AU686455B2 – Thermally-gelling drug delivery vehicles containing cellulose ethers
– Google Patents
AU686455B2 – Thermally-gelling drug delivery vehicles containing cellulose ethers
– Google Patents
Thermally-gelling drug delivery vehicles containing cellulose ethers
Info
Publication number
AU686455B2
AU686455B2
AU34965/95A
AU3496595A
AU686455B2
AU 686455 B2
AU686455 B2
AU 686455B2
AU 34965/95 A
AU34965/95 A
AU 34965/95A
AU 3496595 A
AU3496595 A
AU 3496595A
AU 686455 B2
AU686455 B2
AU 686455B2
Authority
AU
Australia
Prior art keywords
vehicle
gel
cellulose ether
ethyl
storage modulus
Prior art date
1994-08-30
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.)
Ceased
Application number
AU34965/95A
Other versions
AU3496595A
(en
Inventor
Bhagwati P Kabra
John C. Lang
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.)
Alcon Vision LLC
Original Assignee
Alcon Laboratories Inc
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.)
1994-08-30
Filing date
1995-08-23
Publication date
1998-02-05
1995-08-23
Application filed by Alcon Laboratories Inc
filed
Critical
Alcon Laboratories Inc
1996-03-22
Publication of AU3496595A
publication
Critical
patent/AU3496595A/en
1998-02-05
Application granted
granted
Critical
1998-02-05
Publication of AU686455B2
publication
Critical
patent/AU686455B2/en
2015-08-23
Anticipated expiration
legal-status
Critical
Status
Ceased
legal-status
Critical
Current
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Classifications
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K9/00—Medicinal preparations characterised by special physical form
A61K9/0012—Galenical forms characterised by the site of application
A61K9/0048—Eye, e.g. artificial tears
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
A61K47/38—Cellulose; Derivatives thereof
Abstract
Drug delivery vehicles which reversibly increase in either loss modulus or storage modulus, or both, upon contact with the eye, skin, mucous membrane or body cavity are disclosed. The vehicles contain one or more nonionic substituted cellulose ethers and do not require a charged surfactant or a pH-sensitive polymer for such increase in loss modulus or storage modulus, or both, upon administration. In one embodiment, the vehicles gel upon instillation in the eye.
Description
THERMALLY-GELUNG OPHTHALMIC DRUG DELIVERY VEHICLES
CONTAINING CELLULOSE ETHERS
BACKGROUND OF THE INVENTION
This application is a continuation-in-part of U.S. Serial No. 08/298,244, filed on August 30, 1994.
1. Held of the Invention
The present invention relates to pharmaceutical drug delivery vehicles. In particular, this invention relates to ophthalmic drug delivery vehicles which can be administrable as a drop, and which reversibly increase in loss modulus, storage modulus, or both, upon contact with the eye, skin, mucous membrane or a body cavity.
2. Description of Related Art
A variety of gelling drug delivery systems have been developed in an effort to prolong the contact or residence time of pharmaceutical drugs at target sites on or within the body. Drug delivery vehicles containing polysaccharide polymers which gel in response to a pH change have been proposed, such as those described in U.S. Patent Nos. 4,136,173, 4,136,177, and 4,136,178, for example. However, compositions having an initial pH which is too low are irritating when administered to sensitive parts of the body, such as the eye.
Alternatively, drug delivery systems which gel in response to changes in ionic strength have been proposed, such as those described in European Patent No. 0227 494 B1 and U.S. Patent No. 4,861,760. The rates of gelation for systems which gel in response to ionic changes are dependant on the supply and diffusion of ions, and consequently are generally slower than those for thermally gelling systems because the diffusion of ions is generally a slower process than heat transfer. In addition,
certain charged drug compounds cannot be used in drug delivery systems which gel in response to changes in ionic strength because they may cause premature gelation.
U.S. Patent No. 5,212,162 discloses compositions containing both a gelling polysaccharide and a drug carrier substrate, such as finely-divided solids, colloidal particles, or soluble polymers and/or polyelectrolytes which are capable of selective adsorption or binding with drug molecules. The polysaccharide is capable of reversibly gelling based on a change in ionic strength or pH. Such factors as a change in temperature, amount and type of drug carrier substrate, and characteristics and concentrations of drugs or other adjuvants may also affect the ability of the polysaccharide to undergo a liquid-to-gel transition. The preferred polysaccharides are carrageenans.
Drug delivery systems which gel in response to temperature changes have also been proposed. For example, drug delivery systems utilizing Tetronic®, Pluronic®, or other polyols have been disclosed in U.S. Patent Nos. 4,474,751; 4,474,752; and 4,188,373. U.S. Patent Nos. 5,124,151; and 5,306,501 also disclose thermally gelling systems. Several disadvantages are associated with these materials. One disadvantage common to all of these thermally gelling systems is that they require a large amount of polymer (10-50 wt.%), and such large amounts of polymer can be irritating and/or toxic to the eye. Another disadvantage of some of the known thermally gelling systems is that they gel irreversibly. Such thermally irreversible gels require special precautions for product shipping and handling.
It is an inherent requirement that drug delivery systems which gel solely in response to temperature changes undergo the «sol-gel» transition at temperatures lower than physiologic temperature. It is known that methylcellulose and its hydroxyalkyl derivatives reversibly gel with increases in temperature. Generally, however, the iiquid-to-gel transition temperature for cellulose polysaccharides, such as methylcellulose, occurs at temperatures well above physiologic temperature. See, for example, N. Sarkar, ‘Thermal Gelation Properties of Methyl and Hydroxypropyl Methylcellulose,» J. of Applied Polymer Science, Vol. 24, 1073-1087 (1979).
It is known that the addition of salts to methylcellulose can adjust its liquid-to-gel transition temperature; however, the amount of salt required to adjust the transition temperature to the physiologic temperature range often results in hyperosmotic compositions which are imtating. It is also known that the gelation temperature of methylcellulose may be altered by adding hydroxypropyl substituents, but the reported change does not bring the gelation temperature any closer to physiologic temperatures. N. Sarkar, J. of Applied Polymer Science, Vol. 24, 1084 (1979).
One effort to utilize cellulose polysaccharides in liquid pharmaceutical drug delivery vehicles is disclosed in PCT Application Publication No. VVO 92/09307. This reference discloses gelabie carrier compositions containing a water-soluble, nonionic cellulose ether, such as ethylhydroxyethylcellulose, and a charged surfactant. The reference gels are formed by strong hydrophobic interaction between the polymer and the charged surfactant. However, charged surfactants may be toxic if delivered to sensitive parts of the body, such as the eye. Additionally, other adjuvants may detrimentally influence the polymer-charged surfactant gelation.
Various drug delivery systems employing combinations of two types of gelling polymers have also been disclosed. U.S. Patent No. 5,077,033 discloses a thermally irreversible gel system comprising a combination of polyoxyalkylene and ionic polysaccharides. U.S. Patent No. 5,296,228 discloses aqueous reversibly gelling polymeric solutions containing ion exchange resin particles. The polymeric component of the solution may be a pH sensitive polymer, a temperature sensitive polymer, or combinations of both phi-sensitive polymers and temperature sensitive polymers. U.S. Patent No. 5,252,318 also discloses reversibly gelling aqueous compositions containing combinations of polymers, in this case at least one pH-sensitive reversibly gelling polymer and at least one temperature sensitive reversibly gelling polymer. One disadvantage common to systems which require pH changes in order to gel is that they must be administered at a relatively low pH, typically in the range of 2.5 – 4.5. Systems administered to the eye at such a relatively low pH are irritating.
SUMMARY OF THE INVENTION
The present invention is directed toward non-toxic, non-irritating ophthalmic drug delivery vehicles which reversibly increase in either loss modulus or storage modulus, or both, by at least the smaller of 10 Pa or 100 %, upon contact with the eye, skin, mucous membrane or a body cavity. In one embodiment, these drug delivery vehicles are administrable as a drop and, upon instillation in the eye, thicken to form a gel, whereby the residence or contact time of the delivered drugs with ocular tissue is increased. The vehicles do not require a charged surfactant or a pH -sensitive polymer in order for such increase in loss modulus or storage modulus, or both, upon instillation. The drug delivery vehicles of the present invention comprise nonionic cellulose ethers. The nonionic cellulose ethers have a molecular weight no less than 30 kD and are substituted with one or more groups selected from alkyl, hydroxyalkyl and phenyl groups such that:
wherein, n = substituent carbon chain length;
N = maximum value of n,≤22;
Rn = alkyl group of chain length n;
RnO = alkoxy group of chain length n;
MS(Rn) = MS of Rn;
MS(RnO ) = MS σf RnO;
MS(Φ) = MS of phenyl groups;
Q(n) = 0.837 + 0.155*n + 0.0075*n2 ± 0.15;
PN = 4.4 if N≤3; 4.4 – 1.82 if 3
