Field of invention

This invention relates to a stable pharmaceutical compositions providing active ingredients such as ibuprofen and lidocaine. This invention also relates to the symptomatic relief of severe sore throats, topical treatment of backache, muscular pain, sprains, and neuralgia.

Background of the invention

Ibuprofen, chemical name is 2-(4-isobutylphenyl) propionic acid, is a well-known antiinflammatory drug having a molecular weight of 206.28. Ibuprofen is now marketed generically and is patented in the 60's.

Ibuprofen is a racemic mixture, it is only the racemic mixture which has in fact ever been marketed. The S(+) enantiomer is the active form of ibuprofen.

The present invention relates to topical compositions of ibuprofen and methods for making and using the compositions. Past formulations of ibuprofen have chiefly made use of the water- based form (salt form) of ibuprofen. Ibuprofen in its salt forms the basis of such drug products as Advil(R) (potassium salt form of ibuprofen). Use of ibuprofen in its free acid form has been limited to formulations intended for oral administration, e.g., Motrin(R) in tablet and oral suspension.

Lidocaine, chemical name is 2-(diethylamino)- W-(2,6-dimethylphenyl)acetamide, is a well known local anesthetic drug belongs to class-1b antiarrhytmic drugs having a molecular weight of 234.34. Lidocaine, the first amino amide type local anesthetic, was first synthesized under the name 'xylocaine'. Lidocaine is commonly used topically to relieve itching, burning, and pain from skin inflammations, injected as a dental anesthetic, or as a local anesthetic for minor surgery.

Lidocaine is used for the purpose of local or topical anesthesia. The general usage form of lidocaine is an external preparation comprising lidocaine or a patch comprising lidocaine.

Examples of external preparations include ointment, cream, gel, spray, etc., which are used, for example, for topical anesthesia of the skin in the treatment of postherpetic neuralgia. Lidocaine viscous solution is a local anesthetic that is applied topically to treat painful mucous membranes or throat pain associated with oral diseases and for procedures involving the mouth or throat. Lidocaine provides pain relief by inhibiting the influx of sodium ions involved in the initiation and conduction of nerve impulses associated with the perception of pain.

EP2373346 A1 discloses a pharmaceutical topical composition comprising ibuprofen. EP1126830 relates to a pharmaceutically acceptable composition for external use which comprises a non-steroidal anti-inflammatory agent, an anesthetic agent and the skin penetration enhancer.

There are already existing drugs in the form of topical sprays as named Ibuspray marketed by Dermal Laboratories. Dequaspray marketed by Reckitt Benckiser Healthcare and Vemcaine marketed by Vem Pharmaceuticals comprises Iidocaine. But there is not any combined composition consisting of ibuprofen and Iidocaine used as sprays.

None of above mentioned research attempts clearly describe the use of ibuprofen and Iidocaine in the form of topical spray to treat backache, pains, sprains, muscular pain etc. There already exist drugs containing either ibuprofen or Iidocaine for topical administration. Such kinds of active pharmaceutical ingredients need to be combined to support the treatments of backache, muscular pains, sprains, sore throats.

Summary of the invention

In one aspect the present invention relates to topical administration comprising ibuprofen, Iidocaine and one or more pharmaceutically acceptable excipients, to a patient suffering muscular pain, strain, sore throats and mouth pains supported with anesthesia effect.

The invention provides a pharmaceutical composition in the form of topical spray consisting essentially of:

a) ibuprofen or pharmaceutical acceptable salts or enantiomer thereof,

b) Iidocaine or pharmaceutical acceptable salts thereof,

(c) additional excipients.

In one embodiment, active ingredients and excipients are mixed to form a sprayable topical formulation.

Detailed Description of the invention

The invention discloses novel pharmaceutical combinations and methods for the treatment or prevention of muscular pain, sprain with the help of anesthetics.

The present invention provides pain treatment with the help of anesthesia effect. Muscular pain and sprain need to be anaesthetized in some conditions for example; after sport injuries, backache pains, wound healing after a surgery.

In order to understand the invention and to see how it may be carried out in practice, several specific embodiments will now be described. In one embodiment, present invention relates to not only treating the pain but also anesthesizing the part of the body that feels pain.

In one embodiment, present invention has an advantage in the treatment of pain compared to composition that contains only one active ingredient.

In one embodiment, pharmaceutical composition may be formulated in the form suitable for topical administration such as ointment, gel, cream, lotion, spray, plaster, solution.

In one aspect, the components of the pharmaceutical composition according to the present invention are brought together into a spray for topical administration according to standard practice and procedures well known to one of ordinary skill in the art using conventional formulation and manufacturing techniques.

In one embodiment, present invention is a pharmaceutical composition containing ibuprofen and lidocaine; both active ingredients being present in the free state or in the form of a salt, solvate or enantiomer.

In one embodiment, pharmaceutical compositions of the present invention, the active ingredients are generally formulated in the spray form containing from 1 to 20 mg of ibuprofen and 1 to 20 mg of lidocaine per 100 ml_, preferably 5 mg of each active agents.

In one embodiment, pharmaceutical composition of the present invention comprises ibuprofen and lidocaine, in combination with at least one pharmaceutically acceptable excipient.

In one embodiment, pharmaceutical composition of this invention may comprise C1-C4 alcoholic solvents selected from methanol, ethanol, denatured alcohol, n-propanol, isopropanol and butanol.

In one embodiment, prefered solvent is either isopropanol and/or denatured alcohol. Surprisingly these solvents make composition higher stable than other solvents do.

In an embodiment, the process of preparing the stable pharmaceutical composition comprises steps of preparing a first part of composition comprising ibuprofen or salt, solvate, enantiomer thereof, and lidocaine or salt, solvate, enantiomer thereof and separately preparing second part comprising at least one C1-C4 alcohol, at least one polymer and optionally at least one preservative and/or fragrance followed by mixing two parts and making up volume with purified water.

Polymers can be selected from the group, but are not limited to, polypropylene glycol, polyethylene glycols (PEG) as macrogol or cetomacrogol, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose. A mixture of polymers may also be used. A preferred polymer is polyethylene glycol. In one embodiment, the antiinflammatory and anesthetic pharmaceutical preparation of this invention may comprise water soluble polymers such as carboxymethyl cellulose, polivinyl alcohol, polypropylene glycol, polyethylene glycols, hydroxypropyl cellulose etc. Such a polymer may be applied at 0.1 to 15% by weight based upon a total weight at the preparation for external use.

Preservatives can be selected from the group, propyl gallate, propyl paraben, sodium nitrate, benzoic acid, sodium benzoate, hydroxybenzoate, propionic acid, sodium propionate, sulfur dioxide, sulfites, sorbic acid and sodium sorbate. Propyl paraben is prefered.

Fragrances can be selected from groups, but are not limited to, esters, amines, terpenes, aromatics, such as menthol, acetaldehyde, fructone, acetoin, furaneol, isoveraldehyde, vanilin, annisol, cadaverine, terpineol and other materials known to one of ordinary skill in the art.

The present invention consists of ibuprofen and lidocaine resulting in a topical spray. Examples for pharmaceutical compositions combining Ibuprofen and Lidocaine are shown below.

Example 1

Content mg/100mL

Ibuprofen 5

Lidocaine Hydrochloride 5

Cetomacrogol 1000 18.95

Ethanol 96% 63.16

Fragrance 0.40

Purified water qs

Total 100

Ethanol and cetomacrogol are mixed to form the first part of the solution. Separately ibuprofen and lidocaine hydrochloride are mixed in a different container to form the second part. Afterwards, the first part is added into the second part. The mixture is made up volume with purified water by addition of fragrances. The formulation seemed viscous.

Example 2

Content mg/100mL

Ibuprofen 5

Lidocaine Hydrochloride 5.78

Macrogol 400 (PEG 400) 18.95

Ethanol 96% 40.0

Purified water qs

Total 100 The same procedure is followed with example 1. First part is formed with ethanol and macrogol and the second part with ibuprofen and lidocaine hydrochloride. And the mixture is made up volume with purified water. The used ethanol amount is increased and polyethylene glycol amount is decreased. By this way, the formulation was found to be satisfactory but slightly oily.

Example 3

Content mg/100mL

Ibuprofen 5

Lidocaine Hydrochloride 5.78

Macrogol 400 (PEG 400) 18.95

Ethanol 96% 20

Purified water qs

Total 100

The same procedure is followed with example 2. First part is formed with ethanol and macrogol and the second part with ibuprofen and lidocaine hydrochloride. And the mixture is made up volume with purified water. API is not dissolved and more ethanol required so ethanol is added to check API solubility.When the proportion of the monohydric saturated aliphatic alcohol is too low, solubility of NSAIDs is lowered whereby turbidity appears and stability is lowered.

Example 4

Content mg/100mL

Ibuprofen 5

Lidocaine base 5

Macrogol 400 (PEG 400) 8

Ethanol 96% 52

Purified water qs

Total 100

By following the same procedure with example 3, first part is formed with ethanol and macrogol and the second part with ibuprofen and lidocaine. And the mixture is made up volume with purified water. The formulation was found to be satisfactory but impurity result was not good. When amount of ethanol was increased, the total impurity increased at the same time. So there is a need of alternative solvent from monohydric saturated aliphatic alcohols. Example 5

Content mg/100ml_

Ibuprofen 5

Lidocaine Hydrochloride 5.78

Macrogol 400 (PEG 400) 8

Ethanol 96% 52

Purified water qs

Fragrances qs

Total 100

By following the same procedure with example 4, first part is formed with ethanol and macrogol and the second part with ibuprofen and lidocaine hydrochloride. Fragrances are added and the mixture is made up 100 mL volume with purified water. The formulation was found to be satisfactory. In this case, lidocaine hydrochloride is used instead of lidocaine base. But much more impurity was observed in this batch compared to example 4. The impurity results are shown at table .

Example 6

Content mg/100mL

Ibuprofen 5

Lidocaine Base 5

Macrogol 400 (PEG 400) 8

Ethanol 96% 25

Purified water qs

Fragrances

Total 100

By following the same procedure with example 4, first part is formed with ethanol and macrogol and the second part with ibuprofen and lidocaine base, and the mixture is made up 100 mL volume with purified water. The formulation was found to be satisfactory, and less impurity was observed in this batch compared to example 4 and 5 because of using less amount of ethanol.The impurity results are shown at table 1. Example 7

Content mg/100ml_

Ibuprofen 5

Lidocaine Base 5

Macrogol 400 (PEG 400) 8

Isopropanol 20

Purified water qs

Fragrances

Total 100

By following the same procedure with example 6, first part is formed with ethanol and macrogol and the second part with ibuprofen and lidocaine base, and the mixture is made up 100 mL volume with purified water. The formulation was found to be good. By using isopropanol instead of ethanol has changed the stability results in a good way. Less impurity was observed in this batch compared to other examples shown at table 1.

Example 8

Content mg/100mL

Ibuprofen 5

Lidocaine Base 5

Macrogol 400 (PEG 400) 8

Isopropanol 20

Purified water qs

Propyl Paraben 0.10

Total 100

By following the same procedure with example 7, first part is formed with ethanol, propyl paraben and macrogol and the second part with ibuprofen and lidocaine base, and the mixture is made up 100 mL volume with purified water. The best formulation is obtained by using isopropanol and propyl paraben instead of ethanol and by using lidocaine base instead of lidocaine HCI. The comparative results are shown at Table 1.

There is an impurity challenge with the samples that were prepared by using ethanol. There is a problem related to ethanol and ibuprofen mixture as shown in Table . The stability data were corrected by using the original plain products of both ibuprofen (ibuspray = contains 5% ibuprofen) and lidocaine (vemcaine pump spray = contains 10% lidocaine). After checking the stability data, the superior impurity results were seen in the samples of the present invention. Table 1