Lippomix Incorporated : Liposome Technology : Contract Manufacturer

Liposome-Encapsulated Tetracaine Anesthetic (LETA): Pre-Clinical

The next lead candidate in LIPPOMIX's product pipeline is a topical anesthetic cream comprising OPTISOMETM encapsulated tetracaine (5%). This formulation was found to have a more rapid onset and a deeper anesthesia of longer duration compared to two currently commercial available products: EMLA (Astra), and Ela-MAX (Ferndale). Moreover, it was shown that LETA had less variability between subjects when tested in healthy volunteers. LIPPOMIX expects to file the IND for this product in the near future.

In parallel, a 1% tetracaine formulation is being partnered for sales and marketing under an OverThe-Counter monograph. Lippomix is currently working on the development of a marketing agreement and FDA label approval

Introduction

Tetracaine belongs to the family of local, aminoester-type anesthetics that includes benzocaine, lidocaine, and prilocaine. This group of drugs is known to reversibly bind to the hydrophobic drug receptor located on the α subunit of many voltage-gated sodium channels. During periods of high frequency channel activity or prolonged membrane depolarization, these ester-type anesthetics bind to the receptor and inhibit sodium current, ultimately inhibiting the propagation of the action potential through the nerve membrane.

Tetracaine was first introduced in 1932 and has been in use since as an ophthalmic, topical and injectable anesthetic. Ophthalmic tetracaine solutions are commonly used to anesthetize the ocular surface prior to tonometry, gonioscopy, removal of a foreign body, corneal tissue sampling, or before thorough ocular examination or irrigation. Topically, tetracaine hydrochloride is used to numb the nasal or esophageal surfaces before performing such diagnostic procedures as bronchoscopy, bronchography, or esophagoscopy, and to prevent pain in other areas covered by mucosal membranes (ie. Perioral or ano-rectal). Caudal, spinal, or saddle blocks are frequently induced by injection of a tetracaine solution into the cerebral spinal fluid.

In the US, tetracaine is available by prescription either in the free base form as a 0.5% ophthalmic solution (AK-T caine) or 0.5% ophthalmic ointment (Pontocaine). Tetracaine is also available in salt form, and products containing tetracaine hydrochloride include a 2% topical solution (Pontocaine HCl), a 2% solution in a nebulizing dispenser (Cetacaine), a 1% injectable solution (Pontocaine HCl), or a 20 mg dry powder (Pontocaine HCl). A 4% tetracaine hydrochloride gel (Topocaine) is also marketed in European countries, but this \and other, higher strength topical tetracaine products are unavailable in the US.

Of all ester-type anesthetics, tetracaine is the most slowly metabolized of all. It is this characteristic that imparts both an extended duration and depth of action and a higher level of toxicity than its more rapidly metabolized relatives. In humans, it undergoes ester hydrolysis to form p-aminobenzoic acid, a reaction that is catalyzed by a plasma pseudocholinesterase. Metabolites of tetracaine are mainly excreted through the kidneys.

Adverse effects of topically applied tetracaine may occur when an excessive amount of drug is rapidly absorbed into the bloodstream. High concentrations of tetracaine in the blood may lead to depression of the CNS or cardiovascular complications. With these concerns in mind, efforts have been made to develop a liposome-encapsulated topical tetracaine formulation. Liposome-encapsulated drug delivery is a reliable method of depositing a drug into the site of application, while reducing the rate of systemic absorption. A liposome-encapsulated tetracaine formulation could potentially be used to anesthetize an area of the body prior to such procedures as venapuncture, circumsion, or skin, hair, or tattoo removal, without the adverse systemic side effects.

Physical, chemical, and pharmaceutical properties of active ingredient

Generic name
Tetracaine

Chemical name
4-(Butylamino)benzoic acid 2-(dimethylamino)ethyl ester

Physicochemical characteristics
Tetracaine occurs as an odorless, white or pale yellow, crystalline powder. It is freely soluble in ethanol, chloroform, and ether and practically insoluble in water. It has a pKa1 of 2.14 and a pKa2 of 8.26 at 25° C. Tetracaine melts between 41-46°C.

Structural formula

Molecular formula
C15H24N2O2

Molecular weight
264.37

Potential Market

LIPPOMIX's third product is an Optisome- encapsulated topical anesthetic (tetracaine). This topical anesthetic, will potentially become the second long-acting topical anesthetic for application to intact skin introduced to the U.S. market. In 1993, the worldwide market for local anesthetics was estimated at $535M. There are several local anesthetics currently in development with most products being injectables. The need for effective topical anesthetics is somewhat obvious in that such a drug will eliminate painful injections and allow for the painless induction of local anesthesia. The conduct and patient acceptance of many procedures is improved and simplified by the availability of an effective topical (dermal) anesthetic.

Competition

Companies with topical anesthetics in development or currently on the market outside the U.S. include Smith and Nephew (and their U.S. licensee, Mylan Laboratories), Astra, RTP Pharma and Noven. With one exception, the formulations contain either lidocaine or tetracaine as the active ingredient. Presently, Astra Pharmaceutical's EMLA® cream is the only long-acting topical anesthetic currently being marketed in the U.S. Astra is also developing another long-acting topical anesthetic and this product is in Phase I clinical trials. EMLA® cream is a mixture of lidocaine (2.5%) and procaine (2.5%) and has a broad label claim as it is indicated as a topical anesthetic for use on normal intact skin. Published studies in humans have shown that LIPPOMIX's topical tetracaine provides measurably more effective local anesthesia in the clinical setting than EMLA®. Although an increase in the incidence of redness in the area of the application was reported with the topical tetracaine compared to EMLA® in this study, the finding was not considered serious and was attributed to the vasodilator effects of tetracaine. Based upon the overall safety and efficacy profile of the Optisome- encapsulated tetracaine versus EMLA®, sales of LIPPOMIX's product are anticipated to eventually approach or possibly exceed those seen with EMLA®.

Initial Clinical Target

The major attribute of the Optisome encapsulated tetracaine is that it can be applied to intact skin and provide long-lasting anesthesia surrounding the area of application. LIPPOMIX believes based upon the regulatory requirements which were set forth for the EMLA® cream that a broad label claim as a topical anesthetic for intact skin can be obtained based upon properly designed studies involving intravenous catheritization such as the study previously mentioned (Appendix 2). LIPPOMIX will also explore whether its topical tetracaine formulation may have potential in certain anesthesiology settings as an injectable anesthetic, which can provide long-lasting local anesthesia.ustained release characteristics. These include Amway's Hour Guard and Minnetonka Brands and BioPharm Labs, glycerin-based lotion. Many products also make cosmetic claims and in fact, AVON has a product called skin-so-soft which it tried to promote as having sunscreening, conditioning, and repellent properties (it did not contain an effective repelling agent so EPA disallowed label claims).

Regulatory and Clinical Strategy

Limited preclinical studies are anticipated prior to the initiation of clinical trials. Clinical studies involving the application of the product prior to venipuncture will be performed in both adults and children. Appropriate endpoints as well as pharmacokinetics will be performed as part of the trials. Assuming that supportive clinical data becomes available, the second phase involves conducting the appropriate post-marketing studies and to aggressively pursue OTC status for the product.

Commercialization of OptisomeTM Encapsulated Tetracaine (U.S.)

It is known that over 5 million injections are given to children alone in the U.S. each year. For the purpose of this market assessment, the incidence of other surgical procedures or disease conditions in which long-lasting anesthesia would be beneficial has been conservatively totaled at 50 million cases annually.

Annual Incidence*	100,000,000
% Eligible	100,000,000
Penetration	20%
Market Share	10%

*Assumes more than one topical anesthetic on market

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