those skilled in the art can determine optimal doses and dosage schedules.

The gel component of the system may comprise hyaluronic acid. Hyaluronic acid ("HA") is a well known, naturally occurring polysaccharide containing alternating N-acetyl-D-glucosamine and D-gluconic acid. The term "hyaluronan" is sometimes used interchangeably. As used herein, HA is intended to mean hyaluronic acid, salts thereof such as the sodium salt, and chemically modified derivatives of hyaluronic acid such as "hylan." Hylan is a cross-linked, but soluble derivative of HA whose preparation is described in detail in U.S. Pat. No. 4,713,448. Many other forms of HA are also known including those set forth in U.S. Pat. Nos. 5,128,326 and 5,442,053, the disclosures of which are incoφorated by reference. The terms "hyaluronic acid" and "HA" are meant to be broadly inclusive of all forms of hyaluronic acid-related molecules, including those referred to above. HA usually occurs as the sodium salt. The molecular weight of HA is generally within the range of 50,000 to 8 x IO6 or higher. HA is one ofthe major components ofthe extracellular matrix and is found in abundance in tissues like synovial fluid and the vitreous ofthe eye. HA and its salts give very viscous and elastic solutions in water or physiological salt solution.

HA does not produce a foreign body reaction when implanted into a living organism and has an excellent biocompatibility. It is also biodegradable. The combination of these properties together with the known viscoelasticity of HA facilitates the use of HA in the biomedical field. Thus, a 1% solution of sodium hyaluronate (Healon™) is used in eye viscosurgery (L. A. Pape and E. A. Balazs, Ophthalmology, 87, No. 7, 1980). HA also is used to impart biocompatibility to various polymeric materials. (E. A. Balazs and A. Leshchiner, U.S. Pat. No. 4,500,676, 1985).

The preferred composition comprises a gel which is a commercial preparation of sodium hyaluronic acid called Healon™. Healon™ is an HA preparation with a molecular weight of about three million. It can be purchased from Pharmacia. Healon™ can be impregnated with high doses of GS (equivalent to loads of up to 200 mg/ml of gentamicin base, corresponding to 314 mg/ml of GS). The gel can be injected behind the eardrum under local anaesthetic. The preferred method for injection is with a needle. However, other methods, for example, a pumping device with a small orifice, may also be used.

The composition is fluid enough to be injected through a fine gauge needle (as small as 26 gauge), assuring proper placement of the gel, but viscous enough that it will remain in contact with the tissue for an extended period of time. Finally, the Healon™ is biodegradable. After a period of time, the gel decomposes to biocompatible materials and disappears from the site of administration. In the laboratory, the gel appears to be liquid enough to disappear from the site within seven to ten days with minimal agitation. Consequently, the GS/sodium hyaluronic acid composition may provide a superior dosage form for nonsurgical treatment for unilateral vestibular dysfunction and other disorders ofthe middle and inner ears.

The drug delivery composition may include the following: 1. HA solutions in which a drug substance is dissolved or dispersed; 2. A cross-linked HA gel forming a macromolecular "cage" in which a drug substance is dispersed so long as cross-linking does not make the polymer rigid;

3. A cross-linked mixed gel of HA and at least one other hydrophilic polymer in which a drug substance is dispersed;

4. A cross-linked gel of HA or cross-linked mixed gel of HA and at least one other hydrophilic polymer containing a drug substance which is covalently attached to the macromolecules of HA or the other polymer.

Such compositions are set forth in U.S. Pat. No. 5,108,326, which is incoφorated herein by reference. However, they are not disclosed for use in treating middle and inner ear disorders. Any substance which has biological or pharmacological activity and which is normally considered to be a drug or other therapeutic can be used as the drug component in the composition according to the present invention. Exemplary substances are set forth above. The terms "drug" and "drug substance" are also used herein to describe such substances. The substances can be soluble or not soluble in aqueous medium; they can be of relatively low molecular weight or a polymeric substance, and the choice of the substance will clearly depend upon the specific use ofthe end product and disease or other problem to be treated. It should be understood that any combination of one or more such substances can be used in the products and methods according to the invention.

As mentioned above, HA is the preferred polymeric component ofthe composition which controls release ofthe drug. Other biocompatible polymers may also be used including celluloses, gelatins, Pluronics, Tetronics, the latter two being poly (ethylene oxide)/poly (propylene oxide) materials. Other materials that may be used in place of HA include the chondroitin sulfates and the general class of mucopolysaccharides (e.g., glycosaminoglycans) and other biocompatible polymers having characteristics similar to HA. When a drug substance is dissolved or dispersed in the biocompatible polymer, its diffusion is substantially slower than when in solution and this contributes to the delivering properties ofthe system. Without being bound by theory, in the case of a drug containing cationic groups, an ionic interaction can occur between HA macromolecules having carboxyl groups and the drug and this interaction slows down the diffusion ofthe drug from the system even further.

The HA concentration in the products, based on the soluble polymers, can be in the range of from about 0.05 to 4% by wt. and higher, depending on the end use of the product. The drug concentration can be varied over very broad limits and preferably should be chosen depending upon the solubility ofthe drug, its pharmacological activity, the desirable effect of the end product, patient size, weight and so forth, all factors known to those skilled in the art. Although many of the above-discussed medicines can already be used as injectables, the products according to the invention containing non-soluble HA are substantially more efficient as injectable drug delivery systems for use in methods of treating the middle and inner ears.

In a further aspect ofthe present invention, the pharmacologically active agent may be present in the form of a hydrophobic ion pair complex with an amphiphilic material. Incoφoration ofthe pharmacologically active agent in a hydrophobic ion pair complex is particularly useful for slowing the rate of release of the pharmacologically active agent, when a slower release rate is desired. Preferred amphiphilic materials for forming a hydrophobic ion pair with gentamicin are sodium dodecyl sulfate (SDS) and bis-(2-ethylhexyl) sodium sulfosuccinate (AOT). The hydrophobic ion pair complex may be prepared according to procedures known in the art. Additional information concerning hydrophobic ion pair complexes and their preparation may be found in PCT Publication No. WO 94/08599, published April 28,1994, and pending U.S. Patent

Application Serial No. 08/473,008, filed June 6, 1995, the contents of both of which are incoφorated herein in their entireties.

For treating Meniere's disease, the preferred pharmacological agent is gentamicin sulfate. Other ototoxic agents may also be used, including aminoglycosides and other agents, including acetylsalicylic acid, amikacin, aminoglycosides, chloramphenicol, chlorhexidine, chloroquine, cytostatics, dantrolene, deferoxamine, doxycycline, erythromycin, furosemide, gentamicin, kanamycin, minocycline, naproxen, neomycin, piroxicam, propylene glycol, spinal anesthesia, bupivacaine and streptomycin. Other diseases ofthe middle and inner ear may also be treated using the methods and products ofthe invention, including any vestibular dysfunctions, local infections (viral or bacterial) and reduced hearing caused by diminished blood flow. Another aspect ofthe present invention includes the use of a combination of materials in the manufacture of a medicament composition for treatment of a disease of the inner ear or middle ear when transplanted in the middle ear, characterized in that the combination of materials includes a biocompatible polymer and a substance having biological or pharmacological activity. In a further aspect, the present invention includes a method of transplanting the composition into the middle ear comprising placing within the middle ear the composition having the biocompatible polymer and the substance having biological or pharmacological activity.

DESCRIPTION OF THE PREFERRED EMBODIMENT Materials. Gentamicin sulfate (GS), USP, is obtained from Paddock. Sodium hyaluronate gels ( Healon™) are commercially available from Pharmacia. The sodium HA has an initial concentration of 14 mg/ml. Concentrations of gentamicin are given in terms of GS. This corresponds to a gentamicin base concentration that is 0.63 times the concentration of GS.

The Healon™/GS preparations are formed by mixing equal volumes of Healon™ (14 mg/ml) and a concentrated solution of GS dissolved in phosphate- buffered saline (PBS). Healon™ and GS were mixed manually by repeatedly drawing the solution into and out of a syringe through an 18-ga. needle for a minimum of five minutes. Other methods including vortexing or stirring with a stir plate and stir bar were found to be ineffective due to viscosity ofthe Healon™. For most studies, the final GS concentration in the composition is 314 mg/ml (i.e., 200 mg/ml of gentamicin base). Release Studies. Composition samples are incubated at 37 °C in a water bath unless otherwise noted. Release studies are measured as cumulative release, with the entire receiver volume replaced with fresh PBS at the various time points. Amounts are given as the percentage ofthe total dose of GS. For a typical release study, the loading factor is 200 mg of gentamicin base per 1 ml of gel. 0.2 ml of gel is placed into 0.8 ml of receiver fluid. The receiver volume for all ofthe in vitro release studies is 0.8 ml, but the kinetics do not change if the receiver volume is doubled. Therefore, the total dose is 64 mg of GS, which has been found to be effective for inhibition of vestibular function. The remaining sodium hyaluronate completely dissolves within seven to ten days, depending on the extent of agitation, suggesting biodegradation should be rapid.

Analysis. Determination of gentamicin levels in the release medium, either PBS or CSF, is performed on an Abbott TDx clinical analyzer. Calibration standards are run each time a new reageant kit is used on the analyzer. In addition, three controls are run with each individual analysis performed to ensure accuracy. Gentamicin levels are measured by derivitization with o-phthaldehyde (OP A) following Sampath and

Robinson's 1990 procedure (Sampath, S.S., Robinson, D.H. "Comparison of new and existing spectrophotometric methods for the analysis of tobramycin and other aminoglycosides." J. Pharm Sci. 79 (1990) 428-431) with modifications employed by Goosen et al. (Zhang, X., Wyss, U.P., Pichora, D., Goosen, M.F.A. "Biodegradable controlled antibiotic release devices for osteomyelitis: optimization of release properties." J. Pharm. Pharmacol. 46 (1994) 718-724.) The two methods are in excellent agreement (see below).

The target dose for these studies is taken to be approximately 64 mg of GS. As the volume ofthe middle ear is limited, and to allow the administration ofthe drug to be as convenient as possible, the total dose is loaded into 0.2 ml of sodium hyaluronate gel. The middle ear accommodates volumes up to 0.8 ml.

Example 1 - Control Release Studies. Initial release studies are performed into PBS, a common receiver fluid for controlled release studies. The release kinetics are well controlled and reproducible over the first four hours. There appears to be a small burst effect from drug adsorbed to the surface ofthe gel, but it is much less than normally seen with other biodegradable polymers. Steady-state release is rapidly established. By four hours, much ofthe drug is released (50-60%), and the rate of release begins to slow. The drug is nearly completely delivered (-75%) by 24 hours. The variability is very small, with a relative standard deviation of 2-4% from run to run. As an approximation to the environment of the middle ear, release is next measured into CSF. The kinetic profile is approximately the same as in PBS, except that the amount of drug released in a given time is slightly lower (-90% ofthe level for release into PBS at a given time point). At four hours, the amount released is closer to 50% rather than 60%. However, by 24 hours, the total amount released is approximately 80-90%. The correlation between release into PBS and CSF is very high

(r2 = 0.999). It appears the presence of serum components leads to small diminution in the release from the gel, but does not significantly change the kinetics or limit its utility.

To determine the nature ofthe controlled release properties of this system, the rate of initial release is examined carefully. Monitoring the release rate over the first half-hour, steady-state occurs within ten minutes. From that time until the system is nearly depleted of GS, the amount of GS released is linear with the square root of time. Also, the composition displays very little burst effect, even at 200 mg/ml, indicating that very little of the drug is adsorbed to the surface ofthe gel. Comparison ofthe data to the previous release profiles indicates that the rate of release is much faster as the system is sampled more often. The composition is always somewhat fluid, unlike solid implants or microspheres or other controlled release dosage forms. This mobility means that agitation ofthe gel surface will be more disruptive than in those solid preparations, leading to increased rates of release. In addition, all of the release studies are cumulative determinations, meaning receiver fluid is replaced by fresh solution. This has the effect of increasing the concentration gradient that existed just prior to sampling. The more frequently this is done, the faster the release rate. In order to probe the effects of agitation and fluid replacement, another sampling technique is employed, using a microliter syringe to remove lOμ of sample. Comparison of the release profile shows that this sampling method does not lead to rapid GS release over the first thirty minutes.

Example 2 - Effects of Loading Factor. The release of GS from HA is measured for loading factors of 50, 100 and 200 mg/ml. The cumulative percent release into PBS is more rapid for the lower loading factor. However, the total flux decreases with loading factor, as would be expected for diffusion-limited delivery systems. Both preparations display linear release kinetics over the one to four hour time frame.

Example 3 - Comparison of Methods for Quantitation of GS. Two different methods are used to quantitate GS release from the HA gel: (1) spectrophotometric determination of GS following chemical modification with OPA and (2) an automated clinical chemistry method using antibody binding and fluorescence detection. The instrument is called TDx (Abbott Laboratories). Both of these methods are well established for their ability to measure GS at microgram per milliliter concentrations. Both exhibited linearity across the concentration range used in these studies. All samples are diluted 500-1000-fold before being assayed.

Claims

We claim:
1. A method for delivering a medicine to the inner ear of a mammal in need of such medicine comprising inserting into the middle ear a composition comprising a biocompatible polymer and at least one substance having biological or pharmacological activity.
2. A method according to Claim 1 , wherein said biocompatible polymer is hyaluronic acid.
3. A method according to Claim 1, wherein said substance having biological or pharmacological activity is an aminoglycoside antibiotic.
4. A method according to Claim 3, wherein said substance having biological or pharmacological activity is gentamicin or gentamicin sulfate.
5. A method according to Claim 1, wherein said biocompatible polymer is hyaluronic acid and said substance having biological or pharmacological activity is gentamicin or gentamicin sulfate.
6. A method according to Claim 2, wherein said hyaluronic acid is
Healon.™
7. A method according to Claim 4, wherein said substance having biological or pharmacological activity is gentamicin sulfate.
8. A method according to Claim 5, wherein said substance having biological or pharmacological activity is gentamicin sulfate and said hyaluronic acid is
Healon.™
9. The method according to Claim 1, wherein the substance having biological or pharmacological activity is in the form of a hydrophobic ion pair complex with an amphiphilic material.
10. The method according to Claim 9, wherein the amphiphilic material comprises at least one of sodium dodecyl sulfate (SDS) and bis-(2-ethylhexyl) sodium sulfosuccinate (AOT).
1 1. Use of a combination of materials in the manufacture of a medicament composition for treatment of a disease ofthe inner or middle ear when transplanted in the middle ear, characterized in that the combination of materials includes a biocompatible polymer and at least one substance having biological or pharmacological activity.
12. The use ofthe combination of materials as recited in Claim 1 1 , wherein the biocompatible polymer is hyaluronic acid.
13. The use ofthe combination of materials as recited in Claim 11 , wherein the substance having biological or pharmacological activity is an aminoglycoside antibiotic.
14. The use ofthe combination of materials as recited in Claim 1 1, wherein the substance having biological or pharmacological activity is gentamicin or gentamicin sulfate.
15. The use ofthe combination of materials as recited in Claim 1 1, wherein the biocompatible polymer is Healon.™
16. The use of the combination of materials as recited in Claim 1 1 , wherein the substance having biological or pharmacological activity is in the form of a hydrophobic ion pair complex with an amphiphilic material.
17. The use ofthe combination of materials as recited in Claim 16, wherein the amphiphilic material comprises at least one of sodium dodecyl sulfate (SDS) and bis-(2-ethylhexyl) sodium sulfosuccinate (AOT).
18. The use ofthe combination of materials as recited in Claim 1 1, wherein the disease ofthe middle or inner ear is a vestibular dysfunction disease.
19. The use ofthe combination of materials as recited in Claim 1 1, wherein the disease ofthe middle or inner ear is Meniere's disease.
20. The use ofthe combination of materials as recited in Claim 11 , wherein the disease of the middle or inner ear is a localized viral or bacterial infection.
21. The use ofthe combination of materials as recited in Claim 1 1, wherein the disease ofthe middle or inner ear includes a loss of hearing caused by diminished blood flow.
22. A method of transplanting a composition into the middle ear comprising placing within the middle ear a composition characterized as having a biocompatible polymer and at least one substance having biological or pharmacological activity.
PCT/US1997/006507 1996-04-18 1997-04-18 Methods for treating middle and inner ear disorders WO1997038698A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US1557296 true 1996-04-18 1996-04-18
US60/015,572 1996-04-18

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AU2676397A AU2676397A (en) 1996-04-18 1997-04-18 Methods for treating middle and inner ear disorders

Publications (1)

Publication Number Publication Date
WO1997038698A1 true true WO1997038698A1 (en) 1997-10-23

Family

ID=21772209

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/006507 WO1997038698A1 (en) 1996-04-18 1997-04-18 Methods for treating middle and inner ear disorders

Country Status (1)

Country Link
WO (1) WO1997038698A1 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000033775A1 (en) * 1998-12-04 2000-06-15 Durect Corporation Controlled release system for delivering therapeutic agents into the inner ear
EP1073419A2 (en) * 1998-03-18 2001-02-07 University Technology Corporation Sustained-release composition including amorphous polymer
US6984410B2 (en) 2001-08-31 2006-01-10 Heraeus Kulzer Gmbh & Co. Kg Process for antibiotic coating of elements with interconnecting microcavities, elements thus coated as well as their usage
WO2007038949A1 (en) 2005-09-28 2007-04-12 Auris Medical Ag Pharmaceutical compositions for the treatment of inner ear disorders
US7358232B2 (en) 2001-08-31 2008-04-15 Heraeus Kulzer Gmbh & Co.Kg Method for the antibiotic coating of bodies with interconnecting microcavities as well as coated bodies and their usage
CN100490915C (en) 2003-01-17 2009-05-27 先灵有限责任公司 Otolaryngological delivery device
EP2077108A1 (en) 2004-03-29 2009-07-08 Auris Medical AG Use of an NMDA receptor antagonist for the treatment of tinnitus induced by cochlear excitotoxicity
US20100016450A1 (en) * 2008-07-21 2010-01-21 Otonomy, Inc. Controlled release delivery devices for the treatment of otic disorders
US8030297B2 (en) 2008-05-14 2011-10-04 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of OTIC disorders
US8318817B2 (en) 2008-07-21 2012-11-27 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US20120302554A1 (en) * 2005-01-25 2012-11-29 Auris Medical Ag Phantom phenomena treatment
US8349353B2 (en) 2008-06-27 2013-01-08 Otonomy, Inc. Controlled release cytotoxic agent compositions and methods for the treatment of otic disorders
US8399018B2 (en) 2008-07-21 2013-03-19 Otonomy, Inc. Controlled release ion channel modulator compositions and methods for the treatment of otic disorders
US8496957B2 (en) 2008-07-21 2013-07-30 Otonomy, Inc Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US8507525B2 (en) 2004-03-29 2013-08-13 Auris Medical Ag Methods for the treatment of tinnitus induced by cochlear excitotoxicity
US8648119B2 (en) 2008-05-23 2014-02-11 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
US8691288B2 (en) 2006-05-10 2014-04-08 Medtronic, Inc. Gallium-containing sealant for medical use
US8784870B2 (en) 2008-07-21 2014-07-22 Otonomy, Inc. Controlled release compositions for modulating free-radical induced damage and methods of use thereof
US8846770B2 (en) 2008-06-18 2014-09-30 Otonomy, Inc. Controlled release aural pressure modulator compositions and methods for the treatment of OTIC disorders
US8852626B2 (en) 2008-06-27 2014-10-07 Otonomy, Inc. Controlled-release CNS modulating compositions and methods for the treatment of otic disorders
US9072662B2 (en) 2004-03-29 2015-07-07 Auris Medical Ag Methods for the treatment of tinnitus induced by cochlear excitotoxicity
US9119896B2 (en) 2007-02-08 2015-09-01 Medtronic Xomed, Inc. Polymeric sealant for medical use
US9132087B2 (en) 2008-04-21 2015-09-15 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US9173864B2 (en) 2008-10-22 2015-11-03 House Ear Institute Treatment and/or prevention of inner ear conditions by modulation of a metabotropic glutamate receptor
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders
US9700344B2 (en) 2008-06-12 2017-07-11 Medtronic Xomed, Inc. Method for treating chronic wounds with an extracellular polymeric substance solvating system
US10092580B2 (en) 2008-07-21 2018-10-09 Otonomy, Inc. Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5442053A (en) * 1982-09-28 1995-08-15 Fidia, S.P.A. Salts and mixtures of hyaluronic acid with pharmaceutically active substances, pharmaceutical compositions containing the same and methods for administration of such compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5442053A (en) * 1982-09-28 1995-08-15 Fidia, S.P.A. Salts and mixtures of hyaluronic acid with pharmaceutically active substances, pharmaceutical compositions containing the same and methods for administration of such compositions

Cited By (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1073419A2 (en) * 1998-03-18 2001-02-07 University Technology Corporation Sustained-release composition including amorphous polymer
EP1073419A4 (en) * 1998-03-18 2009-03-25 Univ Technology Corp Sustained-release composition including amorphous polymer
US8197461B1 (en) 1998-12-04 2012-06-12 Durect Corporation Controlled release system for delivering therapeutic agents into the inner ear
US6685697B1 (en) 1998-12-04 2004-02-03 Durect Corporation Controlled release system for delivering therapeutic agents into the inner ear
EP1767175A1 (en) 1998-12-04 2007-03-28 Durect Corporation Controlled release system for delivering therapeutic agents into the inner ear
WO2000033775A1 (en) * 1998-12-04 2000-06-15 Durect Corporation Controlled release system for delivering therapeutic agents into the inner ear
US6984410B2 (en) 2001-08-31 2006-01-10 Heraeus Kulzer Gmbh & Co. Kg Process for antibiotic coating of elements with interconnecting microcavities, elements thus coated as well as their usage
US7358232B2 (en) 2001-08-31 2008-04-15 Heraeus Kulzer Gmbh & Co.Kg Method for the antibiotic coating of bodies with interconnecting microcavities as well as coated bodies and their usage
CN100490915C (en) 2003-01-17 2009-05-27 先灵有限责任公司 Otolaryngological delivery device
EP2077108A1 (en) 2004-03-29 2009-07-08 Auris Medical AG Use of an NMDA receptor antagonist for the treatment of tinnitus induced by cochlear excitotoxicity
US9463168B2 (en) 2004-03-29 2016-10-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Methods for the treatment of tinnitus induced by cochlear excitotoxicity
US9072662B2 (en) 2004-03-29 2015-07-07 Auris Medical Ag Methods for the treatment of tinnitus induced by cochlear excitotoxicity
US8268866B2 (en) 2004-03-29 2012-09-18 Matthieu Guitton Methods for the treatment of tinnitus induced by cochlear excitotoxicity
US8507525B2 (en) 2004-03-29 2013-08-13 Auris Medical Ag Methods for the treatment of tinnitus induced by cochlear excitotoxicity
US20120302554A1 (en) * 2005-01-25 2012-11-29 Auris Medical Ag Phantom phenomena treatment
WO2007038949A1 (en) 2005-09-28 2007-04-12 Auris Medical Ag Pharmaceutical compositions for the treatment of inner ear disorders
US9066865B2 (en) 2005-09-28 2015-06-30 Auris Medical Ag Pharmaceutical compositions for the treatment of inner ear disorders
EP2792347A1 (en) 2005-09-28 2014-10-22 Auris Medical AG Pharmaceutical compositions for the treatment of inner ear disorders
US8691288B2 (en) 2006-05-10 2014-04-08 Medtronic, Inc. Gallium-containing sealant for medical use
US9119896B2 (en) 2007-02-08 2015-09-01 Medtronic Xomed, Inc. Polymeric sealant for medical use
US9132087B2 (en) 2008-04-21 2015-09-15 Otonomy, Inc. Auris formulations for treating otic diseases and conditions
US9511020B2 (en) 2008-05-14 2016-12-06 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8680083B2 (en) 2008-05-14 2014-03-25 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8658626B2 (en) 2008-05-14 2014-02-25 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8680082B2 (en) 2008-05-14 2014-03-25 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8828980B2 (en) 2008-05-14 2014-09-09 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US9744126B2 (en) 2008-05-14 2017-08-29 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8546363B2 (en) 2008-05-14 2013-10-01 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8030297B2 (en) 2008-05-14 2011-10-04 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of OTIC disorders
US8648119B2 (en) 2008-05-23 2014-02-11 Otonomy, Inc. Controlled release immunomodulator compositions and methods for the treatment of otic disorders
US9700344B2 (en) 2008-06-12 2017-07-11 Medtronic Xomed, Inc. Method for treating chronic wounds with an extracellular polymeric substance solvating system
US8846770B2 (en) 2008-06-18 2014-09-30 Otonomy, Inc. Controlled release aural pressure modulator compositions and methods for the treatment of OTIC disorders
US8852626B2 (en) 2008-06-27 2014-10-07 Otonomy, Inc. Controlled-release CNS modulating compositions and methods for the treatment of otic disorders
US9333171B2 (en) 2008-06-27 2016-05-10 Otonomy, Inc. Controlled-release CNS modulating compositions and methods for the treatment of otic disorders
US8349353B2 (en) 2008-06-27 2013-01-08 Otonomy, Inc. Controlled release cytotoxic agent compositions and methods for the treatment of otic disorders
US8496957B2 (en) 2008-07-21 2013-07-30 Otonomy, Inc Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US9066855B2 (en) 2008-07-21 2015-06-30 Otonomy, Inc. Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US9867778B2 (en) 2008-07-21 2018-01-16 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9205048B2 (en) 2008-07-21 2015-12-08 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9233068B2 (en) 2008-07-21 2016-01-12 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of OTIC disorders
US8318817B2 (en) 2008-07-21 2012-11-27 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9427472B2 (en) 2008-07-21 2016-08-30 Otonomy, Inc. Controlled release compositions for modulating free-radical induced damage and methods of use thereof
US20100016450A1 (en) * 2008-07-21 2010-01-21 Otonomy, Inc. Controlled release delivery devices for the treatment of otic disorders
US9808460B2 (en) 2008-07-21 2017-11-07 Otonomy, Inc. Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US8784870B2 (en) 2008-07-21 2014-07-22 Otonomy, Inc. Controlled release compositions for modulating free-radical induced damage and methods of use thereof
US9603796B2 (en) 2008-07-21 2017-03-28 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US8575122B2 (en) 2008-07-21 2013-11-05 Otonomy, Inc. Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US8399018B2 (en) 2008-07-21 2013-03-19 Otonomy, Inc. Controlled release ion channel modulator compositions and methods for the treatment of otic disorders
US10092580B2 (en) 2008-07-21 2018-10-09 Otonomy, Inc. Controlled-release otic structure modulating and innate immune system modulating compositions and methods for the treatment of otic disorders
US9173864B2 (en) 2008-10-22 2015-11-03 House Ear Institute Treatment and/or prevention of inner ear conditions by modulation of a metabotropic glutamate receptor
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders

Similar Documents

Publication Publication Date Title
Surendrakumar et al. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs
Kempe et al. In situ forming implants—an attractive formulation principle for parenteral depot formulations
Moritera et al. Microspheres of biodegradable polymers as a drug-delivery system in the vitreous.
US5173298A (en) Nonaqueous fluorinated drug delivery vehicle suspensions
US5624962A (en) Aqueous drug composition having property of reversible thermosetting gelation
US6630486B1 (en) Inorganic-polymer complexes for the controlled release of compounds including medicinals
Larsen et al. Drug delivery systems using hyaluronan and its derivatives
Veyries et al. Controlled release of vancomycin from poloxamer 407 gels
US4730013A (en) Biosoluble ocular insert
US5599534A (en) Reversible gel-forming composition for sustained delivery of bio-affecting substances, and method of use
US20110166060A1 (en) Tympanic membrane permeating ear drops and uses thereof
US20090042834A1 (en) Stabilized Glycosaminoglycan Preparations and Related Methods
Saettone Progress and problems in ophthalmic drug delivery
US20090325938A1 (en) Controlled-release cns modulating compositions and methods for the treatment of otic disorders
US20100022661A1 (en) Controlled release compositions for modulating free-radical induced damage and methods of use thereof
Madan et al. In situ forming polymeric drug delivery systems
US20100015263A1 (en) Controlled release auris sensory cell modulator compositions and methods for the treatment of otic disorders
US5888493A (en) Ophthalmic aqueous gel formulation and related methods
US20100016450A1 (en) Controlled release delivery devices for the treatment of otic disorders
US3911098A (en) Medicament carrier
US20100015228A1 (en) Controlled release ion channel modulator compositions and methods for the treatment of otic disorders
WO2003071986A2 (en) Method for treating otic disorders
Cobo et al. The clearance of intravitreal gentamicin
WO1996039146A1 (en) Non-irritation, non-sensitizing, non-ototoxic otic antibacterial compositions
Hashizoe et al. Scleral plug of biodegradable polymers for controlled drug release in the vitreous

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN YU AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase in:

Ref country code: JP

Ref document number: 97537399

Format of ref document f/p: F

NENP Non-entry into the national phase in:

Ref country code: CA

122 Ep: pct application non-entry in european phase