33 results about "Flurbiprofen" patented technology

The invention relates to the technical field of preparation of small molecule compound medicines, in particular to a preparation method of (S)-flurbiprofen. The method comprises the following steps: dropwise adding a tetrahydrofuran solution of 4-bromo-2-fluorobiphenyl into a mixture of tetrahydrofuran and magnesium, and reacting to generate a Grignard reagent; mixing tetrahydrofuran, (S)-vinyl chloride oxide and ferric acetylacetonate, dropwise adding the Grignard reagent, performing acidolysis ring opening, and performing methylation with methyl iodide and magnesium iodide to obtain an alpha-hydroxyl aromatic carboxylic acid derivative; and reacting with sodium chlorite, nitroxide free radicals and acetonitrile, and oxidizing to obtain the (S)-flurbiprofen. By introducing a chiral induction unit, effective transmission of chiral information is realized in a coupling stage, an original chiral center is not destroyed in a subsequent reaction, and a product is ensured to have a highly consistent configuration. According to the scheme, the technical problem that a method capable of remarkably improving the optical purity and yield of (S)-flurbiprofen is lacked in the prior art can be solved, and the method has good environmental friendliness and industrial application prospects.

The application discloses a synthesis method of flurbiprofen and an intermediate thereof. The intermediate of the flurbiprofen is 3-fluoro-4-biphenyl boronic pinacol ester, and the synthesis method comprises the following steps: step A: 2-fluoro-4-bromobiphenyl is subjected to a coupling reaction with bispinacolyl diboron under the action of an alkali and a metal catalyst to obtain 3-fluoro-4-biphenyl boronic pinacol ester. The synthesis method of the flurbiprofen comprises the following steps: step C: 3-fluoro-4-biphenyl boronic pinacol ester is subjected to a coupling reaction with sodium 2-bromopropionate under the action of an alkali and a metal catalyst, and then the obtained reaction product is acidified to obtain flurbiprofen. According to the application, 2-fluoro-4-bromobiphenyl is prepared into 3-fluoro-4-biphenyl boronic pinacol ester, and then the 3-fluoro-4-biphenyl boronic pinacol ester is subjected to a Suzuki coupling reaction with sodium 2-bromopropionate to prepare flurbiprofen, the method has less side reactions, and the molar yield is high, which is obviously higher than the yield in the literature of preparing flurbiprofen by means of Grignard reaction.

The invention relates to the technical field of biological medicine, in particular to an exosome medicine preparation for treating knee osteoarthritis and a preparation method thereof, and the exosome medicine preparation is characterized in that an exosome is derived from mesenchymal stem cells subjected to three-dimensional culture in a first hydrogel matrix containing sodium alginate and hyaluronic acid; flurbiprofen or a pharmaceutically acceptable salt or ester thereof; and a pharmaceutically acceptable second gel matrix. Sodium alginate and hyaluronic acid composite hydrogel serves as a three-dimensional culture carrier of mesenchymal stem cells, a joint microenvironment is simulated to induce stem cells to secrete high-activity exosomes rich in key functional nucleic acid and active protein, meanwhile, the exosomes are scientifically compounded with flurbiprofen, and synergistic mechanisms of anti-inflammatory analgesia and tissue repair are achieved; and a local slow-release delivery system is constructed through the second gel matrix, so that long-acting stable release of active ingredients is realized, the systemic side effect of the medicine is reduced, the bioavailability of the exosome is improved, and the problems of obvious side effect, limited repair effect and the like in the prior art are solved.

The invention relates to a preparation method of (S)-flurbiprofen with high optical purity. The method comprises the following steps: by taking racemic flurbiprofen as a raw material, reacting with a resolving agent in a solvent to obtain optically pure diastereomer salt; the obtained diastereomer salt is recrystallized and purified by a solvent, so that the optical purity is further improved; acidifying the purified diastereomer, and filtering or extracting with an organic solvent to obtain a crude product (S)-flurbiprofen; and completely dissolving the crude product (S)-flurbiprofen with a benign solvent, adding pure water, and recrystallizing to obtain the (S)-flurbiprofen with high optical purity. The resolving agent required by the preparation method is novel, cheap and easy to obtain, the resolving effect is good, the enantiomeric excess is greater than or equal to 98.0%, the yield is high, the cost is low, the operation is simple, step-by-step amplification from the 10 g level to the hectogram level to the kilogram level is completed, the process is reproducible, and the amplification feasibility is realized.

The invention relates to a preparation method of a diamine chiral resolving agent. The method comprises the following steps: by taking chiral alpha-amino acid as a raw material, reacting the chiral alpha-amino acid with (Boc) 2O and alkali in a solvent to obtain Boc-protected amino acid; in a solvent, the Boc-protected amino acid and secondary amine are subjected to catalysis of a condensing agent and alkali to obtain Boc amino-protected secondary amide; dissolving the Boc amino protected secondary amide in an organic solvent, and removing a Boc protecting group under an acidic condition to obtain chiral alpha-amino secondary amide; and reducing the chiral alpha-amino secondary amide into amine under the action of a reducing agent to obtain chiral amino secondary amine, namely the target product diamine chiral resolving agent. The chiral alpha-amino acid required by the preparation method is cheap and easy to obtain, the operation is simple, the obtained chiral diamine resolving agent is novel in structure, the variety of alkaline resolving agents is enriched, and the chiral diamine resolving agent is applied to resolution of racemic propionic acid compounds such as non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen and has practicability.

By increasing the dissolved concentration of a drug in a composition for external use, said composition including flurbiprofen and an adhesive agent, the present invention provides a transdermal absorption type preparation that demonstrates increased transdermal absorption of flurbiprofen, is smaller, and also has a superior long-term drug preservation property.　This transdermal absorption type preparation comprises a support body layer and an adhesive agent layer that is layered on the support body layer. The adhesive agent layer includes an adhesive agent, flurbiprofen, at least one component selected from a solubilizer and a transdermal absorption promoter, a tackifier, and a plasticizer. The solubilizer includes or does not include cyclodextrin. The adhesive agent layer does not include peppermint oil. Per 100 mass% of the adhesive agent layer, the flurbiprofen content is 3 mass% to 20 mass%, the solubilizer content excluding cyclodextrin is 0 mass% to 20 mass%, the transdermal absorption promoter content is 0 mass% to 40 mass%, the tackifier content is 5 mass% to 60 mass%, and the plasticizer content is 5 mass% to 50 mass%.

The invention relates to a method for efficiently preparing flurbiprofen based on a Suzuki-Miyaura coupling reaction. The preparation method comprises the following steps: taking ethyl cyanoacetate as a raw material, and carrying out methylation reaction on the ethyl cyanoacetate and methyl iodide or dimethyl sulfate to prepare racemic ethyl 2-cyanopropionate; the racemic ethyl 2-cyanopropionate and 4-bromine-2-fluorobiphenyl are subjected to a similar Suzuki-Miyaura reaction under the combined action of a zero-valent palladium metal catalyst, a metal stabilizer phosphine ligand and alkali, and the racemic ethyl 2-cyano-2-(2-fluoro4-biphenyl) propionate is obtained; and carrying out hydrolysis and decarboxylation on the racemic 2-cyano-2-(2-fluoro-4-biphenyl) ethyl propionate to obtain racemic 2-(2-fluoro-4-biphenyl) propionic acid, namely, the flurbiprofen. The process route comprises three steps of reaction, materials are cheap and easy to obtain, operation is simple, aftertreatment is convenient, and the obtained product is high in purity.

The invention belongs to the technical field of medicines, and particularly relates to a high-stability flurbiprofen anti-inflammatory patch and a preparation method thereof. A medicine storage adhesive layer of the high-stability flurbiprofen anti-inflammatory patch is prepared from the following raw materials in percentage by mass: 2 to 3 percent of flurbiprofen, 25 to 35 percent of a first adhesive, 6 to 20 percent of a second adhesive, 2 to 3 percent of menthol, 5 to 15 percent of a tackifier, 40 to 55 percent of a plasticizer, 0.1 to 1 percent of an antioxidant and 0.1 to 2.0 percent of an esterification inhibitor; the first adhesive is a maleic anhydride grafted styrene-isoprene-styrene block copolymer; the second adhesive is a maleic anhydride grafted styrene-isoprene-styrene block copolymer; and the second adhesive is a mixture of high-molecular polyisobutene and low-molecular polyisobutene. The auxiliary materials in the patch can effectively inhibit the reaction of the main drug and the penetration enhancer, the stability and curative effect of the product are improved, and meanwhile, the patch has good drug release property and transdermal property.

The invention provides a preparation method of high-purity efiniprofen axetil, sodium bicarbonate and magnesium sulfate are adopted to pretreat a reaction material 1-bromoethyl acetate, then the product reacts with S-flurbiprofen to prepare the efiniprofen axetil, the obtained target product is very low in impurity content and high in yield and purity, the yield reaches 98% or above, and the purity reaches 99% or above. The single impurity can be controlled to be 0.1% or below, the total impurity can be controlled to be 0.5% or below, complex post-treatment processes such as molecular distillation and column chromatography are avoided, and the whole preparation method is simple and suitable for industrial large-scale production.

The application relates to the technical field of pharmaceutical chemistry, and discloses a flurbiprofen ester enantiomer prodrug compound, a preparation method thereof, a pharmaceutical composition and purposes, the compound is (R)-AF377 or (S)-AF377, is formed by covalently connecting a carboxyl of (R)-flurbiprofen, (S)-flurbiprofen and a phenolic hydroxyl of acetaminophen through an ester bond, corresponding chiral carbons are R configuration and S configuration respectively, and structures are shown in formula (I) and formula (II). The application further provides a preparation method of the compound, a pharmaceutical composition containing the compound and purposes of the compound in pain, inflammation or fever treatment. The compound has high optical purity, releases an active ingredient in the liver, (S)-AF377 has synergistic anti-inflammatory analgesic activity, (R)-AF377 has independent analgesic activity, can reduce side effects of single drug use, improves bioavailability, and provides a new drug selection for treatment of mild to moderate inflammatory pain.

The invention discloses a method for detecting the concentration of flurbiprofen in pig tissue, and belongs to the technical field of biological medicine detection. The method provided by the invention comprises the following steps: cutting a pig tissue sample treated by flurbiprofen plaster into pieces, adding a PBS (Phosphate Buffer Solution), and grinding by using a biological homogenizer to obtain homogenate; performing vortex treatment on the homogenate to obtain vortex homogenate, then mixing the vortex homogenate with an internal standard working solution, performing vortex treatment and centrifugation to obtain a supernatant, then adding a formic acid aqueous solution, performing vortex uniform mixing, and then performing analysis by using liquid chromatography-tandem mass spectrometry. The method provided by the invention has the advantages of good repeatability, wide linear range, high sensitivity, high recovery rate, simple operation and efficient analysis.

1. Name of the product in this design: Medicine Box (Flurbiprofen Gel Patch). 2. Application of this design: This design is used for pharmaceutical packaging boxes. 3. The key design features of this product are the combination of shape and pattern. 4. The image or photograph that best illustrates the design's key points: a 3D model.

The invention relates to application of flurbiprofen in preparation of a medicine for enhancing the colorectal cancer treatment effect of a PD-L1 monoclonal antibody, the flurbiprofen can effectively inhibit the growth of the colorectal cancer, can significantly inhibit the proliferation and migration of a colorectal cancer cell line, can enhance the colorectal cancer treatment effect, and has good potential of assisting the PD-L1 monoclonal antibody in treating the colorectal cancer.

According to the external preparation composition containing the S-flurbiprofen and the preparation method of the external preparation composition, 2-mercapto benzimidazole and isopropyl myristate are compounded to serve as a stabilizer, the dosage and the proportion of the 2-mercapto benzimidazole and the isopropyl myristate are controlled, and the external preparation composition containing the S-flurbiprofen is obtained and has the advantages that the content of the S-flurbiprofen is stable; the external preparation composition of the S-flurbiprofen has the advantages of simple preparation process, low probability of crystallization, uniform release and stable quality, and is suitable for industrial large-scale production, and the whole preparation method is simple.

The invention relates to the technical field of medicines, in particular to a flurbiprofen organic silicon pressure-sensitive adhesive patch and a preparation process thereof. The patch is composed of a backing layer, a medicine storage layer and a protective layer, and the medicine storage layer takes an organic silicon pressure-sensitive adhesive as a matrix and comprises the following components in percentage by weight: 1-15% of flurbiprofen, 85-99% of the organic silicon pressure-sensitive adhesive and 0.5-5% of a composite penetration enhancer. The organic silicon pressure-sensitive adhesive is prepared from vinyl silicone oil, hydrogen-containing silicone oil, MQ silicon resin, a catalyst, an inhibitor and a solvent through hydrosilylation. The preparation method comprises the following steps: dissolving flurbiprofen in a composite penetration enhancer in advance, then mixing with an organic silicon pressure-sensitive adhesive system, coating and curing to prepare the patch. The patch disclosed by the invention has the advantages of high solubility of medicines in a matrix, uniform dispersion, controllable release behavior, moderate adhesion performance and good skin compatibility, can realize stable transdermal release of flurbiprofen, and is suitable for analgesic and anti-inflammatory external treatment.

The invention provides an Efinprofen axetil injection and a preparation method thereof, the injection is an emulsion prepared from Efinprofen axetil, oil for injection, an emulsifier, an auxiliary emulsifier, an osmotic pressure regulator, a buffer salt, a pH regulator and water for injection, compared with an oral administration route, the Efinprofen axetil injection effectively avoids adverse reaction of gastrointestinal tracts, and has the advantages of simple preparation process and low cost. Compared with the existing flurbiprofen axetil injection or emulsion, the flurbiprofen axetil injection or emulsion has the advantages that the stability is better, the dosage is greatly reduced under the condition that the treatment effect is equivalent, and the generation amount of harmful metabolites acetic acid and acetaldehyde in the body can be effectively reduced, so that the medication safety is improved, and the preparation method in the whole process is simple and suitable for industrial large-scale production.

The present application belongs to the field of pharmaceutical chemistry, and relates to a kind of flurbiprofen derivatives and its application in medicine, and pharmaceutical composition comprising such compounds and its application in medicine. Specifically, the present application provides a compound as shown in formula (I), or stereoisomer, geometric isomer, tautomer, metabolite or salt of the compound shown in formula (I), and pharmaceutical composition comprising such compounds and their application in medicine, Q-P-Z (I).

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a flurbiprofen patch composition, a flurbiprofen patch and a preparation method of the flurbiprofen patch. The flurbiprofen patch composition comprises the following components: 0.01 to 10 parts of flurbiprofen or a pharmaceutically acceptable salt thereof, 18 to 35 parts of a styrene-isoprene-styrene block copolymer, 0.1 to 5 parts of L-menthol, 0.5 to 40 parts of a tackifier, 1 to 75 parts of a plasticizer, 0 to 10 parts of an antioxidant and 0.01 to 1 part of a dispersant, and the flurbiprofen and the L-menthol form a solid dispersion. Compared with the prior art, the flurbiprofen patch composition and the flurbiprofen patch have the advantages that the flurbiprofen with relatively high concentration can be dissolved, and the flurbiprofen patch composition and the flurbiprofen patch are stable and not easy to crystallize; the flurbiprofen patch composition and the flurbiprofen patch have the advantages that the adhesion performance is better; the flurbiprofen patch composition and the flurbiprofen patch have a better drug release rate in drug release.

The present application provides a kind of antitussive and expectorant medicine, by adding flurbiprofen to traditional strong loquat, in addition to the anti-inflammatory effect of flurbiprofen, it can also significantly improve the antitussive and expectorant efficacy of traditional strong loquat; Patients do not need to take other expectorant drugs at the same time, such as ambroxol, etc., improve the compliance of cough and phlegm patients for drugs, and show obvious advantages in clinic.

The invention relates to the technical field of medicines, and particularly discloses a non-steroidal anti-inflammatory drug choline salt and a preparation method and application thereof. The salt is formed by combining a non-steroidal anti-inflammatory drug and choline; the non-steroidal anti-inflammatory drug in the salt is a component A, a component B or a component C; the component A is S-flurbiprofen; the component B is naproxen; the component C is diclofenac; the molar ratio of S-flurbiprofen to choline is 1: 5-5: 1, the molar ratio of naproxen to choline is 1: 5-5: 1, and the molar ratio of diclofenac to choline is 1: 5-5: 1. According to the non-steroidal anti-inflammatory drug-choline salt successfully prepared by adopting a melting cooling method, the solubility of the non-steroidal anti-inflammatory drug in water is greatly improved, and the non-steroidal anti-inflammatory drug is stable in structure and is not decomposed at normal temperature. According to the medicine salt, the pharmacological activity of the non-steroidal anti-inflammatory medicine is kept, the analgesic activity is improved, and pains such as headache, limb pains, dysmenorrhea, rheumatic arthritis pains and osteoarthritis pains can be rapidly relieved.

The present application relates to a kind of preparation of flurbiprofen injection method and its application, wherein, the method includes the following steps: (1) aqueous phase: in injection water, osmotic pressure regulator and basic pH regulator are added, stirring is mixed uniformly, heating, form aqueous phase;(2) oil phase: injection oil, flurbiprofen, emulsifier are mixed uniformly, heating, stirring is sheared and dissolved, form oil phase;(3) initial milk: after the oil phase and part of the aqueous phase are mixed and sheared on line, the remaining aqueous phase is all added to oil phase tank flushing, flushing water is again sheared on line, after initial milk is prepared, appropriate amount of acidic pH regulator is added, and pH value is adjusted;(4) final milk: control first temperature, initial milk is homogenized under low pressure, control second temperature, then high pressure homogenization is carried out, and final milk is prepared;(5) injection: final milk is cooled, filtered, filled, sterilized, so that flurbiprofen injection is prepared;Optionally, wherein at least one step in steps (1) to (5) is completed under nitrogen protection.

The invention discloses a flurbiprofen axetil-containing pharmaceutical composition in the technical field of pharmaceutical preparations. The flurbiprofen axetil-containing pharmaceutical composition comprises flurbiprofen axetil and an intestinal carboxylesterase 2 inhibitor. The intestinal carboxylesterase 2 inhibitor can obviously inhibit intestinal carboxylesterase 2 from hydrolyzing flurbiprofen axetil to release flurbiprofen, so that the local concentration and accumulation of flurbiprofen in gastrointestinal tract tissues are obviously reduced, the damage of flurbiprofen to gastrointestinal mucosa is reduced, the bioavailability of flurbiprofen is improved, the effect is enhanced, the toxicity is reduced, and the preparation method is simple and convenient. The composition is suitable for inflammatory disease and pain management requiring long-term administration.

This invention provides a topical composition comprising, by total weight of the composition: 1) 0.5-5% esflurprofen or a pharmaceutically acceptable salt thereof; 2) 1-10% an accelerator; and 3) 0.5-5% peppermint oil; wherein the accelerator is selected from one or more of clomiphene, isopropyl myristate, tributyl acetylacetonate, diethyl phthalate, propylene carbonate, glyceryl triacetate, hexyl laurate, and isopropyl palmitate. The composition provided by this invention exhibits good release and permeation properties, and the topical patch possesses good application properties, good adhesion, and is easy to peel off, maintaining stability during long-term storage.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a flurbiprofen hyaluronic acid coupling drug (conjugate) and a preparation method, a pharmaceutical composition and application thereof. The conjugate provided by the invention is formed by condensation reaction of amino of a compound shown as a formula (I) and carboxyl or carboxylate radical of hyaluronic acid or pharmaceutically acceptable salt thereof, L is C1-C6 alkylene, the average molecular weight of hyaluronic acid is 4-1500KDa, and the introduction rate of the compound shown as the formula (I) in the conjugate is 2-30%. According to the invention, flurbiprofen is taken as a main body, and the properties of the compound coupled with hyaluronic acid with different molecular weights and the treatment effect on osteoarthritis are researched. Results show that the treatment effect of the conjugate is remarkably improved compared with that of a pure hyaluronic acid preparation, and coupling products of flurbiprofen and hyaluronic acids with different molecular weights have good drug effects. And in the druggability aspect, the conjugate with lower molecular weight has better properties.

The application belongs to the technical field of medicine, and particularly relates to a high-stability flurbiprofen anti-inflammatory patch and a preparation method thereof. The raw materials and mass percentage contents in the storage adhesive layer of the high-stability flurbiprofen anti-inflammatory patch are as follows: 2-3% of flurbiprofen, 25-35% of a first adhesive, 6-20% of a second adhesive, 2-3% of menthol, 5-15% of a tackifier, 40-55% of a plasticizer, 0.1-1% of an antioxidant, and 0.1-2.0% of an esterification inhibitor. The first adhesive is a maleic anhydride grafted styrene-isoprene-styrene block copolymer. The second adhesive is a mixture of high-molecular polyisobutylene and low-molecular polyisobutylene. The patch can effectively inhibit the reaction between the main drug and the penetration enhancer, improve the stability and curative effect of the product, and has good drug release and transdermal properties.

Provided is a patch which has a preservative effect even without containing a preservative, and which has good adhesiveness. The present invention relates to an adhesive patch provided with a support and a paste layer laminated on the support, in which the paste layer contains flurbiprofen, a partially neutralized polyacrylic acid, starch-grafted acrylic acid 300, sodium carboxymethyl cellulose, a methyl acrylate-2-ethylhexyl acrylate copolymer resin emulsion, and water, and the paste layer does not contain a preservative. Preferably, on the basis of the total mass of the paste layer, the content of the polyacrylic acid part neutralized substance is 5%-8% by mass, the content of the starch grafted acrylic acid 300 is 4%-6% by mass, the content of the sodium carboxymethyl cellulose is 0.1%-1% by mass, and the content of the methyl acrylate-2-ethylhexyl acrylate copolymer resin emulsion is 5%-10% by mass.

Composition, in particular pharmaceutical composition, especially for use in the prophylactic and / or therapeutic (symptomatic) treatment of veisalgia (alcohol intoxication, hangover), wherein the composition is in the form of a fixed dosage (fixed dosage form) for oral administration, and wherein the composition comprises an effective, in particular pharmaceutically and / or therapeutically effective, amount of active substances from the drug classes (i) non-steroidal anti-inflammatory drug (NSAID), (ii) H1 antihistamine and (iii) calcium channel antagonist, wherein the active substances are selected from Class (i): Acetylsalicylic acid, ibuprofen, dexibuprofen, flurbiprofen, naproxen, ketoprofen, tiaprofenic acid, diclofenac, indomethacin, acemetacin, flufenamic acid, mefenamic acid, piroxicam, tenoxicam, meloxicam, lornoxicam, nabumetone and / or mixtures thereof, Class (ii): Dimenhydrinate, and Class (iii): Cinnarizine.

According to the flurbiprofen-containing transdermal patch and the preparation method thereof, the problems that an existing transdermal patch is low in medicine permeability, large in skin irritation or poor in adhesion and the like are solved, and the obtained transdermal patch is moderate in adhesion performance, free of colloid residues during stripping, small in skin irritation, good in medicine permeability, convenient to take and rapid in effect; the patient compliance is improved; compared with a conventional preparation method of a solvent type patch, the preparation method provided by the invention does not need to use an organic solvent and drying equipment, and the whole preparation method is simple and suitable for industrial large-scale production.

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses an S-flurbiprofen-lidocaine ionic liquid latex agent and a preparation method and application thereof.The S-flurbiprofen-lidocaine ionic liquid latex agent is composed of S-flurbiprofen-lidocaine ionic liquid, an oil-phase substance, a surfactant, a cosurfactant, water and a gel matrix; wherein the mass percent of the S-flurbiprofen-lidocaine ionic liquid is 1-3%, the molar ratio of the S-flurbiprofen to the lidocaine is 1: 1, the mass percent of the oil phase substance is 2-47%, the mass percent of the surfactant is 2-17%, the mass percent of the cosurfactant is 2.5-15%, the mass percent of the gel matrix is 3-6%, and the balance is water; the latex agent has good transdermal performance and stability, can effectively improve the local bioavailability of S-flurbiprofen and lidocaine, and can relieve inflammatory response and pain symptoms at the same time; the traditional Chinese medicine composition is free of obvious red and swollen or anaphylactic reaction, good in safety and suitable for local treatment of various acute and chronic pains and inflammatory skin diseases.

This invention belongs to the field of pharmaceutical technology, specifically relating to a fluorinated long-chain compound, its self-assembly structure, its preparation method, and its uses. The structural formula of the fluorinated long-chain compound of this invention is shown in Formula I. It can undergo self-assembly, achieving a sustained-release effect of flurbiprofen and 4-octylitaconic acid (or analogs of both), thereby enhancing anti-inflammatory and analgesic efficacy and reducing the adverse reactions of both, showing great application potential.