RU2804418C2 - Emulsion composition for topical use containing non-steroid anti-inflammatory agent - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to a composition for the treatment of pain. Emulsion composition for the treatment of pain, selected from the group including pain in the joints, bones, ligaments, tendons and muscles contains the following: (i) from 7 to 15 wt.% of a non-steroidal anti-inflammatory drug; (ii) from 15 to 50 wt.% of isopropyl myristate; (iii) from 25 to 50.2 wt.% of water; (iv) one or more emulsifiers; (v) one or more pH adjusters; and (vi) one or more solubilizers, wherein the said emulsion composition contains 5 or less wt.% of C₁-C₄ alcohols, one or more pH adjusters include diethylamine, one or more solubilizers include propylene glycol, the said non-steroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, and the said emulsion composition has a pH in the range of 5 to 7. A method of treating pain in joints, bones, ligaments, tendons and muscles in a subject is characterized by the following: the composition according to claim 1 is applied dermally at a dosage of 2.67 g, which corresponds to 200 mg of ibuprofen, once to the said subject.

EFFECT: above composition is effective for the treatment of pain selected from the group including pain in the joints, bones, ligaments, tendons and muscles, is characterized by increased bioavailability, stability, while the composition has a lower degree of conversion of ibuprofen to ibuprofen-propylene glycol ester.

7 cl, 4 tbl, 2 ex

Description

PREREQUISITES FOR CREATION OF THE INVENTION

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are commonly used to relieve pain, reduce fever, and reduce inflammation. Although it is often administered orally, a number of topical products containing NSAIDs are also commercially available, such as Voltaren™ gel, which contains diclofenac, and Ibuleve™ cream and Dolgit™ gel, both of which contain ibuprofen. These products are used for topical treatment of joint, bone and/or muscle pain.

Other compositions containing NSAIDs are described in the patent literature, for example: US Patent No. 9,161,915 issued to Strategic Sciences and Technologies LLC, which describes a topical composition with ibuprofen and/or an ibuprofen salt and a nitric oxide donor; US Patent No. 9,205,041 to Aponia Laboratories, which discloses transdermal compositions containing ibuprofen or salts thereof, and a gelling agent with isopropyl alcohol, isopropyl myristate and propylene glycol; and US Patent Application No. 20050032900 to Krauser, which discloses an oil-in-water emulsion containing ibuprofen.

The present invention relates to a new emulsion composition containing NSAIDs, which contains a large amount of isopropyl myristate and which provides local administration of a high percentage of the NSAID contained in the composition.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides an emulsion composition comprising (i) at least 3% by weight of a non-steroidal anti-inflammatory drug; (ii) at least 15% by weight isopropyl myristate; (iii) at least 25% by weight water; and (iv) one or more emulsifiers; wherein the composition is substantially free of C1-C4 alcohols.

In another aspect, the present invention provides a composition comprising at least 3% by weight of a non-steroidal anti-inflammatory drug, wherein: (i) less than 10% of the non-steroidal anti-inflammatory drug is converted to ester after a 30-day accelerated stability test; and (ii) when an amount of the composition containing 200 mg of a non-steroidal anti-inflammatory drug is topically applied to a miniature pig, the composition has an area under the curve of at least 5000 ng*h/ml and a maximum concentration of at least 200 ng/ml.

In another aspect, the present invention provides a method of treating pain, inflammation or swelling in a subject by topical application of such compositions to the subject. In one embodiment, such pain is selected from the group consisting of joint, bone, ligament, tendon and muscle pain. In one embodiment, such pain is selected from osteoarthritis pain in joints, such as the knee and arm.

Other features and advantages of the present invention will be apparent from the detailed description of the invention and the claims.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that by using the description provided herein, one skilled in the art will be able to use the present invention to its fullest extent. The following specific embodiments are to be considered as examples only and are not intended to limit the remainder of the present description in any way.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention relates. In addition, all publications, patent applications, patents and other materials referenced herein are incorporated herein by reference. All percentages herein are expressed by weight (i.e., % w/w) unless otherwise noted.

Non-steroidal anti-inflammatory drug

As described above, the emulsion composition includes a non-steroidal anti-inflammatory drug (NSAID). NSAIDs are often classified based on their chemical structure or mechanism of action. Examples of NSAIDs include: salicylates such as aspirin, diflunisal, salicylic acid and salsalate; propionic acid derivatives such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin and loxoprofen; acetic acid derivatives such as diclofenac, indomethacin, tolmetin, sulindac, etodolac, ketorolac and aceclofenac; phenolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone and droxicam; their stereoisomers; and their salts. In one embodiment, the NSAID is selected from the group consisting of ibuprofen, naproxen, ketoprofen, diclofenac, stereoisomers thereof, and salts thereof.

In one embodiment, the emulsion composition includes at least 1% by weight of one or more NSAIDs, such as at least 3%, such as at least 5%, such as at least 7%, and for example at least 10% by weight. In one embodiment, the emulsion composition includes up to 15% by weight of one or more NSAIDs, for example up to 10% by weight. In one embodiment, the emulsion composition includes at least 3%, for example at least 5%, and for example at least 7% by weight of ibuprofen, its stereoisomers and salts thereof.

Emulsion composition

Emulsion compositions useful in the present invention include those suitable for topical application to the skin. Examples of emulsion compositions include oil-in-water and water-in-oil emulsions.

As described above, in one embodiment, the emulsion composition includes isopropyl myristate, water and one or more emulsifiers. In one embodiment, the emulsion composition includes at least 15% by weight isopropyl myristate, such as at least 20% by weight isopropyl myristate. In one embodiment, the emulsion composition includes from about 15% to about 50% by weight isopropyl myristate. In one embodiment, the emulsion composition includes at least 25% by weight water, such as at least 40% by weight water. In one embodiment, the emulsion composition includes from about 15% to about 80% by weight water. In one embodiment, the emulsion composition includes from about 0.5% to about 5% by weight of one or more emulsifiers.

Examples of emulsifiers include: ethylene glycol stearates, such as ethylene glycol palmitostearate and polyethylene glycol stearates (for example, PEG-30 dipolyhydroxystearate, PEG-6 stearate, PEG-32 stearate and PEG-100 stearate); glyceryl stearate; sorbitan stearate; diethylene glycol monoethyl ether; oleoyl polyoxyglycerides such as linoleoylpolyoxyl-6-glyceride; cetearyl glucoside; stearethes such as steareth-2, steareth-20, steareth-21, steareth-25 and isosteareth-20; cetets such as cetet-2, cetet-10 and cetet-20; cetearethes such as ceteareth-20 and ceteareth-100; cetets such as cetet-1 and cetet-45; polysorbates such as polysorbate-20, polysorbate-60 and polysorbate-80; lecithin, sorbitans such as sorbitan oleate, sorbitan monostearates, sorbitan stearate and sorbitan isostearate; olets such as olet-2, olet-10 and olet-20; and laureths such as laureth-4.

In one embodiment, the emulsion composition further includes one or more thickeners. Examples of thickeners include acrylic acid polymer such as Carbomer 980 and acrylic/acrylamide polymers; gums such as xanthan gum, gellan gum and guar gum; glyceryl behenate; celluloses such as carboxymethylcelluloses, hydroxypropylmethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses and methylcelluloses; poloxamers; collagens; gelatins; agar; carrageenans; pectin; polyethylenes; and polyvinyl alcohols.

The emulsion composition may further include one or more of: chelating agents such as disodium EDTA; pH regulators such as triethanolamine, diethylamine, octylamine and diisopropanolamine; preservatives such as sodium benzoate; solubilizers for NSAIDs such as propylene glycol; and softeners such as silicone fluid and cetyl alcohol.

In one embodiment, the emulsion composition has a pH range of 4-8, such as 5-7. The methodology for determining the pH of the emulsion composition can be tested as described below in Example 2.

Applicants have discovered that some NSAIDs, such as ibuprofen, can form esters with certain alcohols. In one embodiment, the emulsion composition is substantially free of C1-C4 alcohols such as methanol, ethanol, propyl alcohol, and isopropyl alcohol. In one embodiment, the emulsion composition is substantially free of C1-C16 alcohols such as the above C1-C4 alcohols and fatty alcohols such as decanol, lauryl alcohol, myristyl alcohol and cetyl alcohol. In one embodiment, the emulsion composition is substantially free of alcohols capable of esterifying the nonsteroidal anti-inflammatory drug in the emulsion composition. By “substantially free” is meant a concentration of less than 5% by weight, such as less than 2%, such as less than 1%, such as less than 0.5%, such as 0% by weight (ie, none).

Stability

In one embodiment, less than 10% (e.g., less than 5%, e.g., less than 1%) of the nonsteroidal anti-inflammatory drug is converted to ester after 30 days of accelerated stability testing, e.g., after 91 days of accelerated stability testing, e.g., after 182 days of accelerated stability testing . The methodology for accelerated testing of the stability of the emulsion composition is presented below in example 2.

Bioavailability

In one embodiment, when topically applied to a miniature pig with an amount of a composition containing 200 mg of a non-steroidal anti-inflammatory drug, the emulsion composition had an area under the plasma concentration-time curve (AUC) of at least 5000, such as at least 7000, such as at least 9000 ng*hour/ml. In one embodiment, when topically applied to a miniature pig an amount of a composition containing 200 mg of a non-steroidal anti-inflammatory drug, the AUC is at least 5%, such as at least 7%, such as at least 9% of the AUC when 200 mg of a non-steroidal anti-inflammatory drug is administered orally. medicine for dwarf pig.

In one embodiment, when an amount of a composition containing 200 mg of a non-steroidal anti-inflammatory drug is topically applied to a miniature pig, the emulsion composition has a maximum plasma concentration (Cmax) of at least 200, such as at least 250, such as at least 300 ng/ml. In one embodiment, when topically applied to a miniature pig an amount of a composition containing 200 mg of a nonsteroidal anti-inflammatory drug, the Cmax is at least 1%, such as at least 1.5%, such as at least 2% of the AUC of an oral 200 mg dose. non-steroidal anti-inflammatory drug for miniature pigs. The testing procedure for AUC and Cmax for the emulsion composition is presented below in example 2.

Example 1. Preparation of an emulsion containing ibuprofen without propylene glycol

The emulsion composition was prepared using the following procedure and materials shown in Table 1.

1. Isopropyl myristate, glyceryl behenate, PEG-6 stearate and ethylene glycol palmitostearate and PEG-32 stearate, linoleoylpolyoxyl-6-glyceride and ibuprofen were combined in a 4 oz (118.3 ml) clear vial fitted with a screw cap. These materials were considered to be oil phase materials.

2. Sodium benzoate, disodium EDTA, and purified water were combined in a separate 4 oz (118.3 mL) clear container fitted with a screw cap. These materials were considered to be aqueous phase materials.

3. The vessels from steps 1 and 2 were placed in a hot water bath and heated to approximately 70°C.

4. The solid components were dissolved in the solution.

5. The aqueous phase materials were removed and mixed using a high shear mixer and mixed for approximately 3 minutes. Carbomer 980 was added and mixed for approximately 3 minutes.

6. While mixing, the oil phase materials were slowly poured into the water/carbomer mixture and stirred vigorously for approximately 3 minutes.

7. Add triethanolamine and stir for 3 minutes.

Table 1

Material % w/w Batch weight (100 g) Ibuprofen 7.5 7.5 Isopropyl myristate 21.4 21.4 Glyceryl behenate ^a 2.15 2.15 PEG-6 stearate and ethylene glycol palmitostearate
and PEG-32 stearate ^b 10.7 10.7 Linoleoylpolyoxyl-6 glyceride ^c 2.15 2.15 Sodium benzoate 0.2 0.2 Disodium salt EDTA 0.1 0.1 Carbomer ^980d 0.5 0.5 Triethanolamine 0.5 0.5 Purified water 54.8 54.8 TOTAL 100 100

a. Available commercially as Compritol® 888 from Gattefosse, Inc.

b. Available commercially as Tefose® 63 from Gattefosse, Inc.

c. Available commercially as Labrifil® M2125 CS from Gattefosse, Inc.

d. Available commercially under the Lubrizol® brand from Ashland, Inc.

The pH value of the emulsion composition was calculated to be 6.01, for which equal amounts of deionized water and the emulsion composition were first added and mixed before analysis.

Example 2: In vivo test on miniature pigs

The purpose of this study was to evaluate the pharmacokinetics of ibuprofen following single oral or dermal administration in miniature pigs. Topical samples (i.e., the three oil-in-water topical cream samples from Table 2 and the commercially available products Dolgit™ Cream (5% ibuprofen) and Ibuleve™ Cream (5% ibuprofen) were applied to animals dermal for 36 hours (animals were washed after the last data collection).The weight percentage of each material in samples 2a-2c is given in table 3a. To prepare these samples, a mixing procedure similar to that used in example 1 was used. For samples including propylene glycol, cetyl alcohol, polysorbate 80, Transcutol HP™ or Labrasol™, these substances were included in the oil phase materials. In the case of samples containing silicone fluid, it was mixed at high speed with the base emulsion at the end for approximately 3 minutes until completely mixed. containing diethylamine, it was added along with triethanolamine.

The pH values of the emulsion compositions were calculated to be 6.77 (sample 2a), 5.7 (sample 2b) and 6.65 (sample 2c), for which equal amounts of deionized water and the emulsion composition were first added and mixed before analysis.

The dorsal surfaces of the animals were prepared before dosing by trimming the hair close to the skin with a small animal clipper. Care was taken not to damage the skin when cutting. Samples were applied directly to the skin in a uniform layer to each targeted area by gentle rubbing with a disposable plastic applicator. The target area measuring 400 cm ² was covered with a thin uniform film of the appropriate sample. Samples 2a-2c were used at a dose of 2.67 g (ie 200 mg ibuprofen), and Ibuleve™ and Dolgit™ were used at a dose of 4 g (ie 200 mg ibuprofen). All animals had intact skin. The corners of the application sites were marked with permanent ink to reliably identify treated and untreated skin as needed. Residual test material was removed after the appropriate exposure time by gently wiping the area with gauze soaked in reverse osmosis purified water, followed by dry gauze.

table 2

Material Sample 2a
% wt./
wt. Sample 2b
% wt./
wt. Sample 2c
% wt./
wt. Ibuprofen 7.5 7.5 7.5 Propylene glycol 5 5 5 Isopropyl myristate 20 20 20 Glyceryl behenate 2 0 2 Polysorbate 80 0 4 4 PEG-6 stearate and ethylene glycol palmitostearate and PEG-32 stearate 10 8 8 Diethylene glycol monoethyl ether ^a 0 1.4 1.4 Cetyl alcohol 0 2 0 Caprylocaproylpolyoxyl-8-glycerides ^b 0 0 0 Linoleoylpolyoxyl-6 glyceride 2 0 0 Diethylamine 1 0 1 Purified water 50.2 48.8 47.8 Sodium benzoate 0.2 0.2 0.2 Disodium salt EDTA 0.1 0.1 0.1 Silicone liquid ^c 0 1 1 Carbomer 980 1 1 1 Triethanolamine 1 1 1

a. Available commercially under the Transcutol HP™ brand from Gattefosse, Inc.

b. Available commercially under the label Labrasol™ from Gattefosse, Inc.

c. Available as Dow Corning™ Q7-9120 from Dow Corning

Animals were also given an oral tablet containing 200 mg ibuprofen (Motrin™ IB) using a pill gun. The tablet was placed in the open rubber tip of the “pill gun” and the animal’s mouth was opened. The tip was brought to the back of the mouth above the root of the tongue and the tablet was pushed out by pressing the plunger. After administration of the tablet, a stream of reverse osmosis purified water was released to stimulate swallowing.

Each of the topical and oral samples was tested on four miniature pigs and the results of the study are shown below in Table 3a.

Table 3a

Test sample Maximum concentration (Cmax)
[ng/ml] ^a Area under the curve (AUC)
[ng*h/ml] ^b Tmax
[watch] ^c % relative to the bioavailability of orally administered ibuprofen Cmax fold difference for Ibuleve™ AUC fold difference for Ibuleve™ Ibuleve™ 133.25 (27.5) 3905.33 (24.4) 8 (4-24) 4.08 - - Dolgit™ 64.23 (16.1) 1106.67 (24.2) 18 (12-24) 1.16 0.48 0.28 Sample 2a 349.5 (42.8) 9953.87 (35.9) 16 (2-24) 10.39 2.62 2.55 Sample 2b 344 (29.8) 9362.82 (25) 24 (24-24) 9.77 2.58 2.40 Sample 2c 359 (37.1) 9511.32 (35.2) 12 (12-24) 9.93 2.69 2.43 Orally administered ibuprofen 13,862.5 (55.2) 95,807.8 (20.8) 4 (2-4) -- -- --

a. The number in parentheses represents the standard error

b. The number in parentheses represents the standard error

c. The number in parentheses represents the Tmax range

As shown in Table 3a, all samples 2a-2c unexpectedly had superior Cmax, AUC and relative bioavailability compared to Ibuleve™ or Dolgit™. For example, sample 2a had a Cmax value 2.62 times greater and an AUC value 2.55 times greater than Ibuleve™.

Samples 2a-2c were also tested under accelerated stability test conditions to determine the amount of ibuprofen ester formed. Approximately 1 oz (29.6 mL) of samples were stored for 3 months (91 days) in glass vials with lids in a laboratory oven at 40 °C. The results are presented below in Table 3b (values represent the percentage of ibuprofen converted to the indicated ester). For accelerated stability testing, a high-performance liquid chromatography (HPLC) system was equipped with a UPLC C18, 2.1 ID x 50 mm column at 40 °C, 1.7 μm particle size, mobile phase gradient of 0.1% trifluoroacetic acid in water and 0. 1% trifluoroacetic acid in acetonitrile, and the change in the mobile phase ratio was from 95: 5 to 5: 95 for 8 minutes. A flow rate of 0.65 mL/min was used with an injection volume of 0.2 μL and a UV detector at 264 nm.

Table 3b

Ester Sample 2a Sample 2b Sample 2c Ibuprofen diethylene glycol monoethyl ether BUT 0.49 0.34 Ibuprofen cetyl alcohol BUT 3.97 BUT Ibuprofen-propylene glycol 0.65 0.86 0.61

N/A - not found

The above results confirm that ibuprofen forms an ester with the alcohols diethylene glycol monoethyl ester, cetyl alcohol and propylene glycol. It should be noted that samples 2a and 2c had a lower degree of conversion of ibuprofen to ibuprofen-propylene glycol ester than sample 2b, which the applicants believe is due to the presence of the lipophilic pH regulator diethylamine.

It is understood that while the invention has been described in detail, the foregoing description is intended to be illustrative and does not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are included within the scope of the claims.

Claims (18)

1. An emulsion composition for the treatment of pain selected from the group consisting of pain in joints, bones, ligaments, tendons and muscles, containing: (i) from 7 to 15% by weight of a non-steroidal anti-inflammatory drug; (ii) from 15 to 50% by weight isopropyl myristate; (iii) from 25 to 50.2% by weight of water; (iv) one or more emulsifiers; (v) one or more pH regulators; And (vi) one or more solubilizers, wherein said emulsion composition contains 5% or less by weight of C ₁ -C ₄ alcohols, one or more pH adjusters include diethylamine, one or more solubilizers include propylene glycol, said non-steroidal anti-inflammatory drug is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, and wherein said emulsion composition has a pH in the range from 5 to 7. 2. The composition according to claim 1, wherein said composition contains from 20 to 50% by weight of said isopropyl myristate. 3. The composition according to claim 1, wherein said composition contains from 40 to 50.2% by weight of said water. 4. The composition of claim 1, wherein at least one of said one or more emulsifiers is ethylene glycol stearate. 5. The composition according to claim 1, wherein said composition contains 5% or less by weight of alcohols capable of esterifying said non-steroidal anti-inflammatory drug. 6. The composition of claim 1, wherein less than 10% of said non-steroidal anti-inflammatory drug is converted to ester after a 30-day stability test. 7. A method of treating pain in joints, bones, ligaments, tendons and muscles in a subject, characterized in that the composition according to claim 1 is applied dermally in a dosage of 2.67 g, which corresponds to 200 mg of ibuprofen, once to the specified subject.