United States Patent:  6,031,007

Assignee:  Astra AB (SE)

Filed:  August 6, 1997

The invention is directed to a novel pharmaceutical composition comprising one or more local anaesthetics in oil form, one or more surfactants, water and optionally a taste masking agent. The novel composition is advantageously used as a local anaesthetic for pain relief within the oral cavity.

OUTLINE OF THE INVENTION

The invention describes ... "a new pharmaceutical composition which preferably is in form of an emulsion, more preferably in form of a microemulsion, comprising the following ingredients:

(i) One or more local anaesthetics in oil form in the final composition;

(ii) one or more surfactants, together present in an amount effective to produce a homogenous formulation; and

(iii) water up to 100% by weight, based on the total weight of the composition.

The local anaesthetic in the final composition is one or more local anaesthetics in oil form as such, or a eutectic mixture formed by two or more local anaesthetics. The amount of the local anaesthetic in the oil phase depends on the pH-value of the formulation.

In a particularly preferred embodiment of the invention the local anaesthetic is a eutectic mixture of lidocaine base and prilocaine base.

In a further embodiment of the invention a eutectic mixture may also be formed by two or more substances, where at least one of these substances is a local anaesthetic.

The amount of the local anaesthetic or mixture of local anaesthetics is preferably in the range 0.5-20% by weight, more preferably in the range 2-7% by weight, based on the total weight of the composition.

The local anaesthetic(s) in the final composition are present in a non-solid form.

By the wording "surfactant" we mean any agent that acts as a solubilizer and/or as an emulsifier and/or as a thickening agent with thermoreversible gelling properties. The wording surfactant is also intended to include thickening agents without thermoreversible properties. If only one surfactant is used in the composition, it must be selected with care and in suitable amounts so that it acts both as a solubilizer and/or as an emulsifier, as well as a thickening agent with thermoreversible gelling properties. If more than one surfactant is present in the composition, at least one of the surfactants should have thermoreversible gelling properties. The total amount of the surfactant(s) should be present in an amount effective to produce a homogenous formulation.

The surfactants are preferably selected from non-ionic surfactants, more preferably from any non-ionic poloxamer known in the art.

Poloxamers are synthetic block copolymers of hydrophilic ethylene oxide chains and hydrophobic propylene oxide chains, having the general formula HO--[C₂ H₄ O]_a --[C₃ H₆ O]_b --[C₂ H₄ O]_a --H, a and b representing the number of the hydrophilic and hydrophobic chains respectively.

By choosing the surfactant(s) having hydrophobic and hydrophilic domains in appropriate amounts, in combination with an appropriate amount of the local anaesthetic or mixture of local anaesthetics, it is possible to achieve a composition having suitable thermoreversible gelling properties, i.e. the system remains less viscous at room temperature, and upon application into a periodontal pocket the viscosity of the composition is increased. In other words, the pharmaceutical composition according to the present invention is less viscous at room temperature. Above this temperature the composition is more viscous, providing the advantage of remaining in the periodontal pockets for the time necessary to induce local anaesthesia. The change in viscosity is reversible with temperature.

In a particularly preferred embodiment of the invention the surfactant is one or more of Lutrol F68.RTM., which also has the name poloxamer 188 and wherein a=80 and b=27, and Lutrol F127.RTM., which also has the name poloxamer 407 and wherein a=101 and b=56, the definitions being in accordance with USP (1995) NF18, p. 2279. Lutrol F68.RTM. and Lutrol F127.RTM. are commercially available from BASF.

In a further preferred embodiment of the invention the surfactant Arlatone 289.RTM. is used, which also has the name polyoxyethylene hydrogenated castor oil, as well as Adinol CT95.RTM. which is sodium N-methyl N-cocoyl taurate.

The total amount of surfactant(s) is preferably present in an amount of up to 50% by weight, based on the total weight of the composition.

The pH-value of the pharmaceutical composition is adjusted with suitable acid or base in such a way that the final pH-value for the composition is:

(A) pH.gtoreq.[pK_a (local anaesthetic)--1.0] if the composition comprises one local anaesthetic; or

(B) pH .gtoreq.[pK_a (local anaesthetic with the lowest pK_a value)--1.0] if the composition comprises two or more local anaesthetics.

Preferably the pH is over 7.5.

Since local anaesthetics by nature have an unpleasant bitter taste, one or more taste masking agents may optionally be added to the pharmaceutical composition. The choice of taste masking agents will be appreciated by a person skilled in the art, but as an example any fruit flavours may be mentioned.

By topical application within the periodontal pocket, local anaesthesia is achieved in a very localised area, without causing the often extensive soft tissues such as the tongue, cheek and lips, to get anaesthetized which is often the case with infiltration anaesthesia. Preferably the composition is applied into a periodontal pocket by means of a blunt needle, thereby facilitating the administration of the anaesthetic and giving an increased patient comfort.

The pharmaceutical composition of the present invention has a fast onset of action being from seconds and up to approximately 5-15 minutes. The onset time is most preferably from seconds and up to approximately 5 minutes.

For the definition of emulsions, we refer to Pharmaceutics, The Science of Dosage Form Design, 1988, p. 109-110, by ME Aulton.

The pharmaceutical composition according to the present invention is preferably a microemulsion. By microemulsion we mean a formulation that consists of water, oil and amphiphile(s) which constitute a single optically isotropic and thermodynamically stable liquid solution (I. Danielsson and B Lindman, Colloids Surf. 3:391, (1981)). This provides a suitable amount of the local anaesthetic in the oil phase, which in turn confers a fast onset of action. No separate oil needs to be added to the composition, since the oil is already present by the active component(s) as such. A further advantage is that a thermodynamically stable composition is achieved in a temperature range of 5-40^oC.

The pharmaceutical composition according to the present invention may advantageously also be used as a local anaesthetic on other surfaces and/or cavities than in the oral cavity. The composition may thus also be used vaginally, genitally and rectally.

The local anaesthetic(s) used for preparing a pharmaceutical composition according to the present invention may be selected from any local anaesthetic. Preferably the local anaesthetic as the starting material is in a non-ionized form.

In the final composition a fraction of the local anaesthetic or mixture of local anaesthetics are present in oil form. The size of this fraction, local anaesthetics in oil form, depends on the pH of the composition.

The best mode of performing the invention known at present, is to use the composition according to Example 1.

Methods of Preparation

The pharmaceutical composition according to the present invention may be prepared by the following steps:

(i) the local anaesthetic(s) and the surfactant with the lowest molecular weight if more than one surfactant is used, are melted together;

(ii) a part of the water is slowly added to the melt (i) during homogenization, forming an emulsion concentrate;

(iii) if more than one surfactant is used, the surfactant with the higher molecular weight is dispersed in water;

(iv) the emulsion concentrate of step (ii) and part of the surfactant solution of step (iii) are thoroughly mixed;

(v) the pH-value is adjusted by the addition of a suitable acid or base;

(vi) the weight is adjusted with water to the final weight of the composition.

The composition is preferably kept at 5^oC. until a homogenous composition is obtained."

Claim 1 of 17 Claims

1. The pharmaceutical composition comprising:

(i) one or more local anaesthetics in oil form;

(ii) one or more surfactants in an amount effective to produce a homogenous formulation wherein, at least one surfactant has thermoreversible gelling properties; and

(iii) water;

wherein said composition is in the form of an emulsion or microemulsion and has thermoreversible gelling properties such that said composition is less viscous at room temperature than after introduction onto a mucous membrane of a patient.

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