MXPA97009941A - New pharmaceutical composition with anesthesia effect - Google Patents

Abstract

The invention is directed to a new pharmaceutical composition containing one or more local anesthetics in the form of an oil, one or more surfactants, water and optionally a taste masking agent. The new composition is advantageously used as a local anesthetic for pain relief inside the cavity or

Description

NEW PHARMACEUTICAL COMPOSITION WITH ANESTHETIC EFFECT FIELD OF THE INVENTION The present invention is directed to a new pharmaceutical composition and its use in therapy, particularly as an anesthetic for use in mucous membranes and particularly within the oral cavity.

Background and previous art It is estimated that approximately 10-13% of the population suffers from periodontal diseases with pathological periodontal cavities. To eliminate or control the disease and further stop the destruction of the periodontal tissue, the periodontal vesicles need repeated subgingival mechanisms of fragmentation / washing. The number of periodontal cavities in a patient could vary as well as the measurement of the depth of the cavity. Approximately 40% of all developed periodontal detachment procedures involve some type of anesthesia. The accumulation of bacterial plaque in the teeth and in the gingival sulcus causes an inflammatory response in the marginal gingiva that could extend in an apical direction and result in the loss of dental support with the formation of periodontal cavities. The objective of REF: 26259 mechanical fragmentation of the periodontal cavities is to control and also stop the destruction of the dental support by means of the removal of the plaque and the calculations of the interior of the cavities. The majority of the detachment procedures are performed by hygienists. The main use of anesthesia techniques used in conjunction with periodontal detachment is to block a nerve or infiltration. Infiltration anesthesia is carried out alone or in combination with topical anesthesia, mainly gelatin, fat or atomized. However, the problem with the topical products that exist lack efficiency due to the inadequate depth of penetration, also to short duration and difficulties in administration due to spreading, flavor, etc. EP 244 118 discloses a system that delivers controlled release drug to place it in the periodontal cavity, having a plurality of discrete microparticles consisting of a speed controlled polymer matrix having a drug dispersed therein, said microparticles being in the range of 10-500 μm. However, the drug delivery systems set forth in these prior art patents are set forth for the administration of a drug for a longer period of time. Thus, the drug release systems of EP 244 118 and EP 241 178 are not suitable for use in pain control in conjunction with minor surgical procedures, where a rapid onset of action and relatively short duration is required. Thus, the fundamental problem of the present invention is to provide a pharmaceutical composition that would provide effective pain relief in conjunction with periodontal detachment and root plaster followed by local administration. In other words, the aim of the invention is to provide a local anesthetic that can be applied more easily in the oral cavity, and more precisely within the periodontal cavities. A further objective of the invention is to provide a pharmaceutical composition having a short start time and a duration suitable for the proposed procedure, without inconvenient anesthesia.

BRIEF DESCRIPTION OF THE INVENTION The problem identified above has now been solved by providing a new pharmaceutical composition which is preferably in the form of an emulsion, more preferably in the form of a microeptulsion, containing the following ingredients: (i) One or more local anesthetics in the form of oil in the final composition; (ii) one or more surfactants, present together in an effective amount to produce a homogeneous formulation; Y (iii) water up to 100% weight; based on the total weight of the composition.

The local anesthetic in the final composition is one or more local anesthetics in the form of oil as such, or a eutectic mixture formed by two or more local anesthetics. The amount of the local anesthetic in the oily phase depends on the pH value of the formulation. In a particularly preferred embodiment of the invention, the local anesthetic is a eutectic mixture of lidocaine base and prilocaine base. In a further embodiment of the invention a eutectic mixture could also be formed by two or more substances, where at least one of these substances is a local anesthetic. The amount of the local anesthetic or mixture of local anesthetics is preferably in the range of 0.5-20% by weight, more preferably in the range of 2-7% by weight, based on the total weight of the composition. The local anesthetic (s) in the final composition is present in a non-solid form. By the word "surfactant" is meant any agent that acts as a solubilizer and / or as an emulsifier and / or as a thickening agent with thermoreversible gelling properties. The word "surfactant" is also applied to include thickeners without thermoreversible properties. If only one surfactant is used in the composition, it should be selected carefully and in suitable amounts in such a way that it acts 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 must have thermoreversible gelling properties. The total amount of surfactant (s) must be present in an effective amount to produce a homogeneous formulation. The surfactants are preferably selected from non-ionic surfactants, more preferably from any non-ionic poloxamer known in the art. Poloxamers are blocks of synthetic copolymers of hydrophilic chains of ethylene oxide and hydrophobic chains of propylene oxide, having the general formula HO- [C2H40] a- [C3HsO] b- [C2H40] aH, a and b represent the number of 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 anesthetic or mixture of local anesthetics, it is possible to obtain a composition having suitable thermoreversible gelling properties, e.g. ex. the system has less viscosity at room temperature, and in the application within a periodontal cavity the viscosity of the composition increases. 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 staying in the periodontal cavities for the time necessary to induce local anesthesia. The change in viscosity is reversible with temperature. In a particularly preferred embodiment of the invention the surfactant is one or more of Lutrol F68R, which also has the name poloxamer 188 and where a = 80 and b = 27, and Lutrol F127R, which also has the name poloxamer 407 and wherein a = 101 and b = 56, the definition that is in agreement with the USP (1995) NF18, p. 2279. Lutrol F68R and Lutrol F127R are commercially available from BASF. In a preferred further embodiment of the invention the surfactant Arlatone 289R, which also has the name of hydrogenated polyoxyethylene castor oil, as well as Adinol CT95R which is taurate N-methyl N-cocoyl sodium is used. 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 of the composition is: (A) pH = [pKa (local anesthetic) - 1.0] if the composition contains a local anesthetic; or (B) pH = [pKa (local anesthetic with the smallest pKa value) - 1.0] if the composition contains two or more local anesthetics.

Preferably the pH is greater than 7.5. Since local anesthetics by nature have an unpleasant bitter taste, one or more flavor maskers could optionally be added to the pharmaceutical composition. The choice of taste of the masking agents will be appreciated by one skilled in the art, but any flavor of fruit could be mentioned as an example.

By topical application within the periodontal cavity, local anesthesia is achieved in a very localized area, without causing the common extension of soft tissues such as the tongue, cheek and lips, to achieve anesthesia that is often the case with infiltration anesthesia . Preferably the composition is applied in a periodontal cavity by means of a blunt needle, thus facilitating the administration of the anesthetic and giving an increase in the comfort of the patient. The pharmaceutical composition of the present invention has a rapid onset of action that is from seconds to up to about 5-15 minutes. The start time is more preferably seconds and up to about 5 minutes. For the definition of emulsion, it refers to Pharmaceutics. The Science of Dosase Form Design. 1988. p. 1Q9-UQ, by ME Aylton, The pharmaceutical composition according to the present invention is preferably a microemulsion. By microemulsion is meant a formulation consisting of water, oil and amphiphile (s) which constitutes an optically simple and thermodynamically stable isotropic liquid solution (I. Danielsson and B Lindman, Colloids Surf, 3: 391 (1981)). This provides an adequate amount of the local anesthetic in the oily phase, which in turn confers a rapid onset of action. It is not necessary to separate the oil to add it to the composition, since the oil is already present in the active component (s) as such. An additional advantage is that a thermodynamically stable composition is obtained in a temperature range of 5-40 ° C. The pharmaceutical composition according to the present invention could also be advantageously used as a local anesthetic in other surfaces and / or cavities other than the oral cavity. The composition of this form could also be used vaginally, genitally and rectally. The local anesthetic (s) used to prepare a pharmaceutical composition according to the present invention could be selected from any local anesthetic. Preferably the local anesthetic as the initial material is in a non-ionized form. In the final composition a fraction of the local anesthetic or mixture of local anesthetics is present as an oil. The amount of this fraction, local anesthetics in the form of oil, depends on the pH of the composition. The best way to develop the invention known up to now is to use the composition according to Example 1.

PREPARATION METHODS The pharmaceutical composition according to the present invention could be prepared by means of the following steps: (i) the local anesthetic (s) and the surfactant with the lowest molecular weight if more than one surfactant is used, are fused together; (ii) a part of the water is slowly added to the melt (i) during the 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 from step (ii) and part of the surfactant solution from 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 maintained at 5 ° C until a homogeneous composition is obtained.

DETAILED DESCRIPTION OF THE INVENTION The invention will now be described in greater detail by the following examples, which are not intended as limiting the invention.

Example 1 r% by weight] Lidocaine 2.50 Prilocaine 2.50 Lutrol F68R 5.50 Lutrol F127R 15.50 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Example 2 r% by weight! Lidocaine 2.50 Prilocaine 2.50 Lutrol F68R 5.50 Lutrol F127R 16.25 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Example 3 r% in pésol Lidocaine 2.25 Prilocaine 2.25 Lutrol F68R 3.5 Lutrol F127R 14.0 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Example 4 r% by weight! Lidocaine 2 25 Prilocaine 2. 25 Arlatone 289R 1. 90 Adinol CT95R 0. 07 Lutrol F127 14:. 00 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Example 5 r% by weight! Lidocaine 2.25 Prilocaine 2.25 Arlatone 289R 1.90 Adinol CT95R 0.16 Lutrol F127 14.00 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Example 6 f% in pésol Lidocaine 2.25 Prilocaine 2.25 Arlatone 289 1.90 Adinol CT95R 0.28 Lutrol F127 14.00 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Examples 7 and 8 In Examples 7 and 8, a local anesthetic of formula (I) was used as the active ingredient.

This compound is set forth in International Patent Application SE96 / 01361. The following pharmaceutical compositions were prepared.

Example 7 r% by weight] Compound (I) 2.5 Lutrol F127R 17.0 Lutrol F68R 5.5 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Example 8 r% in pésol Compound (I) 2.5 Lutrol F127R 20.0 Lutrol F68R 5.5 purified water up to a total weight of 100%.

The composition was prepared following the procedure described above, and the pH value was adjusted by adding 2M hydrochloric acid.

Biological studies A pharmaceutical composition was applied according to the Example 1 to a human periodontal cavity with a blunt needle. After a start time of 30-35 seconds, a satisfactory anesthetic effect had been achieved so that the periodontal detachment could be performed. The detachment was started, and the time occupied for the detachment in the tooth was recorded. At the end of the detachment, the intensity of pain was measured by means of a visual analogue scale (VAS). The duration of the anesthetic effect was 10-20 minutes.

Claims (18)

1. A pharmaceutical composition, characterized in that (i) one or more local anesthetics in the form of an oil in the final composition; (ii) one or more surfactants, present together in an effective amount to produce a homogeneous formulation; Y (iii) water up to 100% weight; based on the total weight of the composition.

2. A pharmaceutical composition according to claim 1, characterized in that it also contains one or more taste masking agents.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that the amount of the local anesthetic or mixture of local anesthetics is present in an amount of 0.5-20% by weight based on the total weight of the composition.

4. A pharmaceutical composition according to claim 3, characterized in that the amount of the local anesthetic or mixture of local anesthetics is present in an amount of 2-7% by weight based on the total weight of the composition.

5. A pharmaceutical composition according to any of the preceding claims, characterized in that the active ingredient is a eutectic mixture of local anesthetics.

6. A pharmaceutical composition according to claim 5, characterized in that the active ingredient is a eutectic mixture of lidocaine and prilocaine.

7. A pharmaceutical composition according to claim 1, characterized in that the active ingredient is (

8. A pharmaceutical composition according to any of the preceding claims, characterized in that it contains more than one surfactant of which at least one is a surfactant having thermoreversible gelling properties.

9. A pharmaceutical composition according to any of the preceding claims, characterized in that the total amount of the surfactant (s) is present in an amount of up to 50% by weight based on the total weight of the composition.

10. A pharmaceutical composition according to any of the preceding claims, characterized in that the surfactant is a non-ionic surfactant.

11. A pharmaceutical composition according to claim 10, characterized in that the surfactant is a poloxamer.

12. A pharmaceutical composition according to any of the preceding claims, characterized in that they contain the two surfactants Lutrol F68R and Lutrol F127R.

13. A pharmaceutical composition according to any of the preceding claims, characterized in that it is used in therapy.

14. A pharmaceutical composition according to claim 13, characterized in that it is used as a local anesthetic administered on the mucosa of the oral cavity.

15. A pharmaceutical composition according to claim 14, characterized in that the therapeutic indication is pain relief during periodontal detachment.

16. A pharmaceutical composition according to claim 1, characterized in that the preparation of a medicament for relieving pain during periodontal detachment is made.

17. A method for the treatment of pain associated with periodontal detachment, characterized in that a pharmaceutical composition according to claim 1 is applied to a patient in need of pain relief during periodontal detachment.

18. A process for the preparation of a pharmaceutical composition according to claim 1, characterized in that (i) the local anesthetic (s) and the surfactant with the lowest molecular weight if more than one surfactant is used, are fused together; (ii) a part of the water is slowly added to the melt (i) during the 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 from step (ii) and part of the surfactant solution from 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.