AU2021106377A4 - Mechanistic approach of solubility enhancement: development of hydrotropic solid dispersion - Google Patents
Mechanistic approach of solubility enhancement: development of hydrotropic solid dispersion Download PDFInfo
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- AU2021106377A4 AU2021106377A4 AU2021106377A AU2021106377A AU2021106377A4 AU 2021106377 A4 AU2021106377 A4 AU 2021106377A4 AU 2021106377 A AU2021106377 A AU 2021106377A AU 2021106377 A AU2021106377 A AU 2021106377A AU 2021106377 A4 AU2021106377 A4 AU 2021106377A4
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- hydrotropic
- drug
- ketoprofen
- meloxicam
- solid dispersion
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- 230000003165 hydrotropic effect Effects 0.000 title claims abstract description 80
- 238000011161 development Methods 0.000 title claims abstract description 7
- 239000007962 solid dispersion Substances 0.000 title claims description 36
- 238000013459 approach Methods 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 168
- 229940079593 drug Drugs 0.000 claims abstract description 167
- 238000000034 method Methods 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229940042129 topical gel Drugs 0.000 claims abstract description 16
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 56
- 229960001929 meloxicam Drugs 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 40
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 39
- 239000004299 sodium benzoate Substances 0.000 claims description 39
- 235000010234 sodium benzoate Nutrition 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 15
- 239000011521 glass Substances 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 10
- 239000011324 bead Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000004570 mortar (masonry) Substances 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 239000004809 Teflon Substances 0.000 claims description 4
- 229920006362 Teflon® Polymers 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 abstract description 81
- 229960000991 ketoprofen Drugs 0.000 abstract description 81
- 238000005063 solubilization Methods 0.000 abstract description 15
- 230000007928 solubilization Effects 0.000 abstract description 15
- 230000002209 hydrophobic effect Effects 0.000 abstract description 4
- 230000008569 process Effects 0.000 abstract description 4
- 239000003752 hydrotrope Substances 0.000 abstract description 3
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 230000001174 ascending effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 239000012530 fluid Substances 0.000 abstract 1
- 238000002483 medication Methods 0.000 abstract 1
- 239000006069 physical mixture Substances 0.000 description 55
- 238000009472 formulation Methods 0.000 description 37
- 239000000243 solution Substances 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000004458 analytical method Methods 0.000 description 28
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 25
- 229960004025 sodium salicylate Drugs 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 22
- 238000004448 titration Methods 0.000 description 17
- 238000012503 pharmacopoeial method Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 13
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 13
- 238000012937 correction Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 10
- 238000000338 in vitro Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 7
- 229940000406 drug candidate Drugs 0.000 description 7
- -1 alkali metal salts Chemical class 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 4
- 229960003464 mefenamic acid Drugs 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000000935 solvent evaporation Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 229910002483 Cu Ka Inorganic materials 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 238000012430 stability testing Methods 0.000 description 3
- 229920000298 Cellophane Polymers 0.000 description 2
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 150000002634 lipophilic molecules Chemical class 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000011548 physical evaluation Methods 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 238000010972 statistical evaluation Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 239000003684 drug solvent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000012395 formulation development Methods 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N11/00—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties
- G01N11/10—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by moving a body within the material
- G01N11/14—Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties by moving a body within the material by using rotary bodies, e.g. vane
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
- G01N13/02—Investigating surface tension of liquids
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The present invention relates to development of Topical gel and to enhance its solubility by
Hydrotropic solubilization technique. out of 100%, around 40% of drugs exhibit the
lipophilic behavior ultimately leads to poor bioavailability. Most strategies are streamlined to
improve the fluid solvency in order to upgrade the proficiency as well as lessening the
reactions for specific medications. Process of Hydrotropic solubilization persist a novel and
promising methodology to improve the solvency of drugs with poor water solvency by
ascending the dissolvability to many folds with the involvement of hydrotropes meloxicin,
ketoprofen etc . To extricate the balance between hydrophilic as well as hydrophobic part of
hydrotropes counts by the prospects of hydrotropic solubilization. Hence, there is
advancement in hydrotropy plus in novel drug delivery system and also in the mechanism of
hydrotropic drugs with their compatibilities and biocompatibilities.
Description
[0001] The present invention relates to a novel pharmaceutical application of hydrotropic solubilization for solubility enhancement of poorly water-soluble drugs, development of solid dispersion and topical gel
[0002] The dissolution of solid particles (solute) into a liquid phase (solvent) in order to form homogeneous mixture, this phenomenon is known as Solubility The most important pre-formulation parameters i.e. solubility influence the performance of the substances. During the drug development process, solubility is considered to be the most relevant properties. Even though around 40% of new chemical entities hence unfit to reach the market because of its water insoluble behavior. Water insoluble property or poor aqueous solubility fabricates not only during formulation development as well as clinical screening still generate a hindrance while discovering the new chemical entities for various activities In the current scenario, the oral route is preferred as the most conveniently used route for drug administration as compared to the other route of administration.
[0003] For the oral route, the drug to be administered should of good aqueous solubility, poor aqueous solubility of drugs leads to poor absorption of drug which affects the bioavailability and causes gastrointestinal mucosal toxicities Hence, to minimize the solubility obstacles, numerous solubility enhancement techniques should be attempted industrially as well as economically to improve the solubility of poorly soluble drugs Hydrotropic solubilization methods are a promising, eco-friendly, non-inflammable, and cost-effectiveness of hydrotropes results in superior than other solubility enhancement techniques Therefore, an attempt has been made to focus on and highlight the application of hydrotropic solubilization techniques to improve solubility.
[0004] The extension in the solubility of lipophilic drugs through the addition of satisfactorily concentration of alkali metal salts of various organic acids is designated by hydrotropy. The ability to solubilize the lipophilic compounds, various hydrotropic agents has been employed to boost its solubility parameters exhibited non-micelle forming structure, either elaborated through liquid or solids, organic or inorganic nature. Chiefly, it comprises of two significant parts i.e., an anionic group as well as a hydrophobic aromatic ring system demonstrated the chemic al structure of conventional Neubergs hydrotropic salts. [Thus, for hydrophobic substances, the anionic group has a capability to bring about aqueous solubility Contrastingly, the planarity of the hydrophobic part accentuate essential factor in the mechanism of hydrotropic solubilization which is cast by polar group to bring into the solution. the potentiality of particular salts deliberate to solubilize or dissolved the lipophilic compounds show insolubility in water phase by making it soluble in water. Hence, it is widely utilized for the preparation of aqueous dye solutions in chemical industry. In addition to uplift the aqueous solubility of numerous water insoluble drugs hence hydrotropic solubilization had been adopted for the sake of assessment of hydrotropic solubilization utilizing various organic compounds.
[0005] The prior art section being reported:
[0006] A drug-delivery system is described which can serve as a platform for the topical delivery of a wide variety of therapeutic agents to the skin. Specifically, a topical external analgesic gel contains ketoprofen, a skin penetration enhancer/cosolvent, a thickening agent and a base to adjust pH. The formulation uses a relatively small number of safe components and is easy to prepare with a high yield of finished product. The chemical stability of ketoprofen in the gel and the physical stability of the gel itself ensure a satisfactory shelf- life for the product. The gel is aesthetically pleasing (i.e., easy water washability, non-irritating to skin, non-staining of clothing, etc.) and has proven to provide rapid relief of musculoskeletal pain, thereby helping to ensure patient compliance.The prepared topical gel is differ from this as it involves the ehnacement of solubility by Hydrotropic solublization technique.
[0007] SUMMARY
[0008] The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
[0009] The present invention is generally directed to the hydrotropic solubilization to eliminating the organic solvent by aqueous hydrotropic solution.
[00010] The present invention is generally directed to the NSAIDs category drugs candidate were elected as ideal drug and their water solubility properties were upgraded by the numerous hydrotropic agent.
[00011] An embodiment of the present invention is to substitute the toxic, volatile as well as costly organic solvent, with the easily available, Ecofriendly, safe hydrotropic agent.
[00012] An embodiment of the present invention is NSAIDs category drug was selected as a model drug, as a lipophilic drug candidates and their solubility enhanced by hydrotropic agent in which solid dispersion of these drugs were prepared by solvent evaporation method.
[00013] An embodiment of the present invention is hydrotropic agent behave as water-soluble carrier at an temp of 60-65 °C and consequently the solid mass behave as a solid dispersion of lipophilic drugs.
[00014] It is an embodiment of the present invention is prepared Solid dispersion, is expected to give fast dissolution rate of drug resulting in rapid onset of action and better bioavailability An embodiment of the present disclosure
[00015] Figure.1. represents the Fourier transform-infrared spectra of Meloxicam, HSD and PM
[00016] Figure 2. Represents the DSC of Meloxicam bulk drug, HSD, PM
[00017] Fig.3. DSC of Ketoprofen bulk drug, HSD, PM with Sodium benzoate
[00018] Fig: XRD of Meloxicam, HSD, PM
[00019] The following description is of exemplary embodiments only and is not intended to limit the scope, applicability or configuration of the invention in any way. Rather, the following description provides a convenient illustration for implementing exemplary embodiments of the invention. Various changes to the described embodiments may be made in the function and arrangement of the elements described without departing from the scope of the invention.
[00020] The foremost step was to select the different hydrotropic agents for NSAIDs drugs. In this step, the appropriated hydrotropic agents are selected with the drug for the preparation of hydrotropy solid dispersion.
[00021] Pre-formulation studies execute the significant objectives to set up the necessary physicochemical characteristics of the novel dosage form, setup the compatibility between the drug and excipients and essentially determine the kinetic release rate of the drug.
[00022] EXAMPLE 1: FT-IR SPECTROSCOPY:
[00023] The infrared spectrum of pure Meloxicam bulk drug alone is recorded using Fourier transform infrared spectroscopy (FTIR) by involving a neat analysis method. Here, in this method the drugs spread on a KBr plate and pressed under hydraulic pressure. Thus, infrared radiation-exposed into the drug and the signals are collected by the detectors which sequentially liberated spectra provide the detailed functional groups exhibited in the molecule.
IR studies of Ketoprofen bulk drugs alone
[00024] The infrared spectrum of pure Ketoprofen bulk drug alone is recorded using Fourier transform infrared spectroscopy (FTIR) by involving a neat analysis method. Here, in this method the drugs spread on a KBr plate and pressed under hydraulic pressure. Thus, infrared radiation-exposed into the drug and the signals are collected by the detectors which sequentially liberated spectra provide.
[00025] Table.1. FTIR interactions of ketoprofen drug
Functional group Range (Cm-1) Observed frequency (Cm-1)
Alkanes 600-1500 758.24
Aromatic ring 1500-1600 1528.7
Alcohol 1000-1300 1261.6
Amines 3300-3500 3291
Carboxylic acid 1680-1760 1710.7
[00026] EXAMPLE 2: EQUILIBRIUM SOLUBILITY DETERMINATION
[00027] Equilibrium solubility of Meloxicam
[00028] The equilibrium solubility studies implemented in a variety of hydrotropic agents. By making the solution of hydrotropic agent i.e., sodium acetate, sodium benzoate, sodium acetate, and sodium salicylate etc. They are prepared individually at a different molar concentration. To attain the equilibrium solubility add excess amount of Meloxicam in 10 ml of vial contain1Oml of hydrotropic solution shaken mechanically in water bath for about 12 hours thus, saturated solution executed after the equilibration. In order to find out the enhancement ratio in aqueous solubility hence, following formula has been adopted.
[00029] Equilibrium solubility determination of Ketoprofen
[00030] The equilibrium solubility studies implemented in a variety of hydrotropic agents. The aqueous hydrotropic agent prepared individually at a different molar concentration. Similarly, to achieve the equilibrium solubility, the above procedure has been executed by adding excess amount of Ketoprofen shaken in a water bath shaker in order to execute the saturated solution which is equilibrated for 24 hours after shaking mechanically the vial containing the sample. Hence, following formula has been elaborated in order to calculate the enhancement ratio in solubility.
[00031] Enhancement ratio= Solubility of drugs in hydrotropic solution
[00032] Solubility of drugs in distilled water
[00033] Table 2: Equilibrium solubility determination
Drug Solvent Solubility Required Solubility system value (%w/v) Temperature Enhancement (0 C) ratio value
Meloxicam Distilled 0.24% 250C water
Ketoprofen Distilled 0.008% 25 0 C water
Meloxicam 2M Sodium 13.6% 25 0 C 56.6 benzoate
Ketoprofen 2M Sodium 10.8% 25 0 C 105.0
benzoate
4M Sodium salicylate 8.4% 25 0 C 135.0
[00034] EXAMPLE 3: Titrimetric estimation of Meloxicam elected as a model drug candidate For Pharmacopoeial method
[00035] In order to perform the titrimetric estimation through Indian Pharmacopoeial method of meloxicam bulk drug sample, hence weighed accurately 0.lg of bulk drug into conical flask containing 100ml of ethanol (95%). Thus, the solution was titrated with 0.1M sodium hydroxide solution after shaking the flask to dissolve the drug using specified ml of phenolphthalein solution as indicator. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice.
[00036] For Proposed method
[00037] In order to perform the titrimetric analysis of Meloxicam bulk drug sample using 2M Sodium benzoate as a hydrotropic agent exhibit maximum solubility; accurately weighed drug sample around 0.1g to a conical flask to a specified ml of hydrotropic solution shaken 5min of flask to solubilize the drug. Thus, using specified ml of phenolphthalein solution as indicator where 0.1 M sodium hydroxide solution utilized to carry out the Titration. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice. The titrimetric methods of analysis of the bulk drug sample by Pharmacopoeial and proposed methods were followed to estimate the drug contents of the drug samples of Ketoprofen and Meloxicam by Pharmacopoeial and proposed methods.
[00038] EXAMPLE 4: Titrimetric estimation of Ketoprofen (Sodium benzoate) elected as a model drug candidate
[00039] For Pharmacopoeial method
[00040] In order to perform the titrimetric analysis, weighed accurately around 0.1M bulk drug sample i.e., Ketoprofen under the Indian Pharmacopoeial method, sample is transferred to a conical flask containing 100 ml of ethanol (95%). After shaking the flask to dissolve the drug, the sodium hydroxide solution was utilized for titration process with the use of two or three drops of phenolphthalein solution which act as indicator. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice.
[00041] For Proposed method
[00042] In order to perform the titrimetric analysis of Ketoprofen bulk drug sample by the use of hydrotropic gent i.e., 2M Sodium benzoate as a hydrotropic solubilization technique depicted maximum solubility; accurately weighed 0.lg of bulk drug sample is transferred to a conical flask. The flask was shaken for 5 min after adding specified ml of hydrotropic solution to solubilize the drug. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice with sodium hydroxide solution 0.1M and using phenolphthalein. The titrimetric methods of analysis of the bulk drug sample by Pharmacopoeial and proposed methods were followed to estimate the drug contents of the drug samples of Mefenamic acid, Ketoprofen and Meloxicam by Pharmacopoeial and proposed methods.
[00043] EXAMPLE 5: Titrimetric estimation of Ketoprofen (Sodium salicylate) elected as a model drug candidate
[00044] Pharmacopoeial method
[00045] In order to perform the titrimetric analysis under the Indian Pharmacopoeial method, accurately weighed 0.lg of bulk drug sample i.e., Ketoprofen is transferred to a conical flask containing 100 ml of ethanol (95%) After shaking the flask to dissolve the drug. To calculate the drug content, a necessary correction was made by performing Blank titration by 0.1 M sodium hydroxide solution and phenolphthalein solution as indicator thus, analyzing the determination thrice.
[00046] For Proposed method
[00047] In order to perform the titrimetric analysis of Ketoprofen bulk drug sample
4M Sodium salicylate as a hydrotropic agent using hydrotropic solubilization technique showing maximum solubility; accurately weighed 0.lg of bulk drug sample is transferred to a conical flask. The flask was shaken for 5 min after adding specified ml of hydrotropic solution to solubilize the drug. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice. The titrimetric methods of analysis of the bulk drug sample by Pharmacopoeial and proposed methods were followed to estimate the drug contents of the drug samples of Mefenamic acid, Ketoprofen and Meloxicam by Pharmacopoeial and proposed methods using 0.1M sodium hydroxide solution with specified ml of phenolphthalein solution as indicator.
[00048] EXAMPLE 6: titrimetric analysis of marketed formulation of all drugs by pharmacopoeial method (involving organic solvent)
[00049] Titrimetric estimation Meloxicam elected as a model drug candidate
[00050] For Pharmacopoeial method
[00051] First of all weighed accurately 0.lg of bulk drug sample i.e., meloxicam in order to perform the titrimetric analysis, by Indian Pharmacopoeial method, which is successfully transferred to a conical flask containing 100 ml of ethanol (95%). After shaking the flask to dissolve the drug, the titration occurs with 0.1 M sodium hydroxide solution with specified ml of phenolphthalein solution as indicator. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice.
[00052] For Proposed method
[00053] Using hydrotropic solubilization technique in order to carry out the titrimetric analysis of Meloxicam bulk drug sample by 2M Sodium benzoate as a hydrotropic agent exhibit maximum solubility; accurately weighed 0.lg of bulk drug sample is transferred to a conical flask. The flask was shaken for 5 min after adding specified ml of hydrotropic solution to solubilize the drug for titration estimation using 0.1 M sodium hydroxide solution with the addition of phenolphthalein solution as indicator. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice.
Table.3. Titrimetric analysis of poorly soluble drugs by pharmacopoeial method (involving organic solvent)
Amount of Method Estimate % Coefficient of Standard error bulk drug has analysis drug content variation taken (mg) (Mean S.D.) (0)
100 IPM 99.82+0.305 1.76 0.176
100 PTM 98.15+0.25 1.45 0.145
[00054] Titrimetric estimation of Ketoprofen (sodium benzoate) elected as a model drug candidate
[00055] For Pharmacopoeial method
[00056] Ketoprofen bulk drug sample is used in order to perform the titrimetric analysis by Indian Pharmacopoeial method; accurately weighed 0.lg of bulk drug sample is transferred to a conical flask containing 100 ml of ethanol (95%). To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice. After shaking the flask to dissolve the drug, 0.1 M sodium hydroxide solution were used for titration analysis using specified ml of phenolphthalein solution as indicator.
[00057] For Proposed method
[00058] In order to perform the titrimetric analysis of Ketoprofen bulk drug sample using hydrotropic solubilization technique by use of the 2M Sodium benzoate as a hydrotropic agent exhibit maximum solubility; accurately weighed 0.lg of bulk drug sample is transferred to a conical flask. The flask was shaken for 5 min after adding specified ml of hydrotropic solution to solubilize the drug. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice. The titrimetric methods of analysis of the bulk drug sample by Pharmacopoeial and proposed methods were followed to estimate with 0.1 M sodium hydroxide solution using specified ml of phenolphthalein solution as indicator to find out the drug contents of the drug samples of Mefenamic acid, Ketoprofen and Meloxicam by Pharmacopoeial and proposed methods.
[00059] Table 4: Data on an analytical estimation of Ketoprofen (Sodium benzoate) bulk drug sample by IP and Proposed method with statistical evaluation
Amount of bulk Method Estimate % drug Coefficient of Standard analysis content variation error The drug has taken (mg) (Mean S.D.) (%)
100 IPM 99.25+1.155 1.166 0.618
100 SBM 98.97+1.033 1.044 0.596
[00060] Titrimetric estimation of Ketoprofen (sodium salicylate) elected as a model drug candidate
[00061] For Pharmacopoeial method
[00062] The titrimetric analysis of Ketoprofen bulk drug sample hence performed, by Indian Pharmacopoeial method, accurately weighed 0.lg of bulk drug sample is transferred to a conical flask containing 100 ml of ethanol (95%). After shaking the flask to dissolve the drug, the solution was titrated with 0.1 M sodium hydroxide solution using specified ml of phenolphthalein solution as indicator. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice.
[00063] For Proposed method
[00064] In order to perform the titrimetric analysis of Ketoprofen bulk drug sample, hydrotropic solubilization technique were exhibited by the use of 4M Sodium salicylate exhibit maximum solubility; accurately weighed 0.lg of bulk drug sample is transferred to a conical flask. The flask was shaken for 5 min after adding specified ml of hydrotropic solution to solubilize the drug and preformed withO.1 M sodium hydroxide solution using specified ml of phenolphthalein solution as indicator. To calculate the drug content, a necessary correction was made by performing Blank titration and analyzing the determination thrice. The titrimetric methods of analysis of the bulk drug sample by Pharmacopoeial and proposed methods were followed to estimate the drug contents of the drug samples of Mefenamic acid, Ketoprofen and Meloxicam by Pharmacopoeial and proposed methods.
[00065] Table 5 : Data on an analytical estimation of Ketoprofen (Sodium salicylate) bulk drug sample by IP and Proposed method with statistical evaluation
Amount of bulk Method Estimate % drug Coefficient of Standard analysis content variation error The drug has taken (mg) (Mean S.D.) (%)
100 IPM 99.25+1.155 1.166 0.618
100 SBM 98.97+1.033 1.044 0.596
[00066] EXAMPLE 7: PREPARATION OF HYDROTROPIC SOLID DISPERSION AND PHYSICAL MIXTURE
[00067] Preparation of hydrotropic solid dispersion and physical mixture of Meloxicam
[00068] Preparation of hydrotropic solid dispersion of Meloxicam and sodium benzoate in 1:4 ratio, (MeLSB 1:4 HSD), accurately weighed 0.4 g of sodium benzoate and 0.1 g of Meloxicam were used. To prepare this, firstly agitated Teflon coated magnetic beads facilitated for the dissolution of hydrotropic solution into a 250ml beaker and kept on the magnetic stirrer throughout the high speed. After that, weighed 0.lg of meloxicam bulk drug sample into the hydrotropic solution maintain at the temperature of °C by vaporizing the water liberating solvent evaporation method. As the evaporation exceeded, decreased the speed of beads automatically, stop stirring consequently from the hydrotropic solid dispersion. Again in order to remove the remaining moisture, the wet solid dispersion at first kept in a hot air dry oven maintained at 60-65 OC. The solid dispersion is crushed using a clean and dry glass pestle mortar, after a complete drying, and then put in a desiccator for about 6 days, and stored in an airtight container.
[00069] Preparation of hydrotropic solid dispersion and physical mixture of Ketoprofen (Sodium benzoate)
[00070] Preparation of hydrotropic solid dispersion of Ketoprofen and sodium benzoate in 1:4 ratio, (KSB 1:4 HSD), accurately weighed 0.4 g of sodium benzoate and 0.1 g of Ketoprofen were used. In a 250 ml beaker at a high speed magnetic stirrer, Dissolution of the hydrotropic solution which is assisted by the agitation of Teflon coated magnetic bead. Then, 0.1 g of bulk drug are dissolved in the hydrotropic solution, After complete dissolution of the hydrotropic solution, maintain the temperature at 80°C in order to volatilization of the water ensuring the method i.e., solvent evaporation method. When most of the water is evaporated, as evaporation proceeded hence, the speed of the bead decreased automatically, which stopped stirring, results in the formation of the solid dispersion. At 60-65 OC maintained temperature, the prepared wet solid dispersion was kept in a hot air dry oven removing the residual moisture. Using a clean and dry glass pestle mortar, the prepared solid dispersion is crushed, after a complete drying, and then put in a desiccator for about 6 days, and in an airtight glass bottle is stored.
[00071] Preparation of hydrotropic solid dispersion and physical mixture of Ketoprofen (sodium salicylate)
[00072] Preparation of hydrotropic solid dispersion of Ketoprofen and sodium salicylate in 1:4 ratio, (KSS 1:4 HSD), accurately weighed 0.4 g of sodium salicylate and
0.1 g of Ketoprofen were used. At a high speed of magnetic stirrer promoted by the Dissolution of the hydrotropic solution throughout the agitation of Teflon coated magnetic bead containing in a 250 ml beaker. in the above prepared hydrotropic solution, 0.1 g of bulk drug are dissolved where the temperature is maintained at 80°C to gasification of water exhibiting solvent evaporation method. The formation of the hydrotropic solid dispersion had been formed, when most of the water is evaporated by decreasing the speed of the bead automatically, as evaporation preceded hence, stopped stirring after the prepared wet solid dispersion was kept in a hot air dry oven to remove the unused moisture maintaining the temperature of 60-65 °C. At last to store in an airtight bottle, the prepared solid dispersion is crushed using a clean and dry glass pestle mortar, then put in a desiccator for about 6 days, after a complete drying.
[00073] Preparation of physical mixture of Meloxicam
[00074] Accurately weighed 0.1g Meloxicam and 0.4g sodium benzoate were triturated intensely for 10 min to formulate the physical mixture of Meloxicam and sodium benzoate in ratio 1:4 (Mef SB 1:4 PM) to make a use of glass pestle and mortar as well. Then, sieve through #100 and stored in a desiccator.
[00075] Preparation of physical mixture of Ketoprofen (Sodium benzoate)
[00076] In ratio 1:4 (KSB 1:4 PM) prepare physical mixture of Ketoprofen and sodium benzoate, weighed accurately 0.lg Ketoprofen and 0.4g sodium benzoate let into the glass pestle and mortar which was triturated vigorously for 10 min using. It is stored in a desiccator after sieving the powder mass through # 100.
[00077] Preparation of physical mixture of Ketoprofen (Sodium salicylate)
[00078] Using glass pestle and mortar were used to prepare physical mixture of Ketoprofen and sodium salicylate in ratio 1:4 (KSB 1:4 PM). At first weighed accurately 0.lg Ketoprofen and 0.4g sodium salicylate for 10 min were triturated intensely. Powder mass was shifted through sieve # 100 and thus stored in a desiccator.
[00079] Table 6 : Respective drug content of hydrotropic solid dispersion and physical mixture of Ketoprofen + Sodium benzoate (n=3)
Drug name Drug: hydrotropic Percent drug content (Mean S.D.) agent ratio
(Meloxicam:sodium Physical Hydrotropic solid
mixture dispersion benzoate ratio)
Meloxicam 1: 4 7.33+0.03 9.733 0.006
1: 6 4.93+0.014 8.53 0.004
1: 8 5.86+0.014 4.8 0.005
Drug name Drug: hydrotropic agen1 Percent drug content (Mean S.D.) ratio (Ketoprofen: sodium benzoate ratio) Physical Hydrotropic solid mixture dispersion
Ketoprofen 1: 4 6.05+0.03 6.43+0.057
1: 6 5.42+0.057 5.4+0.066
1: 8 4.03+0.21 4.33+0.049
[00080] EXAMPLE 8: Determination of drug content in physical mixtures (PM) and hydrotropic solid dispersions (HSD)
[00081] Determination of drug content in Meloxicam formulations (HSD and PM)
[00082] Accurately weighed and transferred about 10 mg of Meloxicam into a 10.0 ml of volumetric flask in order to prepare powdered solid dispersion and physical mixture as well after that 5ml of distilled water put into the flask, shaken to dissolve the physical mixture and formulation also. Hence, the volume was made up to the mark and at 269 nm the absorbance was examine against the reagent and hence the analysis carried out in triplicate form with the utilization of regression equation Y=0.005X for the determination of drug content.
[00083] Determination of drug content in Ketoprofen (Sodium benzoate) formulations (HSD and PM)
[00084] For the sake of preparing the solid dispersion as well as physical mixture, weighed about 10 mg of Ketoprofen (Sodium benzoate) and put into 10.0 ml of volumetric flask. For complete dissolution of formulation as well as physical mixture add and shake ml of distilled water into the flask. For the analysis, the made solution was estimated at 254nm to examine the absorbance (triplicate) in UV against reagent blank solution and by the use of regression equation Y=0.005X hence, the drug content had been determine.
[00085] Determination of drug content in Ketoprofen (Sodium salicylate) formulations (HSD and PM)
[00086] Weighed 10 mg of Ketoprofen (Sodium salicylate) to formulate the powdered solid dispersion/physical mixture and poured into a 10.0 ml of volumetric flask. Shake to dissolve into 5ml of distilled water and the mark with it. Hence, for the analysis, carryout in triplicate form to determine the absorbance of the solution at 254nm against reagent blank solution. Thus, the obtained regression equation i.e., Y=0.005X hence, the drug content was determined.
[00087] Table 7 : Respective drug content of hydrotropic solid dispersion and physical mixture of Ketoprofen + Sodium salicylate (n=3)
Drug name Drug: hydrotropic Percent drug content (Mean S.D.) agent ratio (Ketoprofen: sodium Physical Hydrotropic solid benzoate ratio) mixture dispersion
Ketoprofen 1: 4 5.38+0.065 6.43+0.03
1: 6 3.53+0.002 5.1+0.004
1: 8 1.93+0.06 3.40+0.08
[00088] EXAMPLE 9: FOURIER-TRANSFORM INFRARED SPECTROSCOPY
[00089] IR studies of formulation of Meloxicam drugs
[00090] (JASCO, FTIR-4100, Japan) Fourier transforms infrared spectroscopy spectra was exhibited for the drug i.e., Meloxicam, Physical mixture and its HSD was determined. To mix with dry potassium bromide at first approximately weighed 1-2 mg of Meloxicam, their Physical mixture and its HSD over a wave number range of 4000 to 400 cm-i for analysis the samples were examined in a transmission mode.
[00091] IR studies of formulation of Ketoprofen (Sodium benzoate) drugs
[00092] Fourier transforms infrared spectroscopy spectra of the Ketoprofen, Physical Mixture and HSD (Sodium benzoate) was observed For data analysis, samples were examined in a transmission mode over a wave number range of 4000 to 400 cm-1. Approximately 1-2 mg of Ketoprofen their PMs and HSD as well were mixed with dry potassium bromide.
[00093] IR studies of formulation of Ketoprofen (Sodium salicylate) drugs
[00094] (JASCO, FTIR-4100, Japan) Fourier transforms infrared spectroscopy spectra of the Ketoprofen, PMs and its HSDs (Sodium salicylate) were observed. To precede the process, approximately 1-2 mg of Ketoprofen, Physical Mixture as well as its HSD was mixed with dry potassium bromide. For data analysis, the samples were examined over a wave number range of 4000 to 400 cm-lin a transmission mode.
[00095] Fig.1. represents the Fourier transform-infrared spectra of Meloxicam, HSD and PM
[00096] EXAMPLE 10: DIFFERENTIAL SCANNING CALORIMETRY
[00097] DSC studies of formulation of Meloxicam drugs
[00098] The Mettler DSC studies were carrying out using the thermal characteristics of meloxicam, physical mixture, and also it's HSD. At first weighed accurately the samples around 5.0 mg were kept in aluminum pans sealed hermetically; heating and cooling cycle was applied from 20-400 oC throughout the constant rate of °C/minute. At a flow rate of 20 ml/min, an inert atmosphere was maintained through purging with nitrogen gas.
[00099] Fig.2. Represents the DSC of Meloxicam bulk drug, HSD, PM
[000100] DSC studies of formulation of Ketoprofen (Sodium benzoate) drugs
[000101] For Ketoprofen (Sodium benzoate), PM, and its HSD hence, a Mettler DSC were evolved to carry out the thermal evaluation. From 20-300 oC at a constant rate of C/min thus, samples were weighed approximately at 5.0 mg were hermetically sealed in aluminum pans, and a heating and cooling cycle was applied where at flow rate of 50 ml/min therefore, Nitrogen gas had been purged.
[000102] DSC studies of formulation of Ketoprofen (Sodium benzoate) drugs
[000103] The thermal characteristics were studied by Mettler DSC for Ketoprofen (Sodium benzoate), PM as well as its HSD. Approximately 5.0 mg sample were weighed accurately and kept aluminum pans which was hermetically sealed and at a constant rate of 10oC/minute where a heating and cooling cycle was applied successfully from 20-300 oC. At flow rate of 50 ml/min, an inert atmosphere i.e., nitrogen gas was purged.
[000104] EXAMPLE 11: X-RAY POWDER DIFFRACTION
[000105] XRD studies formulation of Meloxicam drugs
[000106] The pure form of Meloxicam bulk drugs, their physical mixture, and hydrotropic agents were noted through the (Philips 1710) X-ray powder diffractometer The X-ray diffraction patterns were recorded using Cu-Ka radiation (X= 1.5405980A), a current of 30 mA and a voltage of 40 kV. The samples were analyzed, over 20, range with a scan step size of 20/ 2cm per step.
[000107] XRD studies formulation of Ketoprofen (Sodium benzoate) drugs
[000108] The pure Ketoprofen (Sodium benzoate) bulk drugs, their physical mixture, and hydrotropic agents were recorded by X-ray powder diffractometer (Philips 1710). The X-ray diffraction patterns were recorded using Cu-Ka radiation (X= 1.5405980A), a current of 10 mA and a voltage of 30kV. The samples were analyzed, over 20, range with a scan step size of 5-50 0per step.
[000109] Fig.3. Fig DSC of Ketoprofen bulk drug, HSD, PM with Sodium benzoate
[000110] XRD studies formulation of Ketoprofen (Sodium salicylate) drugs
[000111] X-ray powder diffractometer (Philips 1710) has been used to record the pure Ketoprofen (Sodium salicylate) bulk drugs, their physical mixture, and hydrotropic agents were recorded using Cu-Ka radiation (X= 1.5405980A), a current of 10 mA and a voltage of 30 kV. The samples were analyzed, over 20, range with a scan step size of 5 500per step.
[000112] EXAMPLE 12: Stability study of Meloxicam its HSD and PM
[000113] Similarly, Meloxicam drugs, its prepared hydrotropic solid dispersions and physical mixtures were subjected to chemical stability testing (Thermo Lab, Mumbai, India). Powders of various formulations were kept in 10 ml colorless glass vials and vials
were plugged and sealed. Vials were kept at room temperature, at 55°C in the oven and
°C with 75% RH in ICH certified stability chamber. It used assessed for physical changes and drug content thus, at different time intervals. For each formulation, the initial drug content was maintained at 100.0%.
[000114] Stability study of Ketoprofen (Sodium benzoate) its HSD and PM
[000115] The Ketoprofen (Sodium benzoate) drugs were subjected to chemical stability testing as well as its prepared hydrotropic solid dispersions and physical mixtures (Thermo Lab, Mumbai, India). Powders of various formulations were kept in 10 ml colorless glass vials and vials were plugged and sealed. Vials were kept at room
temperature, at 55°C in the oven and 40°C with 75% RH in ICH certified stability chamber. The samples were withdrawn at different time intervals and assessed for physical changes and drug content. For each formulation, the initial drug content was maintained at 100.0%.
[000116] Stability study of Ketoprofen (Sodium salicylate) its HSD and PM
[000117] Ketoprofen (Sodium salicylate) drugs, its prepared hydrotropic solid dispersions and physical mixtures of were subjected to chemical stability testing (Thermo Lab, Mumbai, India). Powders of various formulations were kept in 10 ml colorless glass
vials and vials were plugged and sealed. Vials were kept at room temperature, at 55°C in
the oven and 40°C with 75% RH in ICH certified stability chamber. At different time intervals and assessed for physical changes and drug content, the sample were withdrawn. For each formulation, the initial drug content was maintained at 100.0%.
[000118] To check the stability of prepared HSD as well as physical mixture for three months specifically at room temperature, around 40°C/75% RH appearing in 55°C of Meloxicam, and Ketoprofen was executed for this studies. The residual drug content after three months storage, these formulations were used to determine the chemical stability where each formulation exhibited their initial drug content which was considered as 100.0%. Hence, it is the residual drug content of all formulations exhibited 98% deliberated very good chemical stabilities. Whereas, all formulations possess 96% at °C/75% RH exhibited good chemical stabilities at moderate temperature. And in other hand all formulation after 3 months of storage exhibited good chemical stabilities above 90.0% at 55°C
[000119] EXAMPLE 13: IN-VITRO DISSOLUTION STUDY
[000120] The dissolution rate of drugs i.e., Meloxicam and Ketoprofen drug alone, PMs and HSDs were executed to performed, the in-vitro dissolution studies containing drug: hydrotropic agent of 1:4 ratio thus weighed having equivalent dose around 0.1g. To process it, it is executed in an USP TypeII i.e., paddle apparatus (Electro lab, Mumbai, India) which was set at 50.0 RPM fill up with the 900ml distilled water by keeping the temperature at 37±0.5 oC throughout the experiment. To precede this, at first takeout 5.0 ml of aliquot throughout the pre-established time interval i.e., 5, 10, 20, 30, 45, and 60 minutes. Hence it was again filter out by Whatmann filter paper possess 0.45 pm pore size. Now, the coming out filtrate were spectrophotometrically analyzed at their specified wavelength by keeping their volume sustained with the replacement of distilled water.
[000121] Table: In-vitro dissolution study of Meloxicam, HSD, PM
Time(min) Pure drug(Meloxicam) PM (Meloxicam 1:4) HSD(Meloxicam 1:4)
0 0 0
12.18 17.24 25.02
18.48 25.42 34.32
20.96 36.84 55.42
24.02 48.16 66.74
26.5 55.16 82.26
28.34 58.26 90.58
[000122] Table: In-vitro dissolution study of Ketoprofen, HSD, PM with Sodium benzoate
Time(min) Pure drug(Ketoprofen + PM (Ketoprofen + HSD(Ketoprofen +
sodium benzoate) sodium benzoate 1:4) sodium benzoate 1:4)
0 0 0
9.25 16.4 25.55
18.3 27.45 39.86
21.01 36.61 49.01
25.86 44.91 63.22
27.45 47.96 78.16
30.5 54.06 87.32
[000123] Table: In-vitro dissolution study of Ketoprofen, HSD, PM with sodium salicylate
Time(min Pure drug(Ketoprofen + PM (Ketoprofen + sodium HSD(Ketoprofen
+ sodium salicylate) salicylate 1:4) sodium salicylate 1:4)
0 0 0
7.15 18.3 26.05
12.2 24.4 37.86
18.3 35.71 48.96
24.4 44.91 58.22
26.55 51.01 71.37
32.81 57.11 84.43
[000124] EXAMPLE 14: PREPARATION OF TOPICAL GEL OF POORLY
[000125] The prepared HSD has been furthermore selected for development of topical gel exhibiting high solubility potential. Dispersing 20 % w/w Carbopol 940, 10% w/w SLS, 10 % w/w SLS, with the addition of sufficient glycerin at proper quantity throughout continuous stirring has been utilized for the Gel formulations at the 2hours period of time. At first the meloxicam drug were dissolved in distilled water and added to the Carbopol 940 solution possess sodium lauryl sulfate as well as glycerin throughout the continuous stirring. Hence, then allowed to hydrate which start to swell long with the pH adjustment and stirred vigorously until the homogeneous gel was formed and allowed to equilibrate for at least 24 hours at room temperature.
[000126] EXAMPLE 15: EVALUATION OF TOPICAL GEL
[000127] PHYSICAL EVALUATION
[000128] The physical evaluation of prepared topical gel was checked on the basis of clarity, color, homogeneity, presence of particles, and fibers.
[000129] SPREADABILITY
[000130] In order to perform the Spreadability of prepared topical gel hence, an apparatus has been utilized contain a wooden block possessing a glass plate as well as pulley attached on other side. First place around 2gm of prepared topical gel placed on the lower plate. A weighed has been placed on the plates concerning to element air between two plated. Hence, to ensure the better Spreadability at shorter time interval, a distance has been covered i.e., 10cm in which the upper plate put through the pull and thus, note the time. The Spreadability value designate the degree of shear required to apply the gel that lie down between 8.4 - 15gm.cm/sec. Table: Showed Spreadability values for the formulation.
[000131] Table: Spreadability of Topical gel of Meloxicam
S.no Formulation Spreadability (g.cm/sec)
1 Meloxicam topical gel 8.35
[000132] MEASUREMENT OF pH
[000133] The pH where measured of prepared gel formulation by the help of digital pH meter which is calibrated utilizing standard buffer solution having pH 4 and 7. Then the pH meter was dipped in the gel solution containing the gel about 2 gm was dispersed in 25 ml of purified water and record the pH respectively.
[000134] The pH of formulations was found in the range of 4.65 to 6 which lies in the normal pH range of skin.
[000135] VISCOSITY
[000136] Brookfield's viscometer determine the viscosity of prepared gel consist of sample holder as well as spindle (No.7) by maintaining constant optimum speed which are lowered perpendicularly into the sample including gel. The spindle was allowed to rotate, recorded at room temperature.
[000137] Summarized the analyzed the viscosity at different RPM of prepared gel i.e., 2, 4, 10, and 20 rpm. As the viscosity is directly proportional to the gelling agent concentration. Thus, it indicate the shear thinning property by lowering the rotating speed as the viscosity decreased
[000138] Table. Viscosity of Topical gel of Meloxicam
S.no. Formulation Required 2 Required 4 Required 10 Required 20 RPM RPM RPM RPM
1 Meloxicam 16000 cps 14300 cps 11500 cps 6100 cps topical gel
[000139] IN-VITRO DIFFUSION STUDY: CELLOPHANE MEMBRANE
[000140] Cellophane membrane i.e., no. 10, pore size 2.4 nm has been used for permeation studies; a modified Franz diffusion cell was incorporated. As it is soaked in a phosphate buffer for 24 hour at pH 6.8 before use. To perform this, it possess two compartments i.e., donor and receptor. To the donor compartment, thus 0.1mg prepared topical gel was placed and in the receptor compartment placed 25 ml of distilled water agitated on a magnetic stirrer at the temperature of 37±1°C at 50 rpm. At a specific interval of time, an Aliquots were withdrawn and hence their absorbance at specified wavelength at 269nm and replaced with an equal volume of fresh phosphate buffer pH 6.8 by suitably diluted it.
[000141] For preparation and diffusion study of prepared gel showed maximum drug release in distilled water presented graphically and exhibits a better release profile. But, the drug release rate diminishes from the formulations as the gelling agent concentration upgraded due to the increase in viscosity of the prepared gel formulation illustrated in Table. In-vitro drug diffusion study
[000142] Table : In-vitro drug diffusion study
Time(min) Cumulative % drug release)
0 0
5 10.24
10 16.44
20 29.48
30 40.62
45 59.09
60 78.22
[000143] While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.
Claims (2)
1. A method for development of meloxicam topical gel with enhanced solubility comprising the steps:
i.place 0.4 gm of sodium benzoate into a 250ml beaker containing teflon coated magnetic beads and kept on the magnetic stirrer throughout the high speed;
ii. add 0.lg of meloxicam drug into the beaker and maintain the temperature at 800 c;
iii. as the evaporation exceeded, decreased the speed of beads automatically;
iv. stop stirring consequently from the hydrotropic solid dispersion;
v.remove the excess moisture, place wet solid dispersion in hot air dry oven maintained at 60-65 Oc;
vi. crushing the solid dispersion using a clean and dry glass mortar pestel;
vii.finally place in desiccator for about 6 days.
2. A method for development of meloxicam topical gel as claimed in claim 1, wherein the preparation method consists of;
i.dissolving prepared hydrotropic meloxicam drug in distilled water;
ii.adding mixture dropwise containing carbopol 940 solution possess sodium lauryl sulfate as well as glycerin throughout the continuous stirring for about 2 hours;
iii.finally pH was adjusted and stirring vigorously to form the homogenous gel and allow to equilibrate for 24 hrs.
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