CN117062603A - Topical formulations containing dispersed pregabalin - Google Patents

Topical formulations containing dispersed pregabalin Download PDF

Info

Publication number
CN117062603A
CN117062603A CN202280022649.6A CN202280022649A CN117062603A CN 117062603 A CN117062603 A CN 117062603A CN 202280022649 A CN202280022649 A CN 202280022649A CN 117062603 A CN117062603 A CN 117062603A
Authority
CN
China
Prior art keywords
mixture
pregabalin
excipients
carbomer
homogenizer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280022649.6A
Other languages
Chinese (zh)
Inventor
A·古丽亚斯
K·莫里茨
D·乌勒
G·吉格勒
E·帕普
A·帕尔夫厄尔吉
I·加奇斯阿利
Z·瓦尔加
A·F·瓦沙
A·巴塔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Egis Pharmaceuticals PLC
Original Assignee
Egis Pharmaceuticals PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Priority claimed from PCT/HU2022/050005 external-priority patent/WO2022157527A1/en
Publication of CN117062603A publication Critical patent/CN117062603A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Topical formulations containing pregabalin with long-term analgesic activity. The composition is prepared using a high shear mixer or homogenizer such as an HPH or ultrasonic device, which alters the structure of the composition. The analgesic effect of the compounds of the invention is significantly increased compared to a reference formulation homogenized with a device having the same quantitative composition but less shear force.

Description

Topical formulations containing dispersed pregabalin
The present invention relates to a topical pharmaceutical composition comprising pregabalin as active ingredient for use in the treatment of pain, in particular for the treatment of chronic pain disorders. Such disorders include, but are not limited to, neuropathic pain, peripheral neuropathic pain, pain experienced by patients such as diabetic patients or patients already suffering from herpes zoster (herpes zomers), and central neuropathic pain, such as pain experienced by patients already suffering from spinal cord injury; diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain (bum pain), and other forms of neuralgia, neuropathic pain, and idiopathic pain syndromes.
Background
The compounds of the invention are known as agents useful in the treatment of pain, in particular in the treatment of neurological disorders and in the anti-epileptic treatment of central nervous system disorders such as epilepsy, huntington's disease, cerebral ischemia, parkinson's disease, tardive dyskinesia, spasticity, and in the treatment of generalized anxiety disorder. Pregabalin was first described as an active ingredient in european patent No. EP 641330. The use for the treatment of pain, including neuropathy, is disclosed for the first time in the specification of european patent No. EP 934061. Pregabalin was administered in solid oral capsules since 2004 (such as) In the form of (c) are marketed in the european union. />Can be obtained as capsules (white: 25, 50 and 150mg; white and orange: 75, 225 and 300mg; orange: 100mg; light orange: 200 mg) and oral solutions (20 mg/ml). Neuropathic pain may be associated with abnormal sensations known as dysesthesias or pain caused by non-painful stimuli in general (hyperalgesia). It may have a continuous and/or sporadic (episodic) composition. The latter is similar to a puncture or electric shock. Common symptoms include burning or cold, a "tingling" sensation, numbness and itching. Up to 7-8% of the european population is affected and 5% of these patients may be severely ill. Neuropathic pain may be caused by disorders of the peripheral or central nervous system (brain and spinal cord). Thus, neuropathic pain can be classified as peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain. Systemic treatment of neuropathy with pregabalin (e.g., using oral capsules) can lead to a variety of adverse effects such as dizziness, somnolence, dry mouth, oedema, blurred vision, weight gain, and "thinking abnormalities" (mainly hard to concentrate/pay attention to). Considering that peripheral neuropathic pain is associated with specific sites on the body surface, topical treatment appears to be possible. The specification of WO14168228 discloses a topical composition comprising 0.2-3% aqueous solution or gel of pregabalin, wherein pregabalin is dissolved in water. Compositions containing 1% and 3% pregabalin have pain-reducing effects, but after 1.5-2 hours the effects are reduced (tables 4 and 9). Gabapentin is a precursor compound of pregabalin, used in combination with ketamine, ibuprofen, and baclofen for the topical treatment of neuropathic pain. At International Journal of Pharmaceutical Compounding, volume 18, phase 6 [11 month 12 month ] ]In 2014 (pages 504-511), the authors examined the local availability of gabapentin in different gel systems. 1% and 5% lipoderm, lipobase gel and poloxamer Sha Mluan phospholipid organogel were examined.
Several liquid or semi-solid compositions are known in the art which appear to be suitable for use in pregabalin formulations in topical delivery systems.
The inventors of international patent application WO2002094220 describe oral solutions. According to an embodiment, gabapentin oral solution can be prepared with water and glycerin suitable for oral solutions. Gabapentin has similar physical, chemical and pharmaceutical properties compared to pregabalin, and therefore compositions containing gabapentin are good starting points for developing compositions containing pregabalin. A similar oral solution is disclosed in european patent application No. EP1543831, except that pregabalin is used as active ingredient and hydroxyethyl cellulose is used as thickener, and no glycerol is contained. The composition has the composition of the pregabalin oral solution sold in the marketSolutions) are similar. Based on the facts disclosed in US10004710B2 patent, we expect that these solutions have a significant pain relieving effect even when applied topically. The inventors of the present specification found that the solution was effective even without any percutaneous absorption promoting ingredient. Pregabalin showed pain relief effect in mouse nerve ligation model/MNL. According to the results, after topical application of a 2.5% aqueous solution without any other ingredients, the relief effect was greatest at 1 hour, followed by a decrease, the relief was remarkable, and after 6 hours the effect was substantially lost. According to one embodiment, the same aqueous solution of pregabalin may reduce neuropathic pain in a human patient for up to 6 hours. Depending on the grade used, pain scores seven on a ten-level scale, which severely hampers sleep. According to the instructions, the pain is significantly reduced after about 30 minutes (grade 3 or grade 4). This suggests that the effect on human patients may be longer than in mice, but the rate of alleviation will be faster. We have tried in experiments using commercial products with similar compositions (except pregabalin and water containing only sweetener and preservative) Oral solutions, however, were unsuccessful. />Is ineffective. Furthermore, it is difficult to apply the liquid preparation to the body surface. The patent suggests that viscosity may be altered by a thickener and suggests that pregabalin may be partially in crystalline form if the concentration is higher, but does not disclose such an embodiment. According to other inventors, compounds such as pregabalin have low permeability through the skin and therefore, modification or addition of permeability enhancers to the compounds is required in order to prepare effective topical compositions. The formation of suitable pregabalin derivatives that decompose to pregabalin in the skin can be used in more effective transdermal compositions according to the specification of U.S. patent application No. US 20050209319. Such compounds may have better permeability than pregabalin, but as new compounds, extensive preclinical testing, toxicological screening and comprehensive clinical studies are also necessary, which are both risky and expensive.
The same problem exists with the newly synthesized excipients mentioned in the description of CN 108703946B. The results using these new excipients are demonstrated in the rat pain threshold experiment. In rat experiments, these compounds demonstrate that enhancers can contribute to the permeability of pregabalin compared to compositions without enhancers. The use of mixtures of fatty acid esters as penetration enhancers is disclosed in the specification of US8394759B2 patent. This patent shows that a mixture of several different cetyl esters can assist in the absorption of pregabalin through the skin. The patent suggests that pregabalin is used in an amount of 0.01-15% in a rod gel. Specific examples of use of pregabalin are not given in the specification. The specification of US20170290778 patent application discloses a composition comprising the following components: one or more active agents; and about 0.1 wt% to about 5.0 wt% of an extracellular matrix component or fragment thereof having an average molecular weight of about 2,000 daltons to about 60,000 daltons. The permeability of the composition through human skin was measured in vitro. Unfortunately, there are no examples of compositions comprising pregabalin. The specification of WO2017172603 discloses compositions comprising dimethyl sulfoxide (DMSO) as penetration enhancer, wherein the amount of DMSO is 1-30% of the composition. DMSO is a very good skin penetration enhancer as a dipolar aprotic solvent. Unfortunately, the use of DMSO may present a risk as it may cause adverse reactions. The DMSO content in the compositions of the examples of the specification of the WO2017172603 patent application is between 14-30%, which is high. Another possibility for transdermal treatment of neuropathic pain is a combination of different active ingredients that may have additive or synergistic effects with pregabalin. US10512655B1 describes B vitamin compositions for the treatment of neuropathic pain and as analgesics. The recommended amount of pregabalin is between 0.001-0.5%, but there are no examples of topical compositions containing pregabalin. WO2020069013A1 suggests that the topical composition should contain, in addition to the components to be absorbed by the skin, vasodilators to aid in the absorption of the active ingredient. This patent application mentions pregabalin as active ingredient, but does not provide working examples nor absorption results of pregabalin-containing compositions. Other patent applications relate to topical gels comprising pregabalin. The inventors of US20090247635 patent application prepared a cream containing 10% pregabalin and used it for the treatment of itching. The composition of the cream is not disclosed. Only a very long list of ingredients is given in the description.
According to our experiments, compositions containing aqueous solutions of pregabalin may not contain sufficient concentrations of pregabalin to maintain analgesic effects for more than 3 hours by topical administration. This occurs even though transdermal bioavailability is acceptable. Considering that the painless sleep time of 3 hours is not short enough, it is apparent that there is a need for a topical composition having a longer pain relieving effect. Thus, there is a long-felt need for a topical therapy for the treatment of diabetic neuropathy or post herpetic neuralgia that has a pain relieving effect, preferably for a period of about at least 5 hours, while having a low systemic exposure to reduce the side effects of pregabalin. Our aim was to develop a stable topical pharmaceutical composition for the treatment of neuropathic pain, preferably peripheral neuropathic pain or post-herpetic neuralgia (PHN), which has a pain-relieving effect longer than 3 hours, more preferably longer than 5 hours. Given that the affected body surface can reach about 28% of the body surface in the case of diabetic neuropathy (DPN), our goal is also to reduce the systemic effects of topical compositions as much as possible.
Summary of The Invention
We have surprisingly found that our object is achieved by preparing a topical composition comprising pregabalin and a phospholipid, wherein the phospholipid phase or the composition comprising pregabalin and a phospholipid and a solvent or solvent mixture is homogenized with a high shear mixing device, preferably with a high pressure homogenizer. More specifically, the topical pharmaceutical composition according to the invention comprises preferably more than 2.5% by weight of pregabalin and 0.1-5% by weight of phospholipids in a gel or cream formulation, wherein the phase comprising said phospholipids is milled with a high pressure homogenizer in the presence or absence of pregabalin. Surprisingly, we have found that pregabalin mixed into the structure thus obtained has a prolonged effect in case the phospholipid phase is milled with a high pressure homogenizer, which has the advantage that the pain relieving effect emerges in a short time and then lasts longer, even more than 5 hours, which is better than the same quantitative composition which lasts less than 3 hours if the components were mixed and homogenized without using a high pressure homogenizer.
All physical properties and stability properties of the compositions having the same constituent composition are the same, but in the case of using a high pressure homogenizer (hereinafter referred to as HPH homogenizer), the pain relieving effect is significantly longer. Thus, the unexpected effect of the improvement is the result of using an HPH homogenizer, which generates high shear forces in the composition in the process. Clearly, these forces result in the unexpected advantageous effects of the present application, and therefore it is reasonably expected that each of the homogenization methods resulting in similar high shear forces are also suitable for preparing the compositions of the present application. The skilled person can select the device and its operating parameters to achieve the required high shear forces. Such equipment that may be suitable for preparing the compositions of the present application is as follows: in which for example similar turbulence, local cavitation, shear tests, impact velocities are applied. Such devices include high shear mixers, homogenizers, crushers, grinders such as ultrasonic mixers, rotor/stator homogenizers, TURRAX homogenizers, bead mills, colloid mills, high shear mixers, slot homogenizers, microfluidizers, and the like.
According to our studies, phospholipid micelles formed in a protic solvent are partially or completely decomposed by high-pressure mixing with high shear force. Low angle X-ray diffraction studies on the formulations confirm this.
Such an effect cannot be observed when using a homogenization method that generates less shear force. Mixing and homogenization of the formulation in each step-when a non-high pressure homogenizer is used-mixing and homogenization was performed using Stephan UMC 5 electronics (see example R-3). Quite surprisingly, the product thus prepared maintains the advantageous form and properties without any change even after 12 months, and the compound prepared according to the invention has the longest pain relieving effect.
Detailed description of the invention
Our objective is achieved by developing a topical pharmaceutical composition containing more than 2.5 wt.% pregabalin and 0.1-5 wt.%, preferably 0.1-3 wt.% phospholipids in a gel or cream formulation, wherein the cream or gel phase of the phospholipid-containing formulation is homogenized with a high shear mixer, most preferably with a high pressure homogenizer, in the presence or absence of pregabalin, preferably micronized pregabalin. Preferably, the homogenization is performed at least once, more preferably with a high shear mixer, most preferably with a high pressure homogenizer 1 to 125 times, preferably 3 to 10 times.
We have surprisingly found that a topical pharmaceutical composition comprising more than 2.5 wt% pregabalin and 0.1-3 wt% phospholipids in a gel or cream formulation, wherein the cream or gel phase of the phospholipid-containing formulation is homogenized at least once by a high shear mixer, most preferably a high pressure homogenizer, in the absence or presence of pregabalin, has a sustained pain relieving effect in a topical treatment of mice (mouse model of neuropathic pain) for at least 5-hours. According to a preferred embodiment, the pregabalin-containing gel or cream is homogenized by means of a high pressure homogenizer 1 to 125 times, preferably 3 to 10 times.
According to the invention, the composition comprises pregabalin in dispersed form. This means that the composition contains pregabalin not only in dissolved form, but also in solid form, because of the low solubility of pregabalin. Pregabalin has poor solubility in any solvent. According to the present invention, water and a protic solvent, for example, a pharmaceutically acceptable alcohol having one or more hydroxyl groups, such as ethanol, propanol, isopropanol, butanol, sec-butanol (as an alcohol having one hydroxyl group), propylene glycol having two hydroxyl groups or glycerin having three hydroxyl groups, are used as solvents.
According to the present invention, water and the above alcohol are used, more preferably water, ethanol or isopropanol as solvents. In an advantageous embodiment, water is used which is mixed with an alcohol, preferably isopropanol. Above 2.5% by weight of pregabalin content in the mixture of pregabalin and water, the remainder of pregabalin, except for dissolved pregabalin, remains in the composition in solid, dispersed form. Thus, according to the present invention, pregabalin is in dispersed form in the sense that the composition comprises pregabalin not only in dissolved form, but also in solid form. The ratio of dissolved and dispersed pregabalin depends on the weight percent of pregabalin in the composition, the solvent used and/or the ratio of solvents used in the mixture, the temperature of the composition and the additional excipients used. Briefly, compositions according to the present invention may comprise dissolved pregabalin in addition to dispersed pregabalin.
We have surprisingly found that the pain relieving effect of the composition depends on the particle size of pregabalin used. According to a preferred embodiment of the invention, the pregabalin used as starting material is milled, which means that the particle size D of the pregabalin used 90 Less than 200 microns, preferably between 20 and 200 microns. More preferably micronized pregabalin is used as starting material, having a D of less than 20 microns 90 。
According to the present invention, a protic solvent is used as the solvent. More specifically, water and a pharmaceutically acceptable alcohol having one or more hydroxyl groups may be used as a solvent. These alcohols may also be substituted. As the alcohol having 1 hydroxyl group, ethanol, propanol, isopropanol, n-butanol, 2-butanol are preferably used. Propylene glycol and glycerol may be used as alcohols having more than one hydroxyl group. Most preferably, the composition of the present invention comprises water, ethanol or isopropanol or a mixture thereof as solvent. According to a further advantageous embodiment of the invention, the composition comprises water and ethanol or a mixture of water and isopropanol. The preferred ratio of alcohol to water is 1:1 to 1:40 by weight, more preferably 1:10 to 1:40, most preferably 1:15 to 1:35.
Certain solvents of the present invention also have penetration enhancing effects. Such solvents are, for example, isopropanol and ethanol. According to the specification, these compounds are considered as solvents. Thus, in the examples and the description, the proportion (e.g., wt%) of these compounds in the composition is accounted for in the proportion of solvent, and the amount of these solvents is not included in the amount of penetration enhancer proportion.
Phospholipids used in the compositions of the present invention are also well known penetration enhancers. Considering that the phospholipid in the process and the phospholipid treatment are critical, the amount of phospholipid used in the high shear mixing, most preferably HPH process is not accounted for in the amount of penetration enhancer. It is not excluded that in addition to the high shear mixed, most preferably HPH treated phospholipid, other phospholipids are added to the composition. In such cases, the other phospholipids used are considered other penetration enhancers.
The phospholipids according to the invention are natural or synthetic phospholipids. As the phospholipid, phosphatidic acid (phosphatidate), phosphatidylethanolamine (cephalin), phosphatidylcholine, phosphatidylserine, phosphoinositides such as phosphatidylinositol, phosphatidylinositol phosphate, phosphatidylinositol diphosphate, phosphatidylinositol triphosphate, ceramide phosphorylcholine, ceramide phosphorylethanolamine, ceramide phosphoryllipid, or derivatives and mixtures thereof can be used. According to the present invention, preferably phosphatidylcholine (lecithin) may be used, more preferably soybean lecithin, deoiled soybean lecithin, lipid P75, lipid S75.
The topical composition of the present invention is a gel, cream or gel cream. In order to achieve advantageous gel, cream or gel cream properties, rheology modifiers are also used in preferred embodiments of the invention. As rheology modifiers, poloxamers, polyethylene glycols, synthetic polymers such as carbomers (polyacrylic acid), hydroxyalkyl celluloses such as hydroxyethyl cellulose, and vegetable gums such as xanthan gum or guar gum may also be used. Carbomers are preferably used, most preferably carbomer 980.
These compositions according to the invention generally comprise, in addition to the pharmaceutically active ingredient, further excipients.
The compositions of the present invention may contain an emollient as an excipient that is an effective wetting agent that can help maintain the natural protective barrier of the skin and rehydrate the skin. According to a preferred embodiment of the present invention, a topical pharmaceutical composition may be obtained by a specific method, wherein it may comprise ammonium lactate, vitamins A, D and E, lanolin alcohol, propylene glycol dibenzoate, vegetable oil, plant extracts, fatty alcohol esters, fatty acid esters, fatty alcohols, synthetic polymers, silicon compounds, fatty acids, mineral oil derivatives, waxes or mixtures thereof as softeners. For example, as the vegetable oil softener, coconut oil, soybean oil, grape seed oil, hazelnut oil, sunflower (helianthus annuus, sun flower) seed oil, hemp seed oil, hydrogenated olive oil, hydrogenated soybean oil, peanut oil, pecan oil, avocado (persea gratissima, avocado) oil, pistachio seed oil, plum seed oil, white flower (limnanthes alba) seed oil, evening primrose oil, olive oil unsaponifiable matter of olive oil, olive oil/olive oil, babassu seed oil, asiatic rice oil, palm oil palm leaf tree extract, apricot, european Li Ziyou, almond, pumpkin seed extract, rapeseed oil, quinoa Gu You (quinoa oil), sweet almond oil, rice bran oil, rice oil, castor oil, safflower seed oil, sesame seed oil, wheat oil, walnut oil, wheat germ oil, watertightness yellow seed oil, moringa seed oil, or a mixture thereof may be used. As plant extracts, emollients such as polyspora schea (haslet) extract, sunflower oil, kelp (Himanthalia elongata) extract, irish moss (Irish moss) extract, mangifera (Mangifera indica, mango) seed fat, carrageen (Mastocarpus stellatus), microcystis aeruginosa (Microcystis aeruginosa), wood Lu Xingguo brown seed fat, padina pavonica extract, babassu seed oil coconut (Orbignya martiana), sweet almond (Prunus amygdalus dulcis), quinoa oil, rosa canina (Rosa canina), rosa senna (Rosa centella), shea butter, hydrolyzed algae extract or mixtures thereof may be used. As fatty alcohol esters, for example, lauryl lactate, myristyl myristate, neopentyl glycol dioctanoate, octyl palmitate, octyl stearate, triisocetyl citrate, tri (octyldodecanol) citrate, radish (Raphanus sativus, radish) seed oil, or mixtures thereof may be used.
As fatty acid ester softeners, for example, stearate, glyceryl stearate, ethylene glycol stearate, hexyl laurate, hydrogenated coco glyceride, hydrogenated palm oil glyceride, methyl glucose sesquistearate, octyl dodecanol myristate, octyl dodecanol pivalate, polyglycerol monostearate, polyglycerol 2 triisostearate, polyglycerol-4 isostearate, polyglycerol-6 isostearate, propylene glycol laurate, stearyl stearate, tridecyl stearate, triglycerides, glyceryl trilaurate, glyceryl trioctanoate, wheat germ glyceride, glyceryl behenate, glyceryl rosinate, lauryl laurate, spanish sage (Salvia hispanica) seed oil, argania spinosa seed oil, capryloyl/caprylyl oleate, ethylhexyl oleate, isopentyl cocoate, sucrose stearate, diisostearyl polyglyceryl-3 dimer dilinoleate, cetyl oleate, 6 behenate, cocoyl stearate, glyceryl behenate, or mixtures thereof may be used. As fatty alcohols, use may be made, for example, of hexyldecane alcohol, octyldodecanol, stearyl alcohol, myristyl alcohol or mixtures thereof. As synthetic polymers, use may be made of softeners such as hydrogenated polydecene, hydrogenated polyisobutene, PEG-10 rapeseed sterol, PEG-100 stearate, PEG-20 methyl glucose sesquistearate, PEG-40 hydrogenated castor oil, PEG-60 mandelic ester, PEG-60 hydrogenated castor oil, PEG-7 glyceryl cocoate, PEG-8, PEG 90M, PEG/PPG-17/6 copolymer (PEG stands for polyethylene glycol; PPG stands for polypropylene glycol), polyethylene, PPG-3 benzyl ether myristate, PEG-7 sodium olive oil carboxylate, triethoxysilylethyl polydimethylsiloxane ethylhexyl polydimethylsiloxane, gluceth-20 benzoic acid methyl ester, polyglyceryl-10 stearate, polyglyceryl-4 laurate, polyglyceryl-4 olive oleate, polyglyceryl-3 stearate or mixtures thereof. As the silicone softener, for example, polymethylsiloxane, PEG-10 polydimethylsiloxane/vinyl polydimethylsiloxane cross-linked polymer, PEG/PPG-18/18 polydimethylsiloxane, PEG/PPG-20/15 polydimethylsiloxane, pentaerythritol tetraoctanoate, methyl trimethicone, methylsilanol mannuronate, methylsilanol PEG-7 glyceryl cocoate, polymethylsilsesquioxane, stearoyl polymethylsiloxane, trimethylsiloxysilicate, or a mixture thereof can be used. As the fatty acid type softener, for example, hydrolyzed jojoba esters, linoleic acid, palmitic acid, stearic acid, trihydroxy glycerol tristearate, or a mixture thereof can be used. As the mineral oil derivative type softener, for example, petrolatum, mineral oil, or mixtures thereof can be used. As wax-type softeners, it is also possible to use, for example, beeswax or synthetic beeswax. Preferably as softeners vitamins A, D and E, lanolin alcohols, propylene glycol dibenzoates, vegetable oils, vegetable extracts, fatty alcohol esters, fatty acid esters, fatty alcohols, synthetic polymers, silicon compounds, fatty acids, mineral oil derivatives, waxes or mixtures thereof are used, most preferably fatty acid esters such as cetyl palmitate, fatty alcohols such as octyldodecanol, fatty acid derivatives such as decyl oleate (Decylis oils), vegetable oil coconut oil or mixtures thereof are used.
According to a preferred embodiment of the present invention, the topical pharmaceutical composition may comprise other penetration enhancers such as the use of DL-alpha-tocopherol, dimethyl sulfoxide diethyl sebacate, tetrahydrofuran polyethylene glycol ether, isopropyl myristate, isopropyl palmitate, lauric acid, linoleic acid, methyl pyrrolidone, myristic acid, oleic acid, oleyl alcohol, palmitic acid, polyoxyethylene alkyl ether, polyoxylglycerides such as caprylocaproyl polyoxylglyceride, polyoxylglyceride ii. lauroyl polyoxylglyceride, polyoxylglycerides such as linoleoyl polyoxylglyceride, polyoxylglyceride thymol, trioctyl, racemic camphor (camphora racemica), menthol, cetyl decanoate, cetyl laurate, cetyl myristate, cetyl oleate, cetyl palmitate, cetyl stearate or a mixture of other penetration enhancers. Alcohols used as solvents also have a penetration enhancer effect.
According to a preferred embodiment of the invention, preservatives are also used. As preservative, EDTA derivatives, aromatic preservatives such as parahydroxybenzoate, thiomersal, chlorhexidine, benzyl alcohol and benzalkonium chloride, phenoxyethanol, preferably benzyl alcohol or mixtures thereof, more preferably mixtures of benzyl alcohol and EDTA, may be used. EDTA is used as a complex-forming compound in addition to its preservative effect.
According to a preferred embodiment of the present invention, the topical pharmaceutical composition may further comprise a pH adjusting agent. Preferably ammonia, an ammonium solution, an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate or an organic base (such as a primary, secondary or tertiary amine), most preferably an aqueous ammonia solution, may be used as a pH adjuster.
Homogenization is a process that plays an important role in the present invention. For clarity, in the case of a high shear mixer, preferably a High Pressure Homogenization (HPH) process, the process is capable of altering the structure of the composition to achieve unexpected results-the fact that the pain relief time is prolonged-is referred to as "homogenization with high shear mixing equipment", most preferably "HPH homogenization", "high pressure homogenization", "homogenization with HPH homogenizer", and the like. Where the homogenization process results in a uniform distribution of the mixed ingredients, the terms "homogenizing," "mixing," and the like are used only. The essential feature of the invention is that the phospholipids must be homogenized with a high shear mixing device, preferably with a high pressure HPH homogenizer, in the presence of a solvent such as water, the above-mentioned alcohols or mixtures thereof, at least in one process step.
As noted above, in the prior art, homogenization using high shear mixing devices can be accomplished with many different devices that differ significantly in structure.
The high shear mixing or homogenizing apparatus of the present invention is a prior art mixing, homogenizing and pulverizing apparatus capable of operation with parameters that allow for phospholipid, water and solvent, preferably water or C 1 -C 4 One or more alcohols or mixtures thereof are mixed with each other or with water or a mixture of components thereof as a component in such a way that micelles formed by phospholipids are partially or completely decomposed. This can be said to be that the mixing must be so intense that high shear forces must be generated so that phospholipid micelles cannot form or must break down due to the mixing forces. Any means of reducing the amount of micelles in the mixture is suitable for this purpose. According to the present invention, an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, a bead mill, a slot homogenizer, a colloid mill, a high shear mixer, more preferably an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, HP is preferably used as the high shear mixer. The high shear mixing device according to the invention, due to its different technical design and operating principle, can reduce the number of micelles with different efficiency (see WE-4 and WE 4/B, high pressure homogenizers or ultrasonic mixers), but if the amount of micelles is reduced, the determination of the technical parameters for preparing the composition of the invention with said device is part of the knowledge of the person skilled in the art. Whether the device reduces the number of micelles can be determined by two easily implemented experimental models, which do not require further investigation. Thus, according to the present invention, any mixing device will reduce the number of micelles in a composition containing the phospholipids of the present invention by: ifa.) repeating the inventive example of reference example R-3 (PGA 0450717) with the mixer described therein and homogenizing 5 the lipid phase after homogenization with a hypothetical high shear homogenizer Once, and then the preparation was completed as described in the examples. The small scatter X-ray patterns of the two products obtained were then obtained according to the procedure described in example 8. If in the diffraction pattern of the product obtained using an unknown stirrer, as shown in FIG. 14, at 0.7nm -1 <q<3nm -1 In the range of (2), the curve obtained using a different stirrer is lower than the reference product (R-3), the mixing reduces micelles, that is to say the mixing device is considered as a high shear mixer in this mode. b. )
However, one can also determine whether mixing the product according to its method reduces the amount of micelles, i.e. whether the particular mixer is a high shear mixer as described in the present application, and if the mixture produced with it is R-3 of the present application, then comparing the resulting composition with a low angle X-ray diffraction test as described above. If the product obtained with the mixer used is operated at a spectrum 0.7nm lower than that of the mixture prepared with the homogenizer described with reference to product (R-3) -1 <q<3nm -1 Within the scope of (2), the mixing already reduces the number of micelles, i.e. the device is considered a high shear mixer according to the application.
The difference may be characterized by a parameter fitted to the curve of the measurement curve, i.e. the size of the scaling factor of the micelle standard deviation. If the conversion factor of the micelle scattered charge of the mixer used is smaller than the result obtained by the curve obtained with the homogenizer in the R-3 experiment, the mixer tested will reduce the number of micelles, i.e. the mixer is considered to be a high shear mixer according to the application. Micelle scattering contributions are parameters of a fitted curve that can be fitted to an X-ray diffraction curve, and the mathematical methods required to determine it are shown below.
In reference example R-3, homogenization was performed in a Stephan UMC 5 electronic mixer at a stirring speed of 300rpm and a spatula stirring speed of 20 rpm.
In practice, however, a mixer may be used to mix the gel/ointment without disrupting the gel/ointment structure. Such devices do not have shear forces that break down phospholipid micelles. Such devices are commercially available. For a detailed description of these and their use, see Encyclopedia of Pharmaceutical Technology, third edition (James Swabrick, 2007,Informa Healthcare USA,Inc.), volumes 3265-66, side pages.
In the process of the present invention, when low shear mixing is used, homogenization is performed in a Stephan mixer at a mixing speed of 300rpm and a scraping speed of 20 rpm.
A common feature of the equipment used is that the phospholipid micelles in the composition are partially or completely decomposed under strong shear forces. In the WE-4/B series of experiments, different mixing equipment was used to prepare formulations of the same composition as PGA2330320 5% pregabalin prepared in WE-4, the only difference between this and PGA2330320 being high shear mixing homogenization with different equipment. Thus, during the trial, the animal's right posterior surgical leg (about 2 cm) was treated with 10 μl of cream (0.5 mg pregabalin) 2 Area). The therapeutic volume was chosen because it was half the amount that was effective for 8 hours in the reference (PGA 2330320). In this trial, using this treatment regimen, we expected that any differences in efficacy will be more pronounced at lower treatment volumes over the five hour duration of the trial. Experiments have shown that the effect is higher in the first 3 hours and decreases by 5 hours, but still significantly higher than baseline, demonstrating that the structure of the invention forms in phospholipid-containing media, which surprisingly does not revert to micelles (short-acting state).
The key impact of high-shear, high-shear effect HPH homogenization on efficacy was clearly demonstrated in a rat model of formalin-induced rat neuropathy. In example 4, two differently prepared gels of the same composition containing 15% pregabalin were compared to placebo formulations of similar composition. That is, PGA0450717 (composition R-3) which had not been HPH homogenized was compared with placebo PGA0440717 (composition P-1) whose lipid phase had not been treated with an HPH homogenizer. The effect of the two formulations in the total measurement time and the second stage (which causes the characteristic symptoms of neuropathic nerve injury) was not different between the two formulations. In the case of comparison of PGA0470717, which also contained 15% pregabalin, with PGA0460717 placebo, the results were completely different, i.e. PGA0470717 caused a significant pain relief throughout the measurement time and in the second phase, also compared to placebo. Two formulations PGA0470717 and placebo PGA0460717 were prepared by homogenizing a mixture of swollen phospholipids and isopropanol 5 times using an HPH homogenizer. The results are shown in fig. 10.
In our development, we have tried to use different gels, such as lipoderm, but the stability of these gels was not acceptable. Surprisingly, we have found that phospholipids can be used as penetration enhancers in topical compositions comprising pregabalin for the treatment of neuropathic pain, preferably peripheral neuropathic pain or post-herpetic neuralgia (PHN), but that a long lasting effect can be achieved only when the phospholipids are homogenized using a high pressure homogenizer in the presence of a solvent, preferably in the presence of water, more preferably in the presence of a mixture of water and an alcohol. The pain relieving effect of different drugs can be modeled according to the plantar medial nerve ligation model (hereinafter referred to as MNLP test) (-Sci Rep-2016,/http:// www.nature.com/scientific /). Using this test, we have surprisingly found that topical treatment with a composition comprising phospholipids homogenized with a High Pressure Homogenizer (HPH) has a significant and long lasting effect in plantar recession threshold experiments. In contrast, for topical treatments in which the phospholipid was not homogenized with a high pressure homogenizer, the effect rapidly decreased after 3 hours. In fig. 1, MNLP tests of three similar compositions are shown below:
Thus, the phospholipids in the compositions of PGA2180719, PGA2190719 and PGA0450717 in the presence of a solvent were not homogenized with the HPH homogenizer, while PGA0470717 and PGA1601018 were prepared according to the present invention.
In all cases, a pain relieving effect was produced within 30 minutes, which suggests that the absorption of the composition through the skin was excellent for each composition, but the effect of the composition PGA2180719 containing pregabalin in dissolved form was reduced almost to the initial level after 5 hours. With the composition PGA2190719 comprising pregabalin in dispersed form, the effect was reduced by almost half of the maximum level after 5 hours. The composition according to the invention PGA1601018 had a remarkable effect after 5 hours. The difference between the intact paw and the mpll paw compared to baseline after 5 hours suggests that the effect is significant even after 5 hours.
Furthermore, based on the article by Bennett GJ et al (paint, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man.4 month 1988; 33 (1): 87-107), we have developed a method for testing the compositions of the invention. Thus, we also examined the composition according to the invention with a different model, also for measuring the relief of peripheral neuropathic pain. That is, we have examined rats using a Chronic Constrictive Injury (CCI) model. Rats were evaluated for hindpaw withdrawal threshold 3 weeks after nerve injury. The Paw Withdrawal Threshold (PWT) was determined using a Electronic von Frey device according to Dixon's modified methods (Efficient analysis of experimental observations, annu Rev Pharmacol Toxicol.1980; 20:441-62). The results also demonstrate that the compositions of the present invention have beneficial effects in alleviating peripheral neuropathic pain. 5mg of pregabalin gel (PGA 2330320)/4 cm in 50 μl of 10% cream was used 2 Resulting in pain relief in rats for more than 5 hours. The method and results are shown in example 3 and fig. 9.
As we mentioned above, the effect of the composition according to the invention can be detected very quickly, also within 30 minutes, for example when using the MPNL model. The absorbent compositions of PGA 1601018 containing 5% pregabalin and PGA 1591018 containing 10% pregabalin were examined. This indicates that the gel was fully absorbed in both cases one hour after treatment, although the gel contained dispersed solid pregabalin particles.Fig. 11 shows photographs of the surface of pigskin before, one hour after and two hours after treatment. After one hour, even 10% pregabalin formulation appears to be fully absorbed. The PGA1671118 composition of the present invention (WE-2 method) was combined with other commercially available creams containing dispersed particles (i.eAnd more advanced forms of Mometasone +>) Comparison was performed. The formulation (PGA 1671118) was "absorbed" in less than one hour, while the other two commercial formulations remained visible on the pigskin after 3 hours. After 3 hours, PGA1671118 had no visible deposition or crystallization under magnification. The experimental photograph is shown in fig. 12.
During our study we did not find any physical differences between the compositions that could explain the differences in effect. Neither the inventive composition nor the reference composition, which was homogenized with the HPH homogenizer, had liposomes. Our first expectation is that when lecithin is used, liposome structures should have been formed, which are expected to produce good absorption properties and long lasting pain relief. In contrast, neither the composition according to the invention homogenized with an HPH homogenizer nor the composition homogenized in a conventional mixing device showed liposome structures that were examined by electron microscopy. Furthermore, there was no significant difference between the different compositions in these experiments. PGA0450717 and PGA0470717 were tested by freeze fracture transmission electron microscopy (FF-TEM). The results do not show significant differences between the compositions. We only found that small particles and drug crystals of several μm in size were dispersed in the matrix of these two samples (FIG. 7).
Subsequently we tested our composition of PGA0450717 and PGA0470717 using SAXS (small angle X-ray scattering) method. The method is used to quantify nanoscale electron density differences in a sample. Fig. 9 shows the measured SAXS curves and fitted model functions for gel formulations PGA0450717 and PG 0470717. Samples PGA0450717 and PGA 0470717S The AXS curve does not show any peaks in the observed q range, indicating a regular periodic structure on the nanometer scale. The only feature that appears is at 0.7nm -1 <q<3nm -1 Is within the range of: the intensity increases from the monotonically decaying baseline. The baseline can be interpreted using PordLaw, a well-known feature in small angle scattering (Pord1951). Accordingly, the tail of the scattering curve of a three-dimensional object (e.g., nanoparticle) with a smooth surface follows a power law function of the-4 index. However, this behavior is not limited to near-spherical particles. Several other systems showed power law scattering with different indices (Schmidt 1991). Thus, we use the power law baseline to explain the contribution of components that can be resolved above SAXS (e.g., pregabalin crystallites, see FF-TEM images in fig. 7 above) and extend with a constant term, which is a common scattering characteristic of small molecule solvents (e.g., water).
As a first approximation, micelles can be regarded as a collection of spheres having a narrow size distribution and a uniform electron density inside them. Their scattering intensity can be calculated as follows:
wherein I/u Ball with ball body (q, r) is the scattering intensity of a sphere of homogeneous electron density having a radius r and a volume V,
Wherein is the scattering intensity of a single sphere of homogeneous electron density having a radius R and a volume V, and the size distribution function P (R, R 0 dR) is assumed to have an expected R 0 Gaussian distribution of values and half width dR.
Data fitted to the scatter plot of the micelle samples are shown in the table below.
Sample of PGA0450717 PG0470717
Power function background conversion coefficient (A) 0.003±0.001 0.004±0.002
Exponentiation background index (alpha) 2.990±0.328 2.813±0.338
Constant background (C; cm) -1 sr -1 ) 0.020 0.020
Micelle scattering contribution conversion coefficient (I) 0 )*100；(cm -1 sr -1 ) 0.028±0.004 0.021±0.005
Average radius of micelle (R 0 ；nm) 2.001±0.266 2.067±0.433
Average radius distribution parameter of micelles (dR; nm) 0.423±0.122 0.470±0.161
Within the experimental uncertainty, the micelle portion (R 0 dR) and the size and shape related parameters of the crystalline fraction (index alpha) are well matched, so that the relative component weight parameters (I) 0 And a). In the case of sample PGA0470717, the scattering contribution of the micelle (its relative weight against the power function background-parameter I 0 ) Smaller sizeI.e. the sample contains fewer micelles. All other parameters, especially the expected values for the size distribution of micelles, 2nm and half-widths near 0.45nm, match well for both samples.
Thus, it has been demonstrated that the difference between the effective and ineffective compositions of the present invention is due to a partial or complete reduction in the amount of micelles in the phospholipid-containing composition prepared by high shear mixing. The high shear forces cause the phospholipid micelles to fully or partially break down, thereby dispersing the phospholipids, which then no longer form the natural micelle form.
Since the SAX method is not suitable for giving absolute amounts of micelles or relative amounts of micelles to total phospholipids, only the production method can characterize the product of the invention. The nature of the invention can thus be broadly described as phospholipid, water and solvent, preferably water or C 1 -C 4 Any method of mixing monohydric alcohols or mixtures thereof with each other or with water in such a way that the phospholipids are present. It can be said that the mixing must be so strong that the phospholipid micelles cannot form or break down under the mixing forces used.
We also examined the effect of the number of HPH homogenization procedures. Surprisingly, it was found that one HPH homogenization produced a longer pain relief effect than the reference product that was not homogenized using the HPH homogenizer. The effect appears to be stronger after 3 or more HPH homogenization steps according to the following test:
the results of homogenizing the same quantitative composition 1, 3, 4, 9 times can be seen in fig. 2. There is some improvement as the number of HPH homogenizations increases. In the course of finding the program limit, we homogenized a similar composition HPH 125 times. The results show that the persistence effect does not disappear even after multiple HPH homogenization steps.
During the development of the present invention, we have surprisingly found that compositions having pregabalin content in a very broad range of 3% to 37.5% can achieve pain relief. Preferably, the pregabalin content ranges from 3 to 15%, more preferably from 3 to 10%, most preferably from 5 to 10%.
/>
Fig. 3 shows the comparison results of the compositions PGA1370718, PGA1450718 and PGA 1460718. All compositions were effective and based on one aspect of the results, it appeared that the effect was proportional to the dose. On the other hand, there is no significant difference between the effects of the compositions comprising 10% or 15% pregabalin. Both compositions had high pain relief at 30 minutes and remained at high levels for at least 5 hours. The effect of the composition containing 5% pregabalin is exerted more slowly. After one hour, the composition has a strong effect, which lasts at least 5 hours. The modifications of other ingredients may promote rapid absorption in comparison to compositions PGA1591018 and PGA 1601018. These compositions likewise act rapidly within 30 minutes and the effect lasts at least 5 hours. In addition, the composition with 37.5% pregabalin also has a long lasting effect. It is apparent that Gao Purui Balin content makes the composition more difficult to spread, but compositions according to the invention comprising a wide range of pregabalin concentrations can be used.
According to another embodiment of the invention, the process comprises not only homogenizing the lipid phase with a high shear mixing device, most preferably with an HPH homogenizer, but also an aqueous suspension of pregabalin. The lipid phase is then homogenized with a high shear mixing device, most preferably with an HPH homogenizer, and the aqueous dispersion is also homogenized, as shown in working example WE-5 below.
According to an advantageous embodiment of the invention, the process is carried out by preparing an aqueous mixture comprising dispersed pregabalin and phospholipids and optionally other excipients and homogenizing together with a high shear mixing device, most preferably with an HPH homogenizer, 1 to 125 times, preferably 3 to 10 times, more preferably 3 to 5 times.
The procedure can be specifically performed as follows: carbopol 980 was swollen in ten times the amount of purified water and then the pH was adjusted to 7.0 by adding aqueous ammonia solution. Lecithin (e.g., lipid P75) is then swollen in ten times the amount of purified water at 25-40℃, and then optionally other excipients such as isopropyl alcohol and DL-alpha-tocopherol are added to the mixture and homogenized with the aqueous dispersion of pregabalin. The thus prepared mixture of dispersed pregabalin and phospholipid is then homogenized with a high shear mixing device, most preferably with an HPH homogenizer 1 to 125 times, preferably 3 to 10 times, more preferably 3 to 5 times. The phase thus obtained, containing pregabalin and phospholipids, is mixed to a gel phase, and then preferably other excipients such as coconut oil, decyl oleate, EDTA and benzyl alcohol are added. Finally, if necessary, further rheology regulators are added.
According to another advantageous embodiment of the invention, the process is carried out by preparing a gelled aqueous mixture comprising dispersed pregabalin and phospholipids and optionally other excipients and homogenizing with a high shear mixing device, most preferably with an HPH homogenizer, 1 to 125 times, preferably 3 to 10 times, more preferably 3 to 5 times. Specifically, the procedure may be performed as follows: carbopol 980 was swollen in ten times the amount of purified water and then the pH was adjusted to 7.0 by adding aqueous ammonia solution. Lecithin (e.g., lipid P75) is then swollen in ten times the amount of purified water at 25-40℃, and then optionally other excipients such as isopropyl alcohol and DL-alpha-tocopherol are added to the mixture and homogenized with the aqueous dispersion of pregabalin. The mixture thus obtained is then mixed into the previously prepared gel phase and the composition thus obtained is homogenized 1 to 125 times, preferably 3 to 10 times, more preferably 3 to 5 times, with a high shear mixing device, most preferably with an HPH homogenizer. If necessary, other excipients such as coconut oil, decyl oleate, EDTA and benzyl alcohol are added to the composition. If necessary, finally, further rheology regulators are added.
Furthermore, we have surprisingly found that in the case of homogenizing a lipid phase with a high-pressure homogenizer and subsequently homogenizing the entire mixture containing pregabalin, the product thus obtained has an even stronger and longer lasting effect compared to a compound in which the lipid phase is homogenized by a high-pressure homogenizer:
Comparing the pain relieving effect of composition PGA1601018 (WE-2 method, results in fig. 3, where the lipid phase was homogenized only 5 times) with composition PGA2150619 (WE-4 method, results in fig. 4, where not only the lipid phase but also the entire composition (before addition of rheology modifier) was homogenized 5 times), WE found that the case of PGA2150619 was more potent after 30 minutes and the difference in stimulus intensity between the intact paw and the MPNL paw was significantly smaller after 5 hours under the same conditions than the case of PGA 1601018. Furthermore, we examined the effect of the particle size of pregabalin used. We have surprisingly found that micronized pregabalin has a stronger effect. During development, we compared the effects of compositions PGA2150619 and PGA 2211119. The only difference between the compositions was that PGA2211119 contained smaller, micronized pregabalin particles. Fig. 4 shows that smaller particle sizes of the product increase the effectiveness of the composition. Thus, in a preferred embodiment of the present invention, pregabalin used is micronized. According to a preferred embodiment of the invention, pregabalin used as starting material is milled, which means that pregabalin D is used 90 The particle size is less than 200 microns, preferably between 20 and 200 microns. More preferably micronized pregabalin is used as starting material, having a D of less than 20 microns 90 。
D 90 Is a parameter that gives a value of less than 90% of the particle size of the test substance, which can be determined by laser diffraction particle size measurement. In the experimental part giveThe measurement method is shown.
We have examined the duration of the effect of the composition of the invention. We have found that the compositions of the invention have a pain relieving effect longer than 5 hours, which is what we want to achieve. For example, we found that PGA2211119 had a significant pain-relieving effect even after 8 hours (fig. 5).
In the development of topical pregabalin formulations, it has been suggested to study not only the therapeutic effect of the target area, i.e. the reduction of mechanical hypersensitivity in the area of neuropathy, but also the systemic efficacy/effect. These studies were also performed in a mouse model of neuropathy. The treatment in these experiments was not applied to the neuropathic leg, but rather away from the other (left) hind leg or shaved back. In each case, the cream was applied by massaging for 1 minute, or until the cream was absorbed. The size of the therapeutic surface of the foot is about 2cm 2 And the size of the treatment surface of the upper back portion near the neck is about 2 or about 6cm 2 。
According to our experiments, topical administration of pregabalin has only a slight systemic effect using the above-described test methods. For example, at 2cm 2 The composition of PGA2211119 (5% pregabalin content) used at a dose of 20 μl on the surface of the MPNL paw had a significant and long lasting pain-relieving effect for 5 or even 8 hours (fig. 5). In applying 2.5 times the amount of the PGA2211119 composition (50 μl) of pregabalin experimental dose to the upper back of the mice, 2cm near the neck 2 On the surface, there was no significant pain relief effect on the MPNL paw. This suggests that no significant amount of pregabalin is absorbed in such a way that sufficient pregabalin is allowed to enter the blood stream, thereby eliciting a systemic pain relieving effect. Furthermore, even if 2.5 times the therapeutic dose is applied to the upper back of the mouse near the cervical region (which occupies a considerable part of the entire surface of the mouse) at 6cm 2 There is also no significant effect on the surface (see fig. 6).
Thus, the compositions of the present invention are effective in the treatment of neuropathic pain. According to our experiments on Wistar rats weighing about 280-300g, pregabalin 16.6mg/kg was administered Rats were given 4cm of CCI surgery and operated on the plantar surface of the rat 2 The superficial sensitivity of the sole of the nerve disease is shown. The hypersensitivity of the animal's paw quickly disappeared after the application of the 5-15% composition of the present invention, and the analgesic effect began to decline only after 5 hours, i.e., the analgesic effect of the composition was still significant even after 5 hours. It is also possible to apply the composition of the present invention in an amount of 33.3mg of 15% PGA0470717 or 50.0mg of 10% PGA2330320 or 100.0mg of 5% PGA1601018 to 4cm of the paw bottom 2 An area. Since topical administration of 16.6mg/kg of the composition of the present invention in rats remained effective for at least 5 hours, although oral administration of the same amount did not cause pain, indicating that less pregabalin is required than oral administration in the case of topical administration of the present invention. Since our pharmacokinetic experiments show that pregabalin enters the blood stream in very small amounts during topical treatment, it is expected that less pregabalin is needed in humans compared to oral administration and therefore no side effects of pregabalin occur except for the relief of neuropathic pain.
In summary, the composition of the present invention has a sustained pain relief effect by topical treatment with a pregabalin-containing composition and no systemic side effects. Thus, for patients receiving oral pregabalin treatment to relieve different types of pain, such as neuropathic pain, peripheral neuropathic pain, pain experienced by patients such as diabetic patients or patients already suffering from shingles (herpes zoster), and central neuropathic pain, such as pain experienced by patients already suffering from spinal cord injuries, diabetic neuropathy, causalgia, brachial plexus avulsions, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain and other forms of neuralgia, neuropathic pain and idiopathic pain syndrome, it may be an alternative, preferably for the treatment of neuropathy, diabetic neuropathy, peripheral neuropathic pain, post-herpetic pain, most preferably neuropathic pain, preferably peripheral neuropathic pain or post-herpetic neuralgia (PHN).
As we disclose above, a key feature of the present invention is that the composition contains phospholipids in a specific processed form as absorption enhancer, i.e. the phospholipids used, or at least a part thereof must be mixed and homogenized with solvent by using an HPH homogenizer or equipment which may provide a similar situation.
According to our studies, the high shear forces generated by the strong movement of the phospholipid-containing fluid change the phospholipid structure in the mixture, making the new structure stable for a long period of time and producing good absorption of pregabalin and prolonged pain relief effects even when pregabalin is dispersed in the composition. According to our theory, the number of micelles is significantly reduced due to the high shear effect of high shear mixing, most preferably HPH homogenization.
Accordingly, the present invention further provides a composition comprising pregabalin and a phospholipid, i.e. a topical pharmaceutical composition obtainable by: wherein the phospholipid and solvent-containing mixture is homogenized with a high shear mixing device, preferably an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, a bead mill, a slot homogenizer, a colloid mill, a high shear mixer, more preferably an HPH homogenizer, a microfluidizer, with an ultrasonic homogenizer, most preferably an HPH homogenizer, most preferably a high pressure homogenizer, and wherein the pregabalin is in dispersed form. According to the invention, the phospholipid may be homogenized at any stage of the process with a high shear mixing device, preferably an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, a bead mill, a slot homogenizer, a colloid mill, a high shear mixer, more preferably an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, most preferably an HPH homogenizer. Pregabalin may be added in an amount that is not completely dissolved in any step of the present invention. Thus, the insoluble fraction of pregabalin is dispersed as solid particles in the mixture.
Thus, our invention also relates to a process for the preparation of a topical pharmaceutical composition comprising pregabalin and a phospholipid, wherein
-homogenizing the phospholipid and the solvent or solvent mixture with a high shear effect of high shear mixing, most preferably a high pressure homogenizer, and mixing pregabalin with the composition, or
-mixing a phospholipid, a solvent and pregabalin and homogenizing the mixture thus obtained with a high pressure homogenizer, wherein
The composition thus obtained comprises pregabalin in dispersed form.
The preparation of such compositions comprising a mixture of phospholipids and solvents in addition to pregabalin (treated with the high shear effect of high shear mixing, most preferably with an HPH homogenizer or equipment capable of producing similar effects on the mixture and other excipients) can be carried out in several different procedures depending, for example, on the order of administration of the ingredients. In our experimental work, we found that the order of administration was inconsequential from the point of view of the results. For example, we can homogenize phospholipids with or without pregabalin or any other excipient. Essentially, before the end of the procedure, the phospholipid must be treated at least once, preferably 1 to 125 times, more preferably 3 to 10 times, most preferably 5 to 10 times, with HPH or a high shear mixing device with similar effect, at least in the presence of a solvent.
In a preferred embodiment, the composition of the invention comprises an additional rheology modifier. In other words, the compositions of the present invention may be formed into gels, creams or gel creams by adding rheology modifiers to the compositions.
The goal of our addition of rheology modifiers is to allow the cream, gel or gel cream to be applied topically as a liquid. In addition, the composition comprises dispersed pregabalin, and the dispersion is more easily stabilized in a composition comprising: rheology modifiers such as poloxamers, polyethylene glycols, synthetic polymers such as carbomers (polyacrylic acid), preferably carbomers 980, hydroxyalkyl celluloses, preferably hydroxyethyl celluloses, and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomers. If the gel phase is added to the composition prior to the high shear mixing, preferably HPH homogenization process, it may be necessary to add additional rheology modifiers to reform the gel, cream or gel cream form of the composition, as the high shear may disrupt the gel, cream or gel cream form.
More specifically, the topical pharmaceutical composition may be prepared in such a way that:
Homogenizing a mixture of phospholipids and a solvent, or a mixture of solvents and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding a rheology modifier and adding pregabalin and optionally other excipients to the mixture thus obtained, and homogenizing the mixture thus obtained, or a mixture of phospholipids and solvents, or
Homogenizing the mixture of solvent and optionally other excipients with a high shear mixer, most preferably with an HPH homogenizer, then adding pregabalin and optionally other excipients to the mixture thus obtained, and homogenizing the mixture thus obtained, then adding a rheology modifier, or
Homogenizing the mixture of phospholipids and solvent, or solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, and adding the mixture thus obtained to a mixture of pregabalin and optionally other excipients, which has been homogenized with a high shear mixer alone, most preferably with an HPH homogenizer, and then if necessary with a rheology modifier, or
Homogenizing the mixture of phospholipid and solvent, or solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding pregabalin and optionally other excipients to the phospholipid phase, then homogenizing the mixture thus obtained with a high shear mixer, most preferably with an HPH homogenizer, then adding rheology modifier, or
-homogenizing the mixture of phospholipid and solvent, or solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding pregabalin and optionally other excipients to the phospholipid phase, then homogenizing the mixture thus obtained with a high shear mixer, most preferably with an HPH homogenizer, then adding other rheology modifiers or excipients if necessary.
Our invention thus relates to the above-described method, e.g. in such a way
Homogenizing a mixture of phospholipids and a solvent, or a solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding a rheology modifier, and adding pregabalin and optionally other excipients to the mixture thus obtained, and homogenizing the mixture thus obtained, or
Homogenizing a mixture of phospholipids and a solvent, or a solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding pregabalin and optionally other excipients to the mixture thus obtained, and homogenizing the mixture thus obtained, then adding a rheology modifier, or
Homogenizing the mixture of phospholipids and solvent, or solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, and
adding the mixture thus obtained to a mixture of pregabalin and optionally other excipients, said mixture comprising pregabalin having been homogenized by means of an HPH homogenizer alone, and then adding a rheology modifier if necessary, or
Homogenizing the mixture of phospholipid and solvent, or solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding pregabalin and optionally other excipients to the phospholipid phase, then homogenizing the mixture thus obtained with a high shear mixer, most preferably with an HPH homogenizer, then adding rheology modifier, or
-homogenizing the mixture of phospholipid and solvent, or solvent mixture and optionally other excipients, with a high shear mixer, most preferably with an HPH homogenizer, then adding pregabalin and optionally other excipients to the phospholipid phase, then homogenizing the mixture thus obtained with a high shear mixer, most preferably with an HPH homogenizer, then adding other rheology modifiers or excipients if necessary.
According to another embodiment of the invention, the topical pharmaceutical composition is obtainable by a specific process which can be achieved in such a way that: homogenizing a mixture of phospholipids and a solvent, or a solvent mixture, pregabalin and optionally other excipients, and
homogenizing with a high shear mixer, most preferably with an HPH homogenizer, then adding a rheology modifier and optionally other excipients to the mixture thus obtained and then homogenizing, or
Adding a rheology modifier and homogenizing the composition thus obtained with a high shear mixer, most preferably with an HPH homogenizer, and then, if necessary, adding further excipients and homogenizing the mixture thus obtained.
Our invention thus relates to the above-described process, for example, wherein a mixture of phospholipids and a solvent, or a solvent mixture, pregabalin and optionally other excipients, is homogenized, and
then homogenizing with a high shear mixer, most preferably with an HPH homogenizer, then adding a rheology modifier and optionally other excipients to the mixture thus obtained and homogenizing, or
Adding a rheology modifier and homogenizing the composition thus obtained with a high shear mixer, most preferably with an HPH homogenizer, then if necessary adding further excipients and homogenizing the mixture thus obtained.
According to the invention, the topical composition is obtainable by a specific process wherein a mixture comprising a phospholipid, a solvent or a mixture of solvents and optionally pregabalin and other excipients is homogenized with a high pressure homogenizer at least 1 time, preferably 1 to 125 times, more preferably 3 to 10 times, most preferably 5 to 10 times.
Thus, the process for preparing a topical pharmaceutical composition may be carried out as described above, wherein the process comprises a high shear mixing process, most preferably HPH homogenization of a phospholipid, a solvent or a mixture of solvents and optionally a mixture of pregabalin and other excipients, wherein high pressure homogenization is carried out at least 1 time, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times.
According to the invention, the topical pharmaceutical composition obtainable by the method according to the invention comprises more than 2.5% by weight of pregabalin and 0.1-5% by weight of high pressure homogenized phospholipid, and pregabalin is in the composition in dispersed form.
More specifically, according to the present invention, the topical pharmaceutical composition obtainable by the method according to the present invention comprises 2.5-40 wt. -%, preferably 3-20 wt. -%, more preferably 3-15 wt. -%, most preferably 5-10 wt. -% pregabalin and 0.1-3 wt. -%, preferably 0.1-1.5 wt. -%, most preferably 0.1-1.2 wt. -% of phospholipids, wherein the pregabalin is in dispersed form.
Thus, in the method, more than 2.5% by weight of pregabalin is added to the composition, and 0.1-5% by weight of phospholipid is added and homogenized with an HPH homogenizer. According to a preferred embodiment of the invention, the mixture thus obtained is formed into a gel, cream or gel cream form.
More specifically, the method according to the invention is carried out in such a way that: 2.5-40 wt%, preferably 3-20 wt%, more preferably 3-15 wt%, most preferably 5-10 wt% pregabalin is added, and 0.1-3 wt%, preferably 0.1-1.5 wt%, most preferably 0.1-1.2 wt% phospholipid is added and homogenized with HPH equipment. According to a preferred embodiment of the invention, the mixture thus obtained is formed into a gel, cream or gel cream form.
As we mention above, the topical pharmaceutical composition obtainable by the method according to the invention may comprise other excipients, for example 40-90 wt%, preferably 70-90 wt%, most preferably 75-85 wt% of a solvent, 0-20 wt%, preferably 0.1-20 wt%, more preferably 2-15 wt%, most preferably 3-10 wt% of a softening agent, 0-20 wt%, preferably 0.1-20 wt%, more preferably 2-15 wt%, most preferably 3-10 wt% of a penetration enhancer, 0-20 wt%, preferably 0.1-20 wt%, more preferably 0.1-20 or 0.1-5 wt%, even more preferably 0.1-2 wt%, most preferably 0.2-0.5 wt% of a rheology modifier or a mixture thereof.
For the preparation of the topical composition according to the invention, the excipients mentioned above may preferably be used. More preferably, the topical composition according to the invention can be obtained by the above-described method using the above-described excipients.
Thus, according to the present invention, we can preferably use, in order to prepare a topical composition according to the above method
Natural or synthetic phospholipids, preferably lecithin, more preferably soy lecithin, de-oiled soy lecithin, lipid P75, lipid S75, as phospholipids,
water, pharmaceutically acceptable C 2 -C 4 Alcohols, more preferably ethanol, propanol, isopropanol, n-butanol, isobutanol, alcohols having more than one hydroxyl group, preferably glycerol, propylene glycol, more preferably ethanol or isopropanol or mixtures thereof, as solvents,
vitamins A, D and E, lanolin alcohols, propylene glycol dibenzoates, vegetable oils, vegetable extracts, fatty alcohol esters, fatty acid esters, fatty alcohols, synthetic polymers, silicon compounds, fatty acids, mineral oil derivatives, waxes or mixtures thereof, most preferably fatty acid esters such as cetyl palmitate, fatty alcohols such as octyldodecanol, fatty acid derivatives such as decyl oleate, vegetable oils such as coconut oil as softeners,
C 2 -C 4 Alcohols, DL-alpha-tocopherols or mixtures thereof, as penetration enhancers other than phospholipids,
EDTA, EDTA derivatives, aromatic preservatives such as parahydroxybenzoate, thimerosal, chlorhexidine benzyl alcohol and benzalkonium chloride, preferably benzyl alcohol, more preferably a mixture of benzyl alcohol and EDTA, as a preservative,
poloxamers, polyethylene glycols, synthetic polymers such as carbomers (polyacrylic acid), preferably carbomers 980, hydroxyalkyl celluloses, preferably hydroxyethyl celluloses, and vegetable gums, preferably xanthan or guar gums, carbomers, as rheology modifiers,
preferably a basic pH adjuster, more preferably ammonia, an ammonium solution, an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, or an organic base such as a primary, secondary or tertiary amine, most preferably an aqueous ammonia solution, as pH adjuster.
The topical compositions of the present invention may be prepared by a process wherein
-homogenizing a mixture of phospholipid and solvent (preferably water or a mixture of water and alcohol, more preferably ethanol or isopropanol, most preferably water and isopropanol) and optionally other excipients (preferably softeners, preferably octyldecane alcohol and/or penetration enhancers, preferably DL- α -tocopherol) with a high shear mixing device, most preferably with an HPH homogenizer preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case of using an HPH homogenizer the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, then adding the mixture thus obtained to the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier (preferably aqueous ammonium solution) if necessary, then mixing pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA into the mixture thus obtained and homogenizing, or
-homogenizing a mixture of phospholipids and a solvent (preferably water or a mixture of water and an alcohol, more preferably ethanol or isopropanol, most preferably a mixture of water and isopropanol) and optionally other excipients (preferably softeners, preferably octyl decane alcohol and/or penetration enhancers, preferably DL- α -tocopherol) with a high shear mixing device, most preferably with an HPH homogenizer preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case an HPH homogenizer is used the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, then mixing pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA solution into the mixture thus obtained, then adding the mixture thus obtained into the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, in a solvent, preferably water, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980, and adjusting the pH of the gel phase with a pH modifier, preferably with an aqueous ammonium solution, if necessary, or
-homogenizing a mixture of phospholipid and solvent (preferably water or a mixture of water and alcohol, more preferably ethanol or isopropanol, most preferably a mixture of water and isopropanol) and optionally other excipients (preferably softeners, preferably octyl decane alcohol and/or penetration enhancers, preferably DL-alpha-tocopherol) with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case of using an HPH homogenizer, the pressure used is between 500 and 2000 bar, preferably between 500 and 1500 bar, most preferably 1000 and 1500 bar, and mixing the mixture thus obtained into a mixture of pregabalin and solvent, preferably water and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably an aqueous EDTA solution, said mixture having been homogenized with a high shear mixing device alone, most preferably with an HPH homogenizer, 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case of using an HPH homogenizer, the pressure between 500 and 1500 bar, most preferably between 500 and 1500 bar, and 500 bar, most preferably between 500 and 1500 bar
The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent (preferably water), and adjusting the pH of the gel phase with a pH modifier (preferably an aqueous ammonium solution) if necessary, or
-homogenizing a mixture of phospholipids with a solvent (preferably water or a mixture of water and an alcohol, more preferably ethanol or isopropanol, most preferably a mixture of water and isopropanol) and optionally other excipients (preferably a softener, preferably octyl decane alcohol and/or penetration enhancer, preferably DL-alpha-tocopherol) with a high shear mixing device, most preferably with an HPH homogenizer preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case an HPH homogenizer is used the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, then
Adding pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, to the lipid phase, then
The mixture thus obtained is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in the case of using an HPH homogenizer the pressure used is between 500 and 2000 bar, preferably between 500 and 1500 bar, most preferably 1000-1500 bar, and the mixture thus obtained is then added to the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent (preferably water), and adjusting the pH of the gel phase with a pH modifier (preferably an aqueous ammonium solution) if necessary, or
-homogenizing a mixture of phospholipids with a solvent (preferably water or a mixture of water and an alcohol, more preferably ethanol or isopropanol, most preferably a mixture of water and isopropanol) and optionally other excipients (preferably a softener, preferably octyl decane alcohol and/or penetration enhancer, preferably DL-alpha-tocopherol) with a high shear mixing device, most preferably with an HPH homogenizer preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case an HPH homogenizer is used the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, then
The mixture thus obtained was added to the gel phase prepared as follows: the rheology modifier, preferably polyethylene glycol, synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 is swollen in a solvent (preferably water) and if necessary the pH of the gel phase is adjusted with a pH modifier (preferably with an aqueous ammonium solution), then pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA are added to the phospholipid phase, the mixture thus obtained is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in the case of using an HPH homogenizer the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, and then if necessary the other rheology modifier or excipient is added to the mixture.
According to a preferred embodiment, the topical composition of the present invention may be obtained by a process wherein
Homogenizing a mixture of phospholipids, pregabalin and a solvent or solvent mixture (preferably water or a mixture of water and an alcohol, more preferably a mixture of water and ethanol or isopropanol, most preferably a mixture of water and isopropanol) and optionally other excipients (preferably a softener, preferably octyldecane alcohol and/or penetration enhancer, preferably DL-alpha-tocopherol) with a high shear mixing device, most preferably with an HPH homogenizer preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and in case an HPH homogenizer is used the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, then
-adding the mixture thus obtained to a gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent (preferably water), and if necessary adjusting the pH of the gel phase with a pH modifier (preferably with an aqueous ammonium solution), adding the rheology modifier and optionally other excipients to the mixture thus obtained and homogenizing, or
Homogenizing a mixture of phospholipids, pregabalin and a solvent or solvent mixture (preferably water or a mixture of water and an alcohol, more preferably a mixture of water and an alcohol or an isopropyl alcohol, most preferably a mixture of water and isopropyl alcohol) and optionally other excipients (preferably a softener, preferably octyldecane alcohol and/or penetration enhancer, preferably DL-alpha-tocopherol) with an HPH homogenizer at a pressure of 500-2000 bar, preferably between 500-1500 bar, most preferably between 1000-1500 bar, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, then
The mixture thus obtained was added to the gel phase prepared as follows: the rheology modifier, preferably poloxamer, polyethylene glycol, synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980, is swollen in a solvent (preferably water) and if necessary the pH of the gel phase is adjusted with a pH modifier (preferably an aqueous ammonium solution) and the thus obtained composition is homogenized preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times with a high shear mixing device, and in case a HPH homogenizer is used the pressure used is between 500-2000 bar, preferably between 500-1500 bar, most preferably 1000-1500 bar, then if necessary further excipients are added and the thus obtained mixture is homogenized.
The HPH homogenization process is critical to the preparation of the present invention. During our experimental work we use a pressure range between 500-2000 bar, more preferably 500-1500 bar, most preferably 1000-1500 bar.
The homogenization process was performed by an EmulsiFlex-C3 homogenizer manufactured by AVESTIN, inc (2450Don Reid Drive,Ottawa,ON, canada, K1H 1E 1) and followed by the manufacturer's instructions. Basically, a sample is placed in a sample chamber and then the homogenizer is activated. Typically, a homogenization pressure of 1000-1500 bar is used, but the procedure may also be carried out at 2000 bar. After homogenization is complete, the sample is returned to the sample chamber for further homogenization, if necessary. As described above, the homogenization was repeated 1 to 125 times. In the case of homogenizing the mixture several times, it may be useful to conduct the pre-homogenization with a lower homogenization pressure between 500 and 800 bar for the first two homogenization steps. The applicable pressure also depends on the geometry of the device and can be determined by one skilled in the art having knowledge of the device. Of course, the disruption and disintegration of micelles by other comminution equipment well known in the pharmaceutical and food industry is illustrated by the use of five devices in example WE-4/B. According to our experiments, each formulation had a significant effect even at the fifth hour after treatment. The application and use of the individual high shear mixing devices and the optimization of the application parameters are within the general knowledge of those skilled in the art.
If the high shear mixing device is used multiple times during the preparation process, different types of mixers can be used in each step.
Batch mixing devices used in embodiments of the present invention. If they are carried out in a recirculation apparatus, in which they are sent from a stirred tank to a high-shear mixer/homogenizer and the resulting mixture is then sent back to the mixing tank, the mixing time required for mixing all the substances at once in the case of batch operation can be calculated from the amount of mixture mixed. Multiplying it by the number of agitations required to properly homogenize a given composition in the case of a batch operation. However, due to the geometry and mixing properties of the storage tank, the experience of the homogenization process is that in such cases, complete homogenization generally requires a longer time than previously calculated, just because the already homogenized product is mixed with the not yet homogenized material. This is typically 1.5-2 times the time, but it depends to a large extent on the geometry of the storage tank used and the efficiency of the agitators used therein, as well as the prevailing flow conditions there. Those skilled in the art will be able to transfer the method of the present invention to such an apparatus based on their general knowledge.
The method for preparing the topical composition can be accomplished by using equipment commonly used in the pharmaceutical industry. The selection and use of these devices forms part of the knowledge of those skilled in the art. Optimization of the process for the available equipment is also part of the knowledge of those skilled in the art. Other information about the technical steps used is generally described, for example, in Encyclopedia of Pharmaceutical TTechnical, third edition ]Informa Healthcare USA, inc.). Different types and operating parameters of the high-pressure homogenizers and the use thereof are also described in Encyclopedia of Pharmaceutical Technology, third edition ()>Informa Healthcare USA, inc.) is fully described in chapter 1996-2003. The selection, use and optimization of use of any of the different commercially available high pressure homogenizers is part of the knowledge of those skilled in the art.
According to a more preferred embodiment of the present invention, the composition can be obtained by the above-described method by using milled pregabalin as an active ingredient. More preferably micronized pregabalin is used. Thus, the pregabalin used is preferably milled with a particle size D of milled pregabalin between 20-200 microns 90 More preferably the pregabalin used is micronized to have a particle size D below 20 microns 90 。
In the process of the present invention pregabalin may be added to the composition in solid form, as a powder or even as a suspension during the preparation of the composition.
In a preferred embodiment of the invention the temperature of the mixture of the invention during HPH homogenization is maintained between 0 and 50℃, preferably 20 and 45℃, most preferably 25 and 35℃, considering that the temperature increase will alter the pregabalin in the solvent and that the high shear mixing process involving HPH homogenization involves heat generation.
According to a preferred embodiment of the invention, the phospholipids are swelled before use. Thus, according to the present invention, a mixture of phospholipids is prepared by swelling the phospholipids, preferably lecithin, more preferably soy lecithin, de-oiled soy lecithin, lipid P75, lipid S75 with water in an amount of 10-30 times, preferably 1-20 times the weight of the phospholipids, and mixing the thus obtained swollen phospholipids with other excipients to form a lipid phase.
In a preferred embodiment, the phospholipids are swollen in 5-25 times, preferably 10-20 times (based on the weight of phospholipids used) water at a temperature between 25-40 ℃, preferably between 25-35 ℃, and the so obtained swollen mixture is then used as a phospholipid mixture. The swelling process takes from 0.1 to 24 hours, preferably from 0.3 to 3 hours. In a preferred embodiment, the mixture may be homogenized directly with a high shear mixing device, most preferably with a high pressure homogenizer, or other excipients such as softeners and penetration enhancers may be added prior to the high shear mixing process, most preferably high pressure homogenization, and then homogenized by the high pressure homogenizer. According to another embodiment, the thus obtained swollen phospholipid mixture may be mixed and homogenized together with other excipients and pregabalin, and the thus obtained mixture is homogenized with a high shear mixing device, most preferably with a high pressure homogenizer. According to a most preferred embodiment of the present invention, the swollen phospholipid mixture is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, then added to the gel phase, the mixture thus obtained is mixed with an aqueous dispersion of pregabalin, and the composition thus obtained is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times.
Similarly, preferably, the gel phase is also prepared by swelling a gel and then adding the so swollen gel phase to the composition. More specifically, the gel phase was prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent (preferably water), wherein a 10-30 times, preferably 1-20 times the weight of the rheology modifier is used in an amount of solvent (preferably water), and adjusting the pH of the gel phase with a pH modifier if necessary. The swelling process takes from 6 to 24 hours, preferably from 8 to 12 hours.
In a preferred embodiment, the gel phase is prepared by swelling the rheology modifier with 5-25 times, preferably 10-20 times, calculated on the weight of rheology modifier used. As rheology modifiers polyethylene glycols, synthetic polymers such as carbomers (polyacrylic acid) and vegetable gums are used, preferably carbomers, most preferably carbomers (carbomer 980). Optionally, the pH of the gelled mixture thus obtained is neutralized by adding a pH adjuster. In the case of carbomers, most preferably carbomer 980, an alkaline pH adjustor is used. Such pH adjusting agents may be used, for example ammonia, ammonium solutions, preferably ammonium aqueous solutions, alkali or alkaline earth metal hydroxides, carbonates, bicarbonates or organic bases such as primary, secondary or tertiary amines, most preferably aqueous ammonia solutions. According to the most preferred procedure, carbomer 980 is swollen in ten or twenty times the weight (based on Yu Kabo m) of water at room temperature for 3-24 hours, preferably 3-12 hours, more preferably 5-8 hours, and the gelled mixture is then neutralised with an aqueous ammonia solution at room temperature.
In the case of vegetable gums, preferably xanthan gums, the gums are swollen in ten or twenty times by weight (based on the weight of the vegetable gums) of water, preferably the xanthan gums are swollen at a high temperature between 40 and 100 ℃, preferably between 50 and 70 ℃, more preferably 60 ℃, and the mixture thus obtained is then cooled to room temperature and homogenized. In the case of using hydroxyalkyl cellulose, preferably hydroxyethyl cellulose, the hydroxyalkyl cellulose is swollen in ten or twenty times by weight (based on the weight of the hydroxyalkyl cellulose) of water, preferably hydroxyethyl cellulose is swollen at a high temperature of 37℃between 35 and 40℃and then the mixture thus obtained is cooled to room temperature (25 ℃) and homogenized. In the case of poloxamer, preferably poloxamer 407, the poloxamer is swollen in water, then kept in a refrigerator between 5-10 ℃ for 24 hours, then it is warmed to room temperature.
The neutralized gel thus obtained may be added to the mixture comprising phospholipids before or after homogenization with HPH. Alternatively, the gelled mixture thus obtained may be mixed with pregabalin or a mixture comprising pregabalin before or after the HPH homogenization process, or the gelled mixture may be added to a mixture comprising phospholipids and pregabalin before or after the high pressure homogenization step.
The topical pharmaceutical composition according to the invention can be used for the treatment of neuropathic pain, peripheral neuropathic pain, such as pain experienced by diabetic patients or patients already suffering from shingles (herpes zoster), and central neuropathic pain, such as pain experienced by patients already suffering from spinal cord injury; diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain and other forms of neuralgia, neuropathic pain and idiopathic pain syndromes, preferably for the treatment of neuropathy, diabetic neuropathy, peripheral neuropathic pain, post-herpetic pain.
According to the invention, in the composition, the phospholipids are dispersed and the solid pregabalin particles are also dispersed. The dispersed phospholipids are emulsions. The composition is formed into a gel, cream or gel cream form by adding a rheology modifier. The solid form of pregabalin may be crystalline or amorphous.
The advantage of the present invention over prior art compositions is that the topical pharmaceutical composition according to the present invention has a durable pain relief effect for at least 5 or 8 hours without severe systemic effects. It can be used on large surfaces of the body, which is important in the case of treatment of neuropathic pain.
Another advantage of the present invention is that the obtained composition has a long shelf life. The composition is stable at room temperature for even more than one year. Surprisingly, the effect of HPH homogenization persists for a long time.
The composition has no serious systemic effects, which is very important in the case of treatment of diabetic neuropathy (DPN), where the affected body surface can reach about 28% of the body surface.
The compositions obtained by the present invention will result in an eight hour sleep stage in patients with neuropathic pain.
The figure:
FIG. 1Plantar recession threshold diagram in NMRI mice 7 days after MPNL surgery:
PGA 2180719 (pregabalin 2.5%,50 μl/right paw, values mean ± s.e.m., n=6), double paw
PGA 2190719 (pregabalin 5%,20 μl/right paw, values mean ± s.e.m., n=7), double paw
PGA 0450717 (pregabalin 15%,50 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 0470717 (pregabalin 15%,50 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1601018 (pregabalin 5%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1601018 (pregabalin 5%,20 μl/right paw, values mean.+ -. S.E.M.), MPN ligated paw
Fig. 2:plantar recession threshold profile in NMRI mice 7 days after MPNL surgery:
PGA 0980418 (pregabalin 15%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 0990418 (pregabalin 15%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1000418 (pregabalin 15%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1040418 (pregabalin 15%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1040418 (pregabalin 15%,20 μl/right paw, values mean.+ -. S.E.M.), MPN ligated paw
PGA 1510918 (pregabalin 10%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1510918 (pregabalin 10%,20 μl/right paw, values mean.+ -. S.E.M.), MPN ligated paw
FIG. 3Plantar recession threshold diagram in NMRI mice 7 days after MPNL surgery:
PGA 1591018 (pregabalin 10%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1601018 (pregabalin 5%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
PGA 1520918 (pregabalin 37.5%,20 μl/right paw, values mean.+ -. S.E.M.), double paw
Comparative plantar recession threshold profile in NMRI mice 7 days after MPNL surgery:
Comparison of effects of PGA1460718 (5%), PGA1450718 (10%), PGA1370718 (15%) (20 μl/right paw, values mean ± s.e.m.), MPN-ligated paw
Fig. 4:plantar recession threshold profile in NMRI mice 7 days after MPNL surgery:
PGA 2211119 (pregabalin 5%,20 μl/right paw, values mean ± s.e.m., n=7), double paw
PGA 2150619 (pregabalin 5%,20 μl/right paw, values mean ± s.e.m., n=6), double paw
Fig. 5:plantar recession threshold profile in NMRI mice 7 days after MPNL surgery:
PGA 2211119 (pregabalin 5%,20 μl/right paw, values mean ± s.e.m., n=8), double paw
PGA 2211119 (pregabalin 5%, 50. Mu.l/2 cm) 2 On the skin near the upper back of the neck, the values are mean ± s.e.m., n=8), double claw
Figure 6 is a graph of plantar recession threshold in NMRI mice 7 days after MPNL surgery:
PGA 2211119 (pregabalin 5%, 50. Mu.l/6 cm) 2 On the skin near the upper back of the neck, the values are mean ± s.e.m.), double claw
FIG. 7 FTEM test images of PGA0470717 and PGA0450717
FIG. 8 shows an EmulsiFlex-C3 high pressure homogenizer.
FIG. 9 schematic representation of plantar recession threshold in rats 21 days after CCI surgery (5 mg pregabalin/4 cm) 2 In 50 μl of 10% cream). Values are mean ± s.e.m., n=15 two-factor Bonferroni p<0.0001 (example 3).
FIG. 10 results of formalin test of neuropathic pain in rats.
Fig. 10/a: in the total time of the trial and the second phase of the trial (from 16 to 45 min), the average ± s.e.m. of the sum of pain scores of 0.1 ml/paw with the P-1 (PGA 0440717) placebo composition and R-3 (PGA 0450717) reference gel used at 0.1 ml/paw.
Fig. 10/B: during the total time of the trial and the second phase of the trial (from 16 to 45 min), the average ± s.e.m. of the sum of pain scores of 0.1 ml/paw with the P-2 (PGA 0460717) placebo composition and WE-1 (PGA 0470717) reference gel used at 0.1 ml/paw.
Fig. 11: absorption of pregabalin cream from the surface of the topically treated isolated pig skin.
Photographs of pigskin surface prior to treatment.
Photographs of pigskin surfaces immediately after treatment with a gel containing 5% pregabalin (left side of PGA 1601018 (WE-2)) and a gel containing 10% pregabalin (right side of PGA 1591018 (WE-2)).
Photographs of the pigskin surface 1 hour after treatment with gel (PGA 1601018 (WE-2) left side) and (PGA 1591018 (WE-2) right side).
Photographs of the pigskin surface 3 hours after treatment with the gel (left side of PGA 1601018 (WE-2)) and (right side of PGA 1591018 (WE-2)).
Microphotographs of pig skin surface prior to treatment (1:10).
Microphotographs (1:10) of pigskin surface 2 hours after treatment with gel (PGA 1601018 (WE-2) left side) and (PGA 1591018 (WE-2) right side).
FIG. 12 andand Mometasone->In contrast, the absorption of pregabalin cream by topically treated ex vivo pigskin.
12-I photograph of pigskin surface prior to treatment.
12-II in the presence of a gel containing 5% pregabalin (PGA 1671118 left side, column A),(column B) and Mometasone->Photographs of the pigskin surface immediately after (column C) treatment.
12-III in the presence of a gel containing 5% pregabalin (PGA 1671118 left side, column A),(column B) and Mometasone->Photographs of the pigskin surface 1 hour after the (C column) treatment.
12-IV on gel with 5% pregabalin (PGA 1671118 left side, column A),(column B) and Mometasone->Photographs of the pigskin surface 3 hours after the (C column) treatment.
Fig. 13: comparison of different high shear mixing devices:
13/a PGA 2310320 (WE-4, HPH) vs AL 2980521 (WE-4/B, IKA colloid mill) vs AL 2990521 (WE-4/B IKA high shear mixer) plantar recession threshold MPNL mean.+ -. S.E.M. (group 6-7 mice) dose 10 μl/paw, 5% pregabalin composition, two-factor analysis of variance, dunnett vs 0: p <0.06 primary column effect: 231/299:p <0.06
AL 3010521 (WE-4/B, SONIC SVCX-500Ultrahangos k szek) plantar recession threshold MPNL mean ± S.E.M. (group 6 mice) dose lOf.ll/paw, 5% pregabalin composition, two-way RM ANOVA, bonferi 0:. P <0.05
13/C13/a AL 2970521 (WE-4/B, DYNO mill) vs AL 3020521 (WE-4/B microfluidizer) plantar recession threshold MPNL mean.+ -. S.E.M. (group 7-9 mice) dose 10 μl/paw, 5% pregabalin composition, two-factor analysis of variance, dunnett vs 0:. P <0.05, effect of homogenization type 231vs 297: +p <0.05
FIG. 14: the SAXS curves of samples PGA0450717, PGA0470717 and the curve of the fitting function.
Fig. 15: stephan UMC 5 electronic homogenizer, 15/a top view, 15/B top view with doctor blade and 15/C schematic.
Our invention is illustrated in more detail by the following examples, but the scope of our invention is not limited to these examples:
example 1.
Mouse model of neuropathic pain
Animals
Experiments were performed in NMRI male mice (Toxi-Coop Ltd). The initial weight of the animal is between 25-35 g. All animals were housed in plastic cages under standard laboratory conditions (24±2 ℃ room temperature, 40-60% relative humidity) with the mice free of standard laboratory feed (standard laboratory pellet) and tap water. They were kept for a 12-hour light/dark period, starting light at 06:00 am. Animals were transferred to the laboratory at least 1 hour prior to the experiment and used only once. Animal care and testing procedures were performed according to European agenda 2010/63/EU instructions and Hungary 1998 XXVIII animal protection welfare (Act on the Protection Welfare of Animals).
Method
Plantar medial nerve ligation (MPNL) model
Under chloral hydrate anesthesia (400 mg/kg intraperitoneally), the skin (0.5 cm length) on the medial surface of the right ankle of the mouse was incised to expose the plantar medial nerve. After exposing the nerve, the nerve was ligated twice with 5-0 wire (Seralon, SERAG-WIESSNER, germany). The ligation is by being firmly tied to the nerves without throttling them. The wound was then closed with 4-0 silk.
Nociceptive assay
One week after the plantar medial nerve ligation, animals were placed one by one in small (12 x15 cm) plastic cages with wire mesh floor. The cage is lifted and illuminated from below. After a long adaptation period of at least 30 minutes, basal plantar recession threshold (PWT) was assessed on the left and right hind paws using von Frey filaments (Touch-Test Sensory Evaluators, north Coast Medical inc. Briefly, a set of 8 calibrated monofilaments providing an approximately logarithmic scale of actual force (von Frey filament sizes: 0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, and 1.0 g) was used to determine the threshold stiffness of the filaments necessary to elicit a paw withdrawal response. First, for baseline determination, three measurements were made using ascending series of wires, then two measurements were made at the following time points. Animals that did not exhibit mechanical hyperalgesia at baseline measurement were excluded from the trial. After baseline measurement, the test material is administered topically, intraperitoneally, or orally. PWT measurements were repeated for each hindpaw 0.5, 1, 3 and 5 (6, 7, 8 in longer experiments) hours after application of the test material.
Measured parameters
Von Frey filament size that causes paw withdrawal behavior. Plantar recession threshold is the average of the recession behavior in grams of induced silk size/time point.
Statistical analysis
Two-way anova and subsequent Bonferroni's post hoc test were used to compare double sided PWT-values at all time points. One-way analysis of variance with repeated measurements and subsequent Dunnett's test were used to compare PWT data on one side (relative to the base). P <0.05 was considered significant.
Example 2.
Investigation of systemic Effect topical compositions for use in mouse models of neuropathic pain
The method comprises the following steps:
our study was performed in a mouse model of neuropathy (according to example 1), in which neuropathic symptoms were caused by surgery on the right hind leg (plantar medial nerve ligation, MPNL). The mechanical hypersensitivity characteristics of neuropathy occur within a week as a result of surgery. The sensitivity of the right sole increases after surgery, which can be verified with Von Frey fibres. The fibers may be used to determine a plantar recession threshold (PWT) for the hind leg. After determining the basal sensitivity of the hind sole, we treated the selected area-left leg or upper back near neck (massage for up to 1 min). After the treatment: at 1/2, 1, 3 and 5h, the lift thresholds for both hind legs were again determined.
Example 3.
Role of topical pregabalin cream in rat model of neuropathy
Animals
Animals were housed in plastic cages under standard laboratory conditions (24±2 ℃,40-60% relative humidity) with the rats free of standard laboratory feed and tap water. They were kept for a 12-hour light/dark period, starting light at 06:00 am.
Method
Chronic Constrictive Injury (CCI) model:
peripheral neuropathy was experimentally induced by the procedure described by Bennett and Xie (Bennett GJ, xie YK. Paint., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man 4 months 1988; 33 (1): 87-107). Briefly, under isoflurane anesthesia, the skin of the right thigh of the rat was subjected to blunt dissection and then three loose contractile ligatures (chronic constrictive injury CCI) were placed around the total sciatic nerve. Three weeks after nerve injury, rats were evaluated for hindpaw withdrawal threshold. The Paw Withdrawal Threshold (PWT) was determined using a Electronic von Frey apparatus according to Dixon's modified methods of up and down (Efficient analysis of experimental observals, annu Rev Pharmacol Toxicol.1980; 20:441-62). There should be at least a 20g difference between the left and right PWT post-surgery. Animals that did not show significant differences between the left and right PWT after surgery were excluded from the experiment.
Different doses of topical pregabalin formulations were used to evaluate the improvement in hypersensitivity reactions caused by CCI-induced neuropathic pain.
Results:
a significant drop in PWT (paw withdrawal threshold) was measured following CCI-induced neuropathy (basal). No significant difference was detected between the intact paw and the injured paw after administration of 50 μl of 10% pregabalin cream (PGA 2330320).
The dosage is as follows: 5mg of pregabalin/4 cm2 in 50. Mu.l of 10% cream.
The data of fig. 9: foot retraction threshold in rats 21 days after CCI surgery (5 mg pregabalin/4 cm) 2 50 μl of 10% cream), mean ± SEM, bipedal n=15 (two-factor anova, bonferroni's p<0.05,****p<0.0001)
PGA2330320 Intact leg Intact leg CCI surgical leg CCI surgical leg Number of rats
T Average of SEM Average of SEM n
Foundation 95.17 3.04 58.35 4.29 15
+1h 83.50 4.62 81.67 4.28 15
+3h 89.61 5.07 81.76 6.32 15
+5h 96.79 6.39 76.57 5.66 15
Although oral administration of 16.66mg/kg resulted in relatively high blood levels based on pharmacokinetic studies, this amount of pregabalin did not reduce hypersensitivity reactions. ( Topical pregabalin cannot reduce systemic hypersensitivity with high blood levels. It has a local effect. )
Example 4
Effect of pregabalin cream for topical application in a rat model of formalin-induced neuropathy
The method comprises the following steps:
As a result of injecting formalin into the hind paws of rats, we found a two-stage pain response in animals, scored according to their behavior: the first stage is direct tissue damage of formalin, which lasts about 10 minutes, and after a short resting period (5 minutes) the animal experiences a second severe pain due to leg inflammation, which can last for up to 1-1.5 hours. The trial was developed for testing non-steroidal anti-inflammatory drugs (NSAIDs) which primarily inhibit the second phase, but the trial has also proven to be useful for testing drugs for the treatment of neuropathic pain. (A Ellis: the rat formalin test: can it predict neuropathic pain treatmentsProceedings of Measuring Behavior 2008.).
Animals:
our experiments were performed on male Wistar rats weighing 240-300 g.
Experiment:
0.1ml of the test composition was applied to the right hind paw of the animal and the animal's foot was wrapped with Folpack (occlusion treatment). After treatment, the rats were placed in 18cm diameter, 40cm high glass cylinders suitable for observing their behavior. After 55 minutes, the Folpack of the leg was removed and placed back into the cylinder. After a further 5 minutes, 0.05ml of 1% formalin solution was subcutaneously injected into the plantar surface of the treated (right posterior) leg.
We began to observe the pain behavior of the animals immediately and every minute for 45 minutes. For each minute, the score for the most severe pain behavior during this period was determined based on the following criteria:
0 point: the formalin-injected claw can bear its own weight,
1, the method comprises the following steps: when the injected foot is loaded less, only the foot can be relaxed, the weight is kept on the opposite limb when moving,
2, the method comprises the following steps: the treated foot is kept lifted, so that it is not in contact with the substrate,
3, the method comprises the following steps: licking, biting, shaking the injected foot.
The score obtained in this way was evaluated in two ways: scores over 45 minutes were added together (total time) and data between 16 and 45 minutes were added (phase 2). Statistical evaluation was performed using Student's t-test.
Measurement:
the P-1 placebo gel (PGA 0440717) was compared to the R-3 (PGA 0450717) reference composition containing 15% pregabalin according to the protocol described above. Two compositions were tested in groups of 8-8 rats by treating each animal with 0.1ml of P-1 placebo composition or 0.1ml of R-3 gel.
WE also compared placebo composition P-2 (PGA 0460717) according to the above protocol with the inventive composition containing 15% pregabalin prepared by WE-1 method (PGA 0450717). Two compositions were tested in groups of 8-8 rats by treating each animal with either 0.1ml of P-2 placebo gel or 0.1ml of WE-1 gel.
Results:
fig. 10/a shows a comparison of the effect of placebo and a reference composition prepared by simple mixing:
the P-1 placebo composition (PGA 0440717) and the R-3 (PGA 0450717) reference compositions were measured throughout the experiment and during the second phase and are graphical representations of mean ± s.e.m. compared with the Student's test, and did not show significant differences, i.e. the composition comprising 15% pregabalin compared to placebo, both throughout the experiment and during the second phase.
Fig. 10/B shows a comparison of placebo formulation with the formulation of the present invention, wherein the lipid phase was subjected to HPH agitation during formulation:
FIG. 10/B is a graphical representation of the results of experiments with the P-2 placebo composition (PGA 0460717) and the WE-1 (PGA 0470717) compositions. Figure 10/B shows mean ± s.e.m., mice behaved significantly differently over time and during the second phase compared to the Student's test, i.e., the 15% pregabalin-containing formulation significantly reduced pain in this model compared to placebo.
This clearly shows that, in the treatment of neuropathic pain, it is necessary according to the invention to vigorously mix the gel, cream or lipid phase of the gel cream with a lower content of pregabalin alone, preferably homogenized with an HPH homogenizer. Such intense mixing can cause certain structural changes in the formulation, which can significantly enhance the therapeutic effect of the formulation.
Example 5
Absorption of pregabalin cream from the surface of a topically treated ex vivo pig skin
The method comprises the following steps:
during the formulation we have examined a quick test to observe absorption from the skin surface. Frozen whole thick in vitro pigskin was used for the test. The thawed skin pieces were placed on paper towels soaked with HBSS solution pH 7.0 and warmed on a heating pad at 32℃for 30 minutes, then 12. Mu.l/cm was applied 2 Is applied by finger to a skin surface of 2x2cm (treated area: 4 cm) 2 ). Photographs were taken with a conventional camera and microscope at various time points before and after treatment to visually inspect the absorption of pregabalin formulation by the skin surface. The skin was kept on a heating pad (32 ℃) during the study.
Results:
5.a examination of the absorption of PGA 1601018 containing 5% pregabalin and PGA 1591018 containing 10% pregabalin shows that at one hour after treatment the gel appears to be fully absorbed in both cases even though the gel contains pregabalin in dispersed solid particles of pregabalin. On fig. 11 are photographs of the surface of pigskin before, immediately after, one hour after and three hours after treatment. After one hour, even gels containing 10% pregabalin appear to be fully absorbed.
Composition of the invention PGA1671118 (WE-2 method) with other commercially available creams containing dispersed particles (i.eAnd more advanced forms of Mometasone +>) Is a comparison of (c).
Formulations tested: 5% pregabalin-PGA 1671118-0700818 (2023/08) (older formulation) Mometasone +.>L02 (05-2019) (newer formulations)
Results: a (PGA 1671118) was compared with a product with old sales approval (neogranomone) and another suspension product (mometasone). The formulation of the invention (PGA 1671118) had been "absorbed" after 1 hour, while the other two formulations were still visible on the pigskin after 3 hours. After 3 hours, PGA1671118 had no visible deposition or crystallization under magnification. The experimental photograph is shown in fig. 12.
Example 6.
HPH homogenizer and homogenization process
The HPH homogenization step was performed using a commercially available HPH homogenizer as follows:
device type EmulsiFlex-C3 (FIG. 8)
Equipment manufacturer, AVESTIN, inc.
2450Don Reid Drive,Ottawa,ON,Canada,K1H 1E1,
Specification of
Compressed air: 4-6 bar
Homogenizing machine: the inner surface is less than 1dm 2
Filling volume: maximum 3l/h
Minimum 10ml
Maximum allowable overpressure: 30,000PSI/2000 bar
Maximum allowable air pressure: 125PSI/0.9MPa
Maximum allowable operating temperature: 70 DEG C
Steam sterilization: 121 DEG C
And (3) refrigerant supply: heat exchange by glycol and connection of the cooling thermostat to a cold water tap by peristaltic pump
The homogenization procedure followed the manufacturer's instructions.
Essentially, the sample is placed in the sample chamber and the homogenizer is then activated.
Air pressure is then applied. The homogenization pressure used is 500-1500 bar. After homogenization has been completed, the sample is returned to the sample chamber for further homogenization, if necessary. The homogenization was repeated 1 to 125 times.
In the case of homogenizing the mixture several times, it may be useful for the first two homogenization steps to perform the pre-homogenization by using a lower homogenization pressure between 500 and 1000 bar.
Example 7.
Particle size analysis of pregabalin
PSD method description of non-micronized pregabalin
Dry Dispersion laser diffraction particle size distribution test conditions (MS 3000)
Instrument: malvern Mastersizer 3000
Accessories: aero S
Particle type: x is non-spherical
Materials: name: defaults to
Refractive index: 1.520
Absorption index: 0.1
Density: g/cm 3 (default: 1 g/cm) 3 )
Measurement duration: background: 5 seconds, sample: 5 seconds
The sequence is as follows: number of measurements: 1
Masking: limit: 1-8%
X automatically starts: stabilization time: 0 seconds
X filtration: pause time: 10 seconds
And (3) auxiliary control: air pressure: 0.5 bar
Feed rate: 30%
Configuration: venturi type: x Standard Venturi disperser
Tray type: x-shaped universal tray
Funnel gap: 4mm mesh
Basket used: without any means for
Ball bearings used: without any means for
And (3) data processing: model: x general purpose type
Fine powder: without any means for
Advanced settings: a single result mode is reserved: without any means for
Results range: limiting the range of result sizes: whether or not X
Type of results: x volume distribution (recommendation)
Sample preparation:
the test sample was homogenized by shaking and rotating the sample bottle by hand for about 1 minute.
The parameters marked with x can be modified according to the adhesion and flow properties of the sample to achieve adequate coverage.
Expression of the results: results d10, d50 and d90 are given as averages of validated measurements obtained from three independent sample preparations.
PSD method description of micronized pregabalin
Instrument: malvern Mastersizer 3000
Accessories: aero S
Particle type: x is non-spherical
Materials: name: defaults to
Refractive index: 1.520
Absorption index: 0.1
Density: g/cm 3 (default: 1 g/cm) 3 )
Measurement duration: background: 5 seconds, sample: 5 seconds
The sequence is as follows: number of measurements: 1
Masking: limit: 1-8%
X automatically starts: stabilization time: 0 seconds
X filtration: pause time: 10 seconds
And (3) auxiliary control: air pressure: 3.0 bar
Feed rate: 40 percent of
Configuration: venturi type: high-energy Venturi disperser
Tray type: x-shaped universal tray
Funnel gap: 4mm of
Basket used: without any means for
Ball bearings used: without any means for
And (3) data processing: model: universal type
Fine powder: without any means for
Advanced settings: a single result mode is reserved: without any means for
Results range: limiting the range of result sizes: without any means for
Type of results: volume distribution (recommendation)
Sample preparation:
the test sample was homogenized by shaking and rotating the sample bottle by hand for about 1 minute.
The parameters marked with x can be modified according to the adhesion and flow properties of the sample to achieve adequate coverage.
Expression of the results: results d10, d50 and d90 are given as averages of validated measurements obtained from three independent sample preparations.
Example 5.
Particle size analysis using SAX
The X-ray scattering of structural elements in the nanoscale range is in the small angle range (between 0 ° and about 10 °). (the Bragg equation establishes a correlation between the large period spacing and the small scattering angle). SAXS measurements were performed on a SAXS instrument named crepo of the institute of biochemistry, institute of environmental chemistry, material science, hungarian, academy of science, center of science, material (Wacha, varga, and B theta 2014; wacha 2015). Because of the low electron density contrast of its components and the matrix, the sample provides weak scattering, thus requiring several hours of measurement, compared to several minutes for typical measurement times, until a sufficient signal to noise ratio is achieved. The measurement of the sample requires an exposure time of more than 23 hours.
For measurement, the samples were filled into borosilicate capillaries with a nominal outer diameter of 1.0mm, a wall thickness of 0.01mm and a circular cross section, which were then sealed with a glass plug and a two-component epoxy to ensure that they were vacuum-tight. The sealed capillary tube is then placed inIn the sample-holding block of the apparatus, its temperature was kept at 25 ℃ during the measurement. Measurements were made at a sample-detector distance of 529.66 mm. In SAXS measurement, the angle dependence of the scattering intensity is expressed using a scattering variable q (also called momentum transfer, defined as q=4pi sin θ/λ, where 2θ is the scattering angle and λ≡0.154nm is the X-ray wavelength of the applied Cu ka radiation). To calibrate the q-scale, and thus the sample to detector distance, a silver behenate sample was used. The intensity scale was calibrated to absolute, instrument-independent differential scatter cross section units (orthoaber, bergmann, and Glatter 2000) using a Glassy Carbon sample pre-calibrated for the scatter intensity of water. Measurements were made using the "cct" program written for the device. The samples were measured with each 300 second repeated exposure. After each exposure, the scatter images are processed and corrected (taking into account instrument and external background signals, sample self-absorption and thickness, and geometrical distortions such as the solid angle differences of each pixel of the detector) by an on-line data evaluation procedure performed in the measurement procedure. Defective exposures were filtered out by statistical analysis and the corrected image for each sample was averaged. The final scattering pattern is azimuthally averaged to produce a scattering curve. The SAXS curve thus obtained was evaluated according to the above mathematical method and the micelle scattering contribution conversion coefficient (I 0 )*100；(cm -1 sr -1 )。
Orthaber, D., A.Bergmann, and O.Glatter.2000, "SAXS Experiments on Absolute Scale with Kratky Systems Using Water as a Secondary Standard," Journal of Applied Crystallography (2): 218-225.
Porod,G.1951.“Dievon Dichtgepackten Kolloiden Systemen.I.Teil.”Colloid&Polymer Science 124(2):83-114.
Schmidt,P.W.1991.“Small-Angle Scattering Studies of Disordered,Porous and Fractal Systems.”Journal of Applied Crystallography 24(5):414-435.
Wacha,András.2015.“Optimized Pinhole Geometry for Small-Angle Scattering.”Journal of Applied Crystallography 48(6):1843-48.https://doi.org/10.1107/S1600576715018932.
Wacha, andras, zolt Varga, and Attilla Bhata.2014, "CREDO: A New General-Purpose Laboratory Instrument for Small-Angle X-Ray scanning." Journal of Applied Crystallography (5): 1749-54.Https:// doi. Org/10.1107/S1600576714019918.
Preparation examples:
placebo preparation P-1 (PGA 0440717-simply mixed placebo)
(topical formulation without pregabalin)
Batch 2000g
Composition (100 g):
/>
method for producing placebo topical preparations
1, preparation of gel phase: carbopol 980 was swollen in twenty times the amount of purified water and then the pH was adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase: swelling soybean lecithin in ten times the amount of purified water at 25-40 deg.c, then adding isopropanol and mixing the resulting mixture with gel.
3. Octyl decane alcohol, DL-alpha-tocopherol, decyl oleate and EDTA are added to the gel phase thus obtained. The resulting mixture was homogenized at room temperature and homogenized.
Placebo formulation P-2 (placebo homogenized with lot PGA 0460717-HPH)
The composition of PGA 0460717 is the same as PGA 0440717.
The difference in the preparation method is only that in step 2, a twenty-fold amount of a mixture of soybean lecithin swelled in purified water was mixed with isopropyl alcohol, and the mixture was homogenized 5 times with an HPH homogenizer, and then the thus-homogenized mixture was added to the gel phase.
Reference example R-1 (PGA 2180719)
(topical formulation containing 2.5% of pregabalin in dissolved form).
Batch size 2000g
Composition of the formulation (100 g):
/>
method for preparing a topical composition comprising pregabalin
1, preparation of gel phase: carbopol 980 was swollen in twenty times the amount of purified water and then the pH was adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase: lipid P75 was swollen in twenty times the amount of purified water at 25-40℃and then isopropanol and DL-alpha-tocopherol were added to the mixture and homogenized.
3. The lipid phase was added to the gel phase while stirring and then homogenized.
5. To the homogenized mixture of lipid phase and gel phase, coconut oil, decyl oleate, aqueous EDTA and benzyl alcohol were added in this order.
6. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the cream at point 4, the resulting cream was then homogenized with a colloid mill for 120min, and the evaporated water was replaced with purified water while stirring. During the homogenization process, pregabalin is dissolved.
7. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in a multilayer foil or aluminum tube).
Results of mouse model of neuropathic pain:
data of fig. 1: plantar recession threshold data in the MPNL model: effect of 50 μl PGA2180719 treatment (2.5% pregabalin cream, 50 μl/right foot, mean ± s.e.m., n=6), PWT values for both feet
n.s. is not significant; * P <0.05
Reference example R-2 (PGA 2190719)
(topical formulation containing 5% of pregabalin in dispersed form).
Batch size 2000g
Composition of the formulation (100 g):
method for preparing a topical composition comprising pregabalin
1, preparation of gel phase: carbopol 980 was swollen in twenty times the amount of purified water and then the pH was adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase: lipid P75 was swollen in twenty times the amount of purified water at 25-40℃and then isopropanol and DL-alpha-tocopherol were added to the mixture and homogenized.
3. The lipid phase was added to the gel phase while stirring and then homogenized.
4. To the homogenized mixture of lipid phase and gel phase, coconut oil, decyl oleate, aqueous EDTA and benzyl alcohol were added in this order.
5. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the cream at point 4, the resulting cream was then homogenized with a colloid mill for 120min, and the evaporated water was replaced with purified water while stirring.
6. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminium or multilayer foil tubes).
Results of mouse model of neuropathic pain:
data of FIG. 1 data of plantar recession threshold data in MPNL model 20. Mu.l effect of PGA 2190719 treatment (5% pregabalin cream, 20. Mu.l/right foot, mean.+ -. S.E.M., n=7), PWT values for both feet
n.s. is not significant; * P <0.05
Reference example R-3 (PGA 0450717)
(topical formulation containing 15% of pregabalin in dispersed form)
Batch size 2000g
Composition of the formulation (100 g):
lot number PGA0450717
Process for producing a solid-state image sensor R-3
Component (A) g
Pregabalin (grinding) 15.0000
Soybean lecithin (deoiled soybean lecithin) 0.5000
Decyl oleate/Kollistream DO- 1.2500
Octyl dodecanol 2.5000
Isopropyl alcohol 5.0000
DL-alpha-tocopherol 0.2500
EDTA 0.0025
Carbomer (980) 0.3750
Ammonium solution (25 wt% aqueous solution) 0.2940
Purified water 74.8285
Sum up: 100.00
times of HPH of lipid phase 0
Method for preparing a topical composition comprising pregabalin
1. Preparation of gel phase: carbopol 980 was swollen in twenty times the amount of purified water and then the pH was adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase: lipid P75 was swollen in ten times the amount of purified water at 25-40℃and isopropanol, DL-alpha-tocopherol and octyldodecanol were then added to the mixture and homogenized.
3. The lipid phase was added to the gel phase while stirring and then homogenized.
4. To the homogenized mixture of lipid phase and gel phase, decyl oleate, aqueous EDTA solution are added in this order.
5. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the cream at point 5, the resulting cream was then homogenized with a colloid mill for 120min, and the evaporated water was replaced with purified water while stirring.
6. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminium or multilayer foil tubes).
Homogenization was performed in a Stephan mixer. Device information: stephan UMC 5 electronics (manufacturing No. 722.780.01) Equipment manufacturer A.stephan undGmbH&Co., year of manufacture 1998.
We completed homogenization at a stirring speed of 300rpm and a spatula stirring speed of 20 rpm.
Results of mouse model of neuropathic pain:
data of FIG. 1 data of plantar recession threshold in MPNL model 50. Mu.l effect of PGA 0450717 treatment (15% pregabalin cream, 50. Mu.l/right foot, mean.+ -. S.E.M., n=5), PWT values for both feet
n.s. is not significant; * P <0.05
Working examples
WE-1 general procedure:
1. preparation of gel phase:
Carbopol 980 is swollen in ten or twenty times the amount of purified water and then the pH is adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase:
swelling soybean lecithin (deoiled soybean lecithin) in twenty times the amount of purified water at 25-40 ℃, and then adding isopropanol, octyldodecanol and DL-alpha-tocopherol to the mixture and homogenizing.
3. HPH homogenization of lipid phase:
homogenizing the solution obtained by using a high-pressure homogenizernAnd twice. The pressure used is preferably between 500 and 1500 bar. During HPH homogenization, the solution is warmed to 25-50 ℃. The lipid phase thus obtained is cooled to between 20 and 30 ℃ and, if necessary, the evaporated water is replaced by adding purified water while stirring.
4. The fat phase was added to the gel phase at 30-35 ℃ while stirring, and then homogenized.
5. To the homogenized mixture of lipid phase and gel phase, decyl oleate and aqueous EDTA solution are added in this order.
6. Pregabalin was suspended in the remaining water and then mixed into the cream at point 5 at 30 ℃, then the resulting cream was homogenized for 120min, then the evaporated water was replaced with purified water.
7. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminium or multilayer foil tubes).
A composition prepared according to the WE-1 process:
results of mouse model of neuropathic pain:
data of fig. 1 plantar recession threshold data in the MPNL model:
effect of 50 μl PGA 0470717 treatment (15% pregabalin cream, 50 μl/right foot, mean ± s.e.m., n=6), PWT values for both feet
n.s. is not significant; * P <0.05
Data of fig. 1:
data of fig. 2 plantar recession threshold data in the MPNL model:
effect of 20 μl PGA 0980418 treatment (15% pregabalin cream, 20 μl/right foot, mean ± s.e.m.), PWT values for both feet
n.s. is not significant; * P <0.05
FIG. 2 effect of 20 μl PGA 0990418 treatment (15% pregabalin cream, 20 μl/right foot, mean.+ -. S.E.M.), PWT values for both feet
n.s. is not significant; * P <0.05
FIG. 2 effect of 20 μl PGA 1000418 treatment (15% pregabalin cream, 20 μl/right foot, mean.+ -. S.E.M.), PWT values for both feet
n.s. is not significant; * P <0.05
FIG. 2 effect of 20 μl PGA 1040418 treatment (15% pregabalin cream, 20 μl/right foot, mean.+ -. S.E.M.), PWT values for both feet
/>
n.s. is not significant; * P <0.
WE-2 general procedure:
1. preparation of gel phase:
carbopol 980 was swollen in twenty times the amount of purified water and then the pH was adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase:
lipid P75 (lecithin) was swollen in twenty times the amount of purified water at 25-40℃and isopropanol and DL-alpha-tocopherol were then added to the mixture and homogenized.
3. HPH homogenization of lipid phase:
homogenizing the solution obtained by using a high-pressure homogenizern＝5And twice. The pressure used is between 500 and 1500 bar. During HPH homogenization, the solution is warmed to 25-50 ℃. The lipid phase thus obtained is cooled to between 20 and 30 ℃ and, if necessary, the evaporated water is replaced by adding purified water while stirring.
4. The lipid phase was added to the gel phase while stirring and then homogenized.
5. To the homogenized mixture of lipid phase and gel phase, coconut oil, decyl oleate, aqueous EDTA and benzyl alcohol were added in this order.
6. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the cream at point 5, the resulting cream was then homogenized for 120min, and the evaporated water was replaced with purified water.
7. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminium or multilayer foil tubes).
A composition prepared according to the WE-2 process:
lot number PGA1591018 PGA1601018 PGA 1671118
Compounds of formula (I) g g g
Type of process WE-2 WE-2 WE-2
Pregabalin (micronization) 10.0000 5.0000 5.0000
Phospholipid (lecithin (lipoid P75) 1.0000 1.0000 1.0000
Decyl oleate/Kollistream DO- 1.2500 1.2500 1.2500
Octyl dodecanol 0.0000 0.0000 0.0000
Coconut oil 10.0000 10.0000 10.0000
Isopropyl alcohol 10.0000 10.0000 10.0000
DL-alpha-tocopherol 0.2500 0.2500 0.2500
EDTA 0.0025 0.0025 0.0025
Benzyl alcohol 2.0000 2.0000 1.000
Carbomer (carbopol 980) 0.3750 0.3750 0.3750
Ammonium solution (25 wt% aqueous solution) 0.2940 0.2940 0.2940
Purified water 64.8285 69.8285 71.7285
Sum total 100.00 100.00 100.00
n (times of HPH of lipid phase) 5 5 5
Results of mouse model of neuropathic pain:
FIG. 3.20. Mu.l effect of PGA 1591018 treatment (10% pregabalin cream, 20. Mu.l/right foot, mean.+ -. S.E.M.), PWT values for both feet
n.s. is not significant; * P <0.05
FIG. 3.20. Mu.l effect of PGA 1601018 treatment (5% pregabalin cream, 20. Mu.l/right foot, mean.+ -. S.E.M.), PWT values for both feet
n.s. is not significant; * P <0.05
WE-3 general procedure:
1. preparation of gel phase:
carbopol 980 was swollen in twenty times the amount of purified water and then the pH was adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase:
lipid P75 was swollen in twenty times the amount of purified water at 25-40℃and then isopropanol and DL-alpha-tocopherol were added to the mixture and homogenized.
3. HPH homogenization of lipid phase:
homogenizing the solution obtained by using a high-pressure homogenizern＝5And twice. During HPH homogenization, the solution is warmed to 25-50 ℃. The lipid phase thus obtained is cooled to between 20 and 30 ℃ and, if necessary, the evaporated water is replaced by adding purified water while stirring.
4. The lipid phase was added to the gel phase while stirring and then homogenized.
5. To the homogenized mixture of lipid phase and gel phase, decyl oleate and aqueous EDTA solution are added in this order.
6. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the cream at point 5, the resulting cream was then homogenized for 120min, and the evaporated water was replaced with purified water.
7. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminium or multilayer foil tubes).
A composition prepared according to the WE-3 process:
/>
results of mouse model of neuropathic pain:
fig. 3, schematic diagram of comparative plantar recession threshold in NMRI mice 7 days after MPNL surgery:
comparison of effects of PGA1460718 (5%), PGA1450718 (10%), PGA1370718 (15%) (20 μl/right foot, mean ± s.e.m.), PWT values for both feet. Fig. 3 shows only the data of the processed foot.
n.s. is not significant; * P <0.05
n.s. is not significant; * P <0.05
n.s. is not significant; * P <0.05
FIG. 2 effect of 20. Mu.l PGA 1510918 cream (10% pregabalin, 20. Mu.l/right foot, mean.+ -. S.E.M.), bipedal
n.s. is not significant; * P <0.05
FIG. 3 effect of 20. Mu.l PGA 1520918 cream (37.5% pregabalin, 20. Mu.l/right foot, mean.+ -. S.E.M.), bipedal
n.s. is not significant; * P <0.05
WE-4 general procedure:
1. preparation of gel phase:
a. ) Carbopol 980 (batch labeled PGA) was used:
carbopol 980 is swollen in ten or twenty times the amount of purified water and then the pH is adjusted to pH 7.0 by adding aqueous ammonia solution.
b. ) Xanthan gum (batch AL 2890321) was used:
the xanthan gum was gelled in 10 times the amount of purified water at 60 ℃ and homogenized by cooling to 25 ℃.
c. ) Hydroxyethyl cellulose (batch AL 2900321) was used:
HEC (hydroxyethylcellulose) was gelled in 10-fold purified water at 37 ℃ (35-40 ℃) and homogenized by cooling to 25 ℃.
d. ) Poloxamer (batch AL 2910321) was used:
poloxamer 407 was gelled in 10 times purified water, then stored in a refrigerator for 24 hours, then allowed to warm to room temperature.
2. Preparation of lipid phase:
lipid P75 (lecithin) was swollen in twenty times the amount of purified water at 25-40℃and isopropanol and DL-alpha-tocopherol were then added to the mixture and homogenized.
3. HPH homogenization of lipid phase:
homogenizing the solution obtained by using a high-pressure homogenizern＝5And twice. The pressure used is preferably between 500 and 1500 bar. During HPH homogenization, the solution is warmed to 25-50 ℃. The lipid phase thus obtained is cooled to between 20 and 30 ℃ and, if necessary, the evaporated water is replaced by adding purified water while stirring.
4. To the homogenized lipid phase mixture, further additives, preferably coconut oil, decyl oleate, aqueous EDTA and benzyl alcohol, are added in this order.
5. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the mixture at point 4 and homogenized for 30 minutes. The resulting mixture was then homogenized with a high pressure homogenizerm＝3And twice. The pressure used is preferably between 500 and 1500 bar. During HPH homogenization, the solution is warmed to 30-50 ℃. The evaporated water is then replaced with purified water if necessary.
6. The lipid suspension phase was added to the gel phase while stirring, and then the mixture of lipid suspension phase and gel was homogenized at 25 ℃ for 60 minutes.
7. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminum multilayer foil tubes).
A composition prepared according to the WE-4 process:
gelling agent: * : carbomer (980): xanthan gum, #: hydroxyethyl cellulose (Natrosol 250HHX Pharm Bag), # #: poloxamer 407
* Micronized or ground PGA 2150619 pregabalin was used. Phospholipid: lecithin, # lecithin (lipoid P75, lipoid S75)
Gelling agent: * : carbomer (980): xanthan gum, #: hydroxyethyl cellulose (Natrosol 250HHX Pharm Bag), # #: poloxamer 407
* Micronized or ground PGA 2150619 pregabalin was used. Phospholipid: lecithin, # lecithin (lipid P75, lipid S75),
results of mouse model of neuropathic pain:
figure 5 is a graph of plantar recession threshold in NMRI mice 7 days after MPNL surgery, effect of 20 μl PGA 2211119 cream (5% pregabalin, 20 μl/right foot, mean ± s.e.m., n=8), bipedal.
n.s. is not significant; * P <0.05
FIG. 4 effect of 20 μl PGA 2150619 cream (5% pregabalin, 20 μl/right foot, mean.+ -. S.E.M., n=6), bipedal
n.s. is not significant; * P <0.05
WE-4/B general procedure:
1. preparation of gel phase:
carbopol 980 is swollen in ten or twenty times the amount of purified water and then the pH is adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase:
swelling lipid P75 (lecithin) in twenty times the amount of purified water at 25-40℃followed by addition of isopropanol and DL-alpha-lipid phase:
homogenizing the solution obtained by using a high shear mixer homogenizern＝5And twice. During the homogenization process, the solution was warmed to 25-50 ℃. The lipid phase thus obtained is cooled to a temperature of between 20 and 30℃and, if necessary, by addingPurified water was added in place of the evaporated water while tocopherol was added to the mixture and homogenized.
3. Stirred HPH was homogenized.
4. To the homogenized lipid phase mixture, further additives, preferably coconut oil, decyl oleate, aqueous EDTA and benzyl alcohol, are added in this order.
5. Pregabalin was suspended in the remaining water at 30 ℃ and mixed into the mixture at point 4 and homogenized for 30 minutes. The resulting mixture is then homogenized with a high shear devicem＝3And twice. During the homogenization process, the solution was warmed to 30-50 ℃. The evaporated water is then replaced with purified water if necessary.
6. The lipid suspension phase was added to the gel phase while stirring, and then the mixture of lipid suspension phase and gel was homogenized at 25 ℃ for 60 minutes.
7. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminum multilayer foil tubes).
A composition prepared according to the WE-4/B process:
/>
use of high shear mixing equipment in each process:
WE-4/B1:AL2980621
use of colloid mill MK Modulemagic/>The following settings were made according to the instructions in the manual: application speed: 3000rpm
Setting angle [ °] Adjusting ring rotation [] Radial gap distance [ mm]
180 1/2 0,159
WE-4/B2:AL 2990521
Use of CMS (high shear mixer) modulesmagic/>The device performs the following settings according to the instructions in the manual:
The application speed was 3000rpm.
WE-4/B3:AL3010521
Using a Sonic Vibra Cell VCX 500 ultrasonic cutter, the following settings were made according to the instructions in the manual:
breaking head: 219-type B
Pulse time: 2/2 seconds.
Amplitude of: 50-60%
Duration 3 hours.
The temperature of the composition is maintained between 27-30deg.C during this process. WE-4/B4:AL2970521AMill ML (MultiLab) manufacturer (Will. I. Y A. Bachofen AG Maschinenfabrik) laboratory mixing bead MILL was hand-heldThe instructions in the book are used and the following settings are made:
application speed of 2600-2660rpm
Application pressure 0.1 bar pressure
WE-4/B5:AL3020521
Microfluidizer was used as described in the manufacturer's manual: the application pressure is as follows: 2000 bar efficacy results:
in the mouse model of neuropathy (plantar medial nerve ligation (MPNL) at least 7 days post surgery), samples were compared in pairs with efficacy of the reference PGA2310320 cream. During the trial, the animals were treated with 10 μl of cream (0.5 mg pregabalin) for the right posterior surgical leg (about 2cm 2 Area). The reason for choosing this treatment volume is that in this trial using this treatment regimen, this volume is half the amount of active reference (PGA 2310320) for up to 8 hours, and any difference in efficacy at lower treatment volumes is expected to be more pronounced during the 5 hours of the trial. The effect of pregabalin cream was confirmed by an increase in the stimulation threshold of the neuropathic (hypersensitive ) sole, which was measured multiple times during the experiment using von Frey filaments; pre-treatment, 0.5, 1, 3 and 5 hours before treatment and 0.5, 1, 3 and 5 hours after treatment.
Results:
a.)
PGA 2310320vs AL 2980521vs AL 2990521 (HPH vs IKA colloid mill vs IKA high shear mixer)
All three formulations act rapidly and produce a strong effect within 3 hours after treatment: the stimulation threshold of the surgical leg was significantly increased and at these time points the sensitivity of the surgical leg was not different from the sensitivity of the intact leg. For all three creams, the sensitivity threshold on the treatment side was significantly lower than on the intact side at the fifth hour.
FIG. 13/a shows the sensitivity variation of MPNL surgical leg for three samples: PGA 2310320 (WE-4, HPH) vs AL 2980521 (WE-4/B, IKA colloid mill) vs AL 2990521 (WE-4/B IKA high shear mixer) plantar recession threshold MPNL mean.+ -. S.E.M. (group 6-7 mice), dose 10 μl/paw, 5% pregabalin composition, two-factor anova, dunnett vs 0: * p <0.06 primary column effect: 231/299: p <0.06. It can clearly be seen that the HPH homogenized product had minimal decrease in efficacy at hour 5, while the other two formulations had lower effects on the curve parallel to HPH, but they were also significantly more effective than baseline after 5 hours. The use of higher doses or multiple high shear mixing cycles will make these samples even more effective.
b.)
The results of AL 3010521 (WE-4/B, SONIC SVCX-500 ultrasound device) showed no significant difference between the feel of the treated foot and the feel of the intact foot even after 5 hours of treatment. Even at such low therapeutic doses, the effect of HPH is not much worse than that of the homogenized product (PGA 2310320).
c.)
PGA 2310320vs AL 2970521 (WE-4/B, DYNO mill) vs AL 3020521 (WE-4/B microfluidizer)
All three formulations act rapidly and exert a strong effect up to 3 hours after treatment: the stimulation threshold of the surgical leg increases significantly and at these time points the sensitivity of the surgical leg does not differ from the sensitivity of the intact leg. The sensitivity threshold on the fifth hour was significantly lower on the treatment side than on the intact side for all three creams. FIG. 13/C shows the results of a comparison of AL 2970521 (WE-4/B, DYNO mill) vs AL 3020521 (WE-4/B microfluidizer) in a plantar recession threshold MPNL mouse test. Clearly, HPH homogenized products showed minimal decrease in potency at 5 hours, while in the other two formulations, the curves were parallel to HPH, with lower effects, but they were also significantly more effective than baseline after 5 hours. The use of higher doses or multiple high shear mixing cycles will make these samples even more effective. Thus, these results, i.e. products made with other high shear mixing processes, demonstrate that they also achieve the intended therapeutic objectives of producing a topical product for at least 5 hours, even 5 hours after application. Thus, while high pressure homogenizers appear to be the most efficient process, other high shear mixing methods suitable for decomposing phospholipid micelles are also suitable for preparing the long sustained release compositions of the present invention.
WE-5 general procedure:
1. preparation of gel phase:
carbopol 980 is swollen in ten or twenty times the amount of purified water and then the pH is adjusted to pH 7.0 by adding aqueous ammonia solution.
2. Preparation of lipid phase:
lipid P75 (lecithin) was swollen in ten or twenty times the amount of purified water at 25-40℃and isopropanol and DL-alpha-tocopherol were then added to the mixture and homogenized.
3. HPH homogenization of lipid phase:
homogenizing the solution obtained by using a high-pressure homogenizern＝5And twice. The pressure used is preferably between 500 and 1500 bar. During HPH homogenization, the solution is warmed to 25-50 ℃. The lipid phase thus obtained is cooled to between 20 and 30 ℃ and, if necessary, the evaporated water is replaced by adding purified water while stirring.
4. The lipid phase was added to the gel phase while stirring, and then the mixture of lipid phase and gel was homogenized at 25 ℃ for 30 minutes.
5. To the homogenized mixture of the lipid phase and the gel phase, further additives, preferably coconut oil, kollistream DO (decyl oleate), aqueous EDTA and benzyl alcohol, are added in this order.
6. Suspending pregabalin in the remaining water and homogenizing with a high pressure homogenizerm＝5And twice. The pressure used is preferably between 500 and 1500 bar. During HPH homogenization, the solution is warmed to 30-50 ℃. The evaporated water is then replaced with purified water if necessary.
7. The dispersion of pregabalin homogenized by HPH was mixed into the cream at point 5 at 30 ℃, then the resulting cream was homogenized for 120min, then the evaporated water was replaced with purified water.
8. The cream thus obtained is cooled to 25 ℃ and filled into containers (preferably in aluminium or multilayer foil tubes).
A composition prepared according to the WE-5 process:
lot number PGA2050519
Type of process WE-5
Compounds of formula (I) g
Pregabalin (grinding) 5.0000
Lecithin (lipoid P75) 0.5000
Decyl oleate/Kollistream DO- 1.2500
Refined coconut oil 5.0000
Isopropyl alcohol 10.0000
DL-alpha-tocopherol 0.2500
Benzyl alcohol 1.0000
EDTA 0.0025
Carbomer (980) 0.4000
Ammonium solution (25 wt% aqueous solution) 0.3136
All components 23.7161
Purified water 76.2839
100.00
Times of HPH of lipid phase (n) 5
Number of pregabalin dispersions (m) 5

Claims (35)

1. A topical pharmaceutical composition comprising pregabalin and a phospholipid obtainable by a specific process in which a mixture comprising a phospholipid and a solvent is homogenized with a high shear mixing device and wherein said pregabalin and said phospholipid are in the composition in dispersed form.
2. A topical pharmaceutical composition comprising pregabalin and a phospholipid according to claim 1 obtainable by a specific method in which preferably an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, a bead mill, a slit homogenizer, a colloid mill, a high shear mixer, most preferably an HPH homogenizer is used as high shear mixing device.
3. A topical pharmaceutical composition comprising pregabalin and a phospholipid obtainable by a specific process according to claim 1 or 2, wherein the composition comprises a rheology modifier.
4. A topical pharmaceutical composition obtainable by the process according to any one of claims 1-3, wherein the mixture of phospholipids and solvent, or solvent mixture and optionally other excipients, is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, then a.)
a.1. ) Adding a rheology modifier, and
a.2 Adding pregabalin and optionally other excipients to the mixture thus obtained and homogenizing the mixture thus obtained, or
b.)
b.1. ) Adding pregabalin and optionally other excipients to the mixture thus obtained, homogenizing the mixture thus obtained, and then
b.2 Adding rheology modifiers, or
c.)
c.1. ) To the mixture thus obtained is added a mixture of pregabalin and optionally other excipients, which mixture was previously homogenized by high shear mixing equipment alone, most preferably by an HPH homogenizer, and then
c.2. ) Adding rheology regulators, or
d.)
d.1. ) Pregabalin and optionally other excipients are added to the phospholipid phase, and the mixture thus obtained is then homogenized with a high shear mixing device, most preferably with an HPH homogenizer, and
d.2. ) Adding rheology regulators, or
e.)
e.1. ) Adding a rheology modifier to the mixture, then
e.2. ) Adding pregabalin and optionally other excipients to the phospholipid phase, then homogenizing the thus obtained mixture with a high shear mixing device, most preferably with an HPH homogenizer, and
if necessary, other rheology modifiers or excipients are added.
5. A topical pharmaceutical composition obtainable by the process according to any one of claims 1 or 2, wherein a mixture of phospholipids and a solvent or solvent mixture, pregabalin and optionally other excipients is homogenized and
homogenizing with a high shear mixing device, most preferably with an HPH homogenizer, then adding a rheology modifier and optionally other excipients to the mixture thus obtained and homogenizing, or
Adding a rheology modifier and homogenizing the composition thus obtained with a high shear mixing device, most preferably with an HPH homogenizer, then adding, if necessary, further excipients and homogenizing the mixture thus obtained.
6. The topical pharmaceutical composition obtainable by a specific process according to any one of claims 1 to 4, wherein the phospholipid, solvent or solvent mixture and optionally pregabalin and other excipients are homogenized at least once, preferably 1 to 125 times, more preferably 3 to 10 times, most preferably 5 to 10 times with a high pressure homogenizer.
7. A topical pharmaceutical composition obtainable by the process according to any one of claims 1-6, wherein more than 2.5% by weight of pregabalin and 0.1-5% by weight of high pressure homogenized phospholipid are used and the pregabalin is in dispersed form in the composition.
8. Topical pharmaceutical composition obtainable by the process according to any one of claims 1-7, wherein 2.5-40 wt%, preferably 3-20 wt%, more preferably 3-15 wt%, most preferably 5-10 wt% pregabalin and 0.1-3 wt%, preferably 0.1-1.5 wt%, most preferably 0.1-1.2 wt% phospholipids are used and the pregabalin is in dispersed form in the composition.
9. The topical pharmaceutical composition obtainable by the process according to any one of claims 1 to 8, wherein 40 to 90 wt. -%, preferably 70 to 90 wt. -%, most preferably 75 to 85 wt. -% of a solvent, 0 to 20 wt. -%, preferably 2 to 15 wt. -%, more preferably 3 to 10 wt. -% of a softening agent, 0 to 20 wt. -%, preferably 2 to 15 wt. -%, more preferably 3 to 10 wt. -%, of a penetration enhancer, 0 to 5 wt. -%, preferably 0.1 to 2 wt. -%, most preferably 0.2 to 0.5 wt. -% of a rheology modifier or a mixture thereof may be used as further excipient.
10. The topical pharmaceutical composition obtainable by the process according to any one of claims 1-9, wherein for the preparation of the composition, use can be made of
Natural or synthetic phospholipids, preferably lecithin, more preferably soy lecithin, de-oiled soy lecithin, lipid P75, lipid S75, as phospholipids,
water, pharmaceutically acceptable C 2 -C 4 Alcohols, more preferably ethanol, propanol, isopropanol, n-butanol, isobutanol, alcohols having more than one hydroxyl group, preferably glycerol, propylene glycol, more preferably ethanol or isopropanol or mixtures thereof, as solvents,
vitamins A, D and E, lanolin alcohols, propylene glycol dibenzoates, vegetable oils, vegetable extracts, fatty alcohol esters, fatty acid esters, fatty alcohols, synthetic polymers, silicon compounds, fatty acids, mineral oil derivatives, waxes or mixtures thereof, most preferably fatty acid esters such as cetyl palmitate, fatty alcohols such as octyldodecanol, fatty acid derivatives such as decyl oleate, vegetable oils such as coconut oil as softeners,
C 2 -C 4 alcohols, DL-alpha-tocopherols, mixtures thereof, as penetration enhancers other than phospholipids,
EDTA, EDTA derivatives, aromatic preservatives such as parahydroxybenzoate, thimerosal, chlorhexidine benzyl alcohol and benzalkonium chloride, preferably benzyl alcohol, more preferably a mixture of benzyl alcohol and EDTA, as a preservative,
Polyethylene glycol, synthetic polymers such as carbomers (polyacrylic acid), preferably carbomers 980, hydroxyalkyl celluloses, preferably hydroxyethyl celluloses, and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomers, as rheology modifiers,
preferably a basic pH adjuster, more preferably ammonia, an ammonium solution, an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, or an organic base such as a primary, secondary or tertiary amine, most preferably an aqueous ammonia solution, as pH adjuster.
11. Topical pharmaceutical composition obtainable by the process according to any one of claims 1-10, wherein the mixture of phospholipids, preferably with a solvent, preferably water or a mixture of water and alcohol, more preferably ethanol or isopropanol, most preferably a mixture of water and isopropanol and optionally other excipients, preferably a softener, preferably octyl decane alcohol and/or penetration enhancer, preferably DL-alpha-tocopherol, is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, then
a.)
a.1. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonium solution, if necessary, then
a.2 Pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, are mixed into the mixture thus obtained and homogenized, or
b.)
b.1. ) The pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, are mixed into the mixture thus obtained and homogenized, then
b.2 The mixture thus obtained is added to a gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonium solution, if necessary, or
c.)
c.1. ) The mixture thus obtained is added to a mixture of pregabalin and optionally other excipients, preferably a softener, preferably decyl oleate, and a preservative, preferably an aqueous EDTA solution, which mixture was previously homogenized, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, with a high shear mixing device, most preferably an HPH homogenizer, alone, and
c.2. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonium solution, if necessary, or
d.)
d.1. ) Adding pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, to the lipid phase, and then homogenizing the thus obtained mixture with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and then
d.2. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase if necessary with a pH modifier, preferably with an aqueous ammonium solution, or adding a rheology modifier, or
e.)
e.1. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonium solution, if necessary, then
e.2. ) Adding pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, to the phospholipid phase, and then homogenizing the thus obtained mixture with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, and then
If necessary, other rheology modifiers or excipients are added.
12. Topical pharmaceutical composition obtainable by the process according to any one of claims 1-11, wherein a mixture of phospholipids, pregabalin and a solvent or solvent mixture, preferably water or a mixture of water and alcohol, more preferably a mixture of water and ethanol or isopropanol, most preferably water and isopropanol and optionally an excipient, preferably a softener, preferably octyl decane alcohol and/or penetration enhancer, preferably DL-alpha-tocopherol
Homogenizing preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, with a high shear mixing device, most preferably with an HPH homogenizer, and then adding the mixture thus obtained to a gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase if necessary with a pH modifier, preferably with an aqueous ammonium solution, adding the rheology modifier and optionally other excipients to the mixture thus obtained and homogenizing, or
-adding the mixture thus obtained to a gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably with an aqueous ammonium solution, if necessary, and homogenizing the thus obtained composition with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, then adding other excipients, if necessary, and homogenizing the thus obtained mixture.
13. The topical pharmaceutical composition obtainable by the process according to any one of claims 1 to 12, wherein the mixture of phospholipids is prepared by swelling the phospholipids with water in an amount of 10-30 times, preferably 1-20 times the weight of phospholipids, preferably lecithin, more preferably soy lecithin, deoiled soy lecithin, lipid P75, lipid S75 and mixing the thus obtained swollen phospholipids with other excipients to form a lipid phase.
14. The topical pharmaceutical composition obtainable by a specific process according to any one of claims 1 to 13, wherein the gel phase is prepared by swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, in an amount of 10-30 times, preferably 1-20 times the weight of the rheology modifier, and adjusting the pH of the gel phase with a pH modifier.
15. Passable specific according to any one of claims 1-11The topical pharmaceutical composition obtained by the process wherein pregabalin used preferably has a particle size D of milled pregabalin between 20-200 microns 90 More preferably the pregabalin used is micronized to have a particle size D below 20 microns 90 。
16. The obtainable topical pharmaceutical composition according to any one of claims 1 to 15, wherein the temperature of the mixture is maintained between 0-50 ℃, preferably 20-45 ℃, most preferably 25-35 ℃ during homogenization with high shear mixing equipment, most preferably with HPH.
17. The topical pharmaceutical composition obtainable by a specific process according to any one of claims 1 to 16, wherein the HPH homogenization is performed such that the pressure used is between 500 and 2000 bar, preferably between 500 and 1500 bar, most preferably between 1000 and 1500 bar.
18. A process for the preparation of a topical pharmaceutical composition comprising pregabalin and a phospholipid according to any one of the claims 1-17, characterized in that,
-homogenizing the phospholipid and the solvent or solvent mixture with a high shear mixing device and mixing pregabalin into the composition, or
-mixing a phospholipid, a solvent and pregabalin and homogenizing the mixture thus obtained with a high shear mixing device, wherein
The composition thus obtained comprises pregabalin in dispersed form.
19. The method according to claim 18, characterized in that in the method preferably an HPH homogenizer, a microfluidizer, an ultrasonic homogenizer, a bead mill, a slot homogenizer, a colloid mill, a high shear mixer, most preferably an HPH homogenizer is used as high shear mixing device.
20. A method according to claim 18 or 19, characterized in that the resulting composition is formed into a gel, cream or gel cream by adding a rheology modifier to the composition.
21. A process according to claim 18 or 20, characterized in that the mixture of phospholipids and solvent, or solvent mixture and optionally other excipients, is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, and then
a.)
a.1. ) Adding a rheology modifier, and
a.2 Adding pregabalin and optionally other excipients to the mixture thus obtained and homogenizing the mixture thus obtained, or
b.)
b.1. ) Adding pregabalin and optionally other excipients to the mixture thus obtained, homogenizing the mixture thus obtained, and then
b.2 Adding rheology modifiers, or
c.)
c.1. ) To the mixture thus obtained is added a mixture of pregabalin and optionally other excipients, which mixture was previously homogenized by high shear mixing equipment alone, most preferably by an HPH homogenizer, and then
c.2. ) Adding rheology regulators, or
d.)
d.1. ) Pregabalin and optionally other excipients are added to the phospholipid phase, and the mixture thus obtained is then homogenized with a high shear mixing device, most preferably with an HPH homogenizer, and
d.2. ) Adding rheology regulators, or
e.)
e.1. ) A rheology modifier is added to the mixture,
e.2. ) Pregabalin and optionally other excipients are added to the phospholipid phase, and the mixture thus obtained is then homogenized with a high shear mixing device, most preferably with an HPH homogenizer, and
if necessary, other rheology modifiers or excipients are added.
22. The method according to any one of claims 18-21, characterized in that a mixture of phospholipids, pregabalin and a solvent or solvent mixture and optionally other excipients is homogenized and
homogenizing the mixture thus obtained with a high shear mixing device, most preferably with an HPH homogenizer, then adding a rheology modifier and optionally further excipients to the mixture thus obtained and homogenizing, or
Adding a flow-modifying regulator to the mixture thus obtained and homogenizing the composition thus obtained with a high shear mixing device, most preferably with an HPH homogenizer, then if necessary adding further excipients and homogenizing the mixture thus obtained.
23. The method according to any one of claims 18-22, characterized in that a mixture comprising phospholipids, solvents or solvent mixtures and optionally pregabalin and other excipients is homogenized with a high pressure homogenizer at least 1 time, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times.
24. The method according to any one of claims 18-23, characterized in that more than 2.5 wt.% pregabalin and 0.1-5 wt.% high pressure homogenized phospholipid are used.
25. The method according to any one of claims 18-24, characterized in that 2.5-40 wt. -%, preferably 3-20 wt. -%, more preferably 3-15 wt. -%, most preferably 5-10 wt. -% pregabalin and 0.1-3 wt. -%, preferably 0.1-1.5 wt. -%, most preferably 0.1-1.2 wt. -% of phospholipids are used.
26. The method according to any one of claims 18-25, characterized in that 40-90 wt%, preferably 70-90 wt%, most preferably 75-85 wt% of a solvent, 0-20 wt%, preferably 2-15 wt%, more preferably 3-10 wt% of a softening agent, 0-20 wt%, preferably 2-15 wt%, more preferably 3-10 wt% of a penetration enhancer, 0-5 wt%, preferably 0.1-2 wt%, most preferably 0.2-0.5 wt% of a rheology modifier or a mixture thereof may be used as further excipients.
27. The method according to any one of claims 18-26, characterized in that for the preparation of the composition, use is made of
Natural or synthetic phospholipids, preferably lecithin, more preferably soy lecithin, de-oiled soy lecithin, lipid P75, lipid S75, as phospholipids,
Water, pharmaceutically acceptable C 2 -C 4 Alcohols, more preferably ethanol, propanol, isopropanol, n-butanol, isobutanol, alcohols having more than one hydroxyl group, preferably glycerol, propylene glycol, more preferably ethanol or isopropanol or mixtures thereof, as solvents,
vitamins A, D and E, lanolin alcohols, propylene glycol dibenzoates, vegetable oils, vegetable extracts, fatty alcohol esters, fatty acid esters, fatty alcohols, synthetic polymers, silicon compounds, fatty acids, mineral oil derivatives, waxes or mixtures thereof, most preferably fatty acid esters such as cetyl palmitate, fatty alcohols such as octyldodecanol, fatty acid derivatives such as decyl oleate, vegetable oils such as coconut oil as softeners,
C 2 -C 4 alcohols, DL-alpha-tocopherols, mixtures thereof, as penetration enhancers other than phospholipids,
EDTA, EDTA derivatives, aromatic preservatives such as parahydroxybenzoate, thimerosal, chlorhexidine benzyl alcohol and benzalkonium chloride, preferably benzyl alcohol, more preferably a mixture of benzyl alcohol and EDTA, as a preservative,
polyethylene glycol, synthetic polymers such as carbomers (polyacrylic acid), preferably carbomer 980, hydroxyalkyl celluloses, preferably hydroxyethyl cellulose, and vegetable gums, preferably xanthan gum or guar gum, as rheology modifiers,
Preferably a basic pH adjuster, more preferably ammonia, an ammonium solution, an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, or an organic base such as a primary, secondary or tertiary amine, most preferably an aqueous ammonia solution, as pH adjuster.
28. The process according to any one of claims 18-27, characterized in that the mixture of phospholipids and preferably solvent, preferably water or a mixture of water and alcohol, more preferably ethanol or isopropanol, most preferably a mixture of water and isopropanol and optionally other excipients, preferably softeners, preferably octyl decane alcohol and/or penetration enhancers, preferably DL- α -tocopherol is homogenized with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, then
a.)
a.1. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonium solution, if necessary, then
a.2 Pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, are mixed into the mixture thus obtained and homogenized, or
b.)
b.1. ) The pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, are mixed into the mixture thus obtained and homogenized, then
b.2 The mixture thus obtained is added to a gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase if necessary with a pH modifier, preferably with an aqueous ammonia solution, or
c.)
c.1. ) The mixture thus obtained is added to a mixture comprising pregabalin and optionally other excipients, preferably a softener, preferably decyl oleate and a preservative, preferably an aqueous EDTA solution, said mixture being previously homogenized, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, with a high shear mixing device, most preferably with an HPH homogenizer, and then
c.2. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase if necessary with a pH modifier, preferably with an aqueous ammonia solution, or
d.)
d.1. ) Adding pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, to the phospholipid phase, and then homogenizing the thus obtained mixture with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, and then
d.2. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase if necessary with a pH modifier, preferably with an aqueous ammonia solution, or adding a rheology modifier, or
e.)
e.1. ) The mixture thus obtained was added to the gel phase prepared as follows: swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonia solution, if necessary, then
e.2. ) Adding pregabalin and optionally other excipients, preferably softeners, preferably decyl oleate and preservatives, preferably aqueous EDTA, to the lipid phase, and then homogenizing the thus obtained mixture with a high shear mixing device, most preferably with an HPH homogenizer, preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, using a pressure between 500 and 2000 bar, preferably between 500 and 1500 bar, most preferably between 1000 and 1500 bar, and then
If necessary, other rheology modifiers or excipients are added.
29. The process according to any one of claims 18-28, characterized in that the phospholipid, pregabalin and the solvent or solvent mixture, preferably water or a mixture of water and alcohol, more preferably a mixture of water and ethanol or isopropanol, most preferably a mixture of water and isopropanol and optionally other excipients, preferably softeners, preferably octyl decane alcohol and/or penetration enhancers, preferably a mixture of DL- α -tocopherol, is then mixed with
Homogenizing preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times with an HPH homogenizer, and then adding the mixture thus obtained to a gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and vegetable gums, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase if necessary with a pH modifier, preferably an aqueous ammonia solution, adding the rheology modifier and optionally other excipients to the mixture thus obtained and homogenizing, or
-adding the mixture thus obtained to a gel phase prepared as follows: swelling a rheology modifier, preferably poloxamer, polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, and adjusting the pH of the gel phase with a pH modifier, preferably an aqueous ammonia solution, if necessary, and homogenizing the thus obtained composition with an HPH homogenizer preferably 1-125 times, more preferably 3-10 times, most preferably 5-10 times, then adding other excipients, if necessary, and homogenizing the thus obtained mixture.
30. The process according to any one of claims 18-29, characterized in that pregabalin used preferably has a particle size D of milled pregabalin between 20-200 microns 90 More preferably the pregabalin used is micronized to have a particle size D below 20 microns 90 。
31. A method according to any one of claims 18-30, characterized in that the mixture of phospholipids is prepared by swelling the phospholipids, preferably lecithin, more preferably soy lecithin, de-oiled soy lecithin, lipid P75, lipid S75 with water in an amount of 10-30 times, preferably 1-20 times the weight of the phospholipids and mixing the thus obtained swollen phospholipids with other excipients to form a lipid phase.
32. The method according to any one of claims 19-31, characterized in that the gel phase is prepared by swelling a rheology modifier, preferably polyethylene glycol, a synthetic polymer, preferably carbomer (polyacrylic acid), more preferably carbomer 980, a hydroxyalkyl cellulose, preferably hydroxyethyl cellulose and a vegetable gum, preferably xanthan gum or guar gum, most preferably carbomer 980 in a solvent, preferably water, in an amount of 10-30 times, preferably 1-20 times the weight of the rheology modifier, and adjusting the pH of the gel phase with a pH modifier.
33. A method according to any of claims 18-32, characterized in that the temperature of the mixture is kept between 0-50 ℃, preferably between 20-45 ℃, most preferably between 25-35 ℃ during homogenization with high shear mixing equipment, most preferably with HPH.
34. A method according to any of claims 18-32, characterized in that the HPH homogenization is performed such that the pressure used is between 500 and 2000 bar, preferably between 500 and 1500 bar, most preferably between 1000 and 1500 bar.
35. The composition according to any one of claims 1-18, for use in the treatment of neuropathic pain, peripheral neuropathic pain, such as pain experienced by diabetic patients or patients already suffering from shingles (herpes zoster), and central neuropathic pain, such as pain experienced by patients already suffering from spinal cord injury; diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain and other forms of neuralgia, neuropathic pain and idiopathic pain syndromes, preferably for the treatment of neuropathy, diabetic neuropathy, peripheral neuropathic pain, post-herpetic pain.
CN202280022649.6A 2021-01-22 2022-01-24 Topical formulations containing dispersed pregabalin Pending CN117062603A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HUP2100019 2021-01-22
HUP2100021 2021-01-22
HUP2100021A HU231389B1 (en) 2021-01-22 2021-01-22 Topical pharmaceutical composition comprising modified phospholipid
PCT/HU2022/050005 WO2022157527A1 (en) 2021-01-22 2022-01-24 Topical formulation containing dispersed pregabalin

Publications (1)

Publication Number Publication Date
CN117062603A true CN117062603A (en) 2023-11-14

Family

ID=89993279

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202280022650.9A Pending CN117062604A (en) 2021-01-22 2022-01-24 Topical formulations containing modified phospholipid compounds
CN202280022649.6A Pending CN117062603A (en) 2021-01-22 2022-01-24 Topical formulations containing dispersed pregabalin

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN202280022650.9A Pending CN117062604A (en) 2021-01-22 2022-01-24 Topical formulations containing modified phospholipid compounds

Country Status (2)

Country Link
CN (2) CN117062604A (en)
HU (1) HU231389B1 (en)

Also Published As

Publication number Publication date
CN117062604A (en) 2023-11-14
HU231389B1 (en) 2023-06-28
HUP2100021A1 (en) 2022-07-28

Similar Documents

Publication Publication Date Title
US20070082042A1 (en) Multiple-layered liposome and preparation method thereof
BRPI0410503B1 (en) TOPIC COMPOSITION AND USE OF COMPOSITION
EP3853204A1 (en) Improved and stable apremilast pharmaceutical compositions
JP7268132B2 (en) topical composition
CN104507470A (en) O/w-emulsion-type topical pharmaceutical compositions containing a retinoid
EP1588697A1 (en) Emulsion gel for topical application of pharmaceuticals
CN117062603A (en) Topical formulations containing dispersed pregabalin
JP5833541B2 (en) Oil-in-water emulsion of mometasone and propylene glycol
US20240100045A1 (en) Emulsion composition and uses thereof in the prevention and/or treatment of skin damage caused by radiation
US20240082191A1 (en) Topical formulation containing modified phospholipid compounds
US20240082190A1 (en) Topical pharmaceutical composition containing phospholipids
KR101410042B1 (en) Composition of moisturizing cosmetics containing propolis nano-vesicle
US20240091138A1 (en) Topical composition comprising pregabalin
US11400048B2 (en) Pharmaceutical oil-in-water nano-emulsion
DE60101370T2 (en) PHARMACEUTICAL COMPOSITIONS CONTAINING TERBINAFIN
HU231398B1 (en) Topical pharmaceutical composition comprising phospholipids
JP2024507266A (en) Hydrogel compositions and their use in the prevention and/or treatment of radiation-induced skin damage
JP2002193790A (en) Oil-in-water type emulsion containing scarcely water- soluble drug and method of producing the same
KR100831627B1 (en) Reverse-Phase Multi-Lamella Vesicle Capturing Aqueous Physiologically Active Ingredients
NO334330B1 (en) Anhydrous skincare comprising micronized urea, and method of preparation thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination