291 results about "Lactide" patented technology

The invention discloses an absorbable suture line for surgical suture and a preparation method thereof, and relates to the technical field of medical materials. The absorbable suture line for surgical suture is prepared from the following raw materials in parts by weight: 50 to 65 parts of polylactic acid, 15 to 20 parts of polyglycolic acid, 3 to 5 parts of sodium carboxymethyl cellulose, 3 to 8 parts of a toughening agent, 3 to 6 parts of an antibacterial agent, 0.3 to 0.8 part of a lubricating agent, 1 to 2 parts of sodium hyaluronate and 5 to 10 parts of polyvinyl alcohol. The toughening agent is obtained by reacting hydroxyethyl acrylate with ethylenediamine to generate a four-arm compound and then reacting with 6-caprolactone and DL-lactide. The absorbable suture line for surgical suture prepared by the invention has excellent tensile property and antibacterial property, and can meet the application requirements of clinical medical treatment.

The invention provides a poly-L-lactic acid microsphere. The poly-L-lactic acid microsphere is obtained by performing membrane emulsification on a poly-L-lactic acid-polyethylene glycol copolymer synthesized by taking lactide and polyethylene glycol as raw materials. According to the L-polylactic acid microspheres disclosed by the invention, the uniformity, the stability and the biocompatibility of the microspheres are improved, and meanwhile, the synthesis of skin collagen is promoted.

The invention relates to the technical field of polyester degradable plastics, and discloses a biodegradable shrink film as well as a preparation method and application thereof. The preparation method of the biodegradable shrink film comprises the following steps: reacting (R)-3-hydroxybutyric acid with 1, 4-dibromobutane to obtain a dihydric alcohol monomer; the preparation method comprises the following steps: copolymerizing a dihydric alcohol monomer and L-lactide to obtain modified polylactic acid; carrying out copolymerization on the geraniol-based compound and L-lactide to obtain a bio-based plasticizer; modifying the bio-based plasticizer with allyl trimethyl ammonium chloride to obtain a modified bio-based plasticizer; the biodegradable shrink film is prepared by taking modified polylactic acid, poly (butylene adipate-co-terephthalate), a modified bio-based plasticizer, a functional filler and palm wax as raw materials. The biodegradable shrink film has the advantages of flexibility, shrinkage performance, lasting antibacterial performance and good barrier performance, and can be used in food packaging materials.

The invention discloses a preparation method of antibacterial modified polylactic acid for a packaging material, and belongs to the technical field of functional modification of polylactic acid.The preparation method comprises the steps that an antibacterial barrier type polylactic acid composite material is prepared through ring opening polymerization of an initiator, grafting of antibacterial molecules and blending of montmorillonite, a chlorine-terminated initiator is generated from ethanolamine and chloroacetyl chloride, and the antibacterial modified polylactic acid is prepared; the preparation method comprises the following steps: initiating ring-opening polymerization of L-lactide to form polylactic acid with terminal group activity, covalently grafting terminal group chlorine with an antibacterial modifier through nucleophilic substitution, endowing the polylactic acid with antibacterial property, coupling modified montmorillonite with silane through organic intercalation, and then carrying out melt blending with the modified polylactic acid with antibacterial property to form a layered barrier structure and enhance interface bonding. Therefore, the film has the advantages of high barrier property, high tensile strength, excellent antibacterial activity and good degradability.

The invention belongs to the technical field of high polymer materials, and discloses copolyester based on 4-aryl-epsilon-caprolactone and lactide as well as a preparation method and application of the copolyester. The copolyester is composed of a lactide structural unit and a 4-aryl-epsilon-caprolactone structural unit. A rigid benzene ring is introduced into a molecular chain, so that the synergistic balance of toughness and rigidity is successfully realized, and the toughness is remarkably improved while the high strength of the material is maintained. In addition, the introduction of phenyl endows the material with intrinsic ultraviolet resistance, the material can be used as an efficient ultraviolet absorbent, protective spherical protrusions are formed on the surface of the material under ultraviolet irradiation, and photooxidative degradation is effectively delayed. The material can be widely applied to the fields of high-performance degradable packaging, biomedical materials, outdoor articles, textiles and the like.

The invention discloses an absorbable suture line containing fibroin and a preparation method of the absorbable suture line, and relates to the technical field of absorbable suture lines. The absorbable suture line containing the silk protein is prepared from the following raw materials in parts by weight: 35 to 50 parts of silk protein, 10 to 20 parts of polylactic acid, 15 to 25 parts of polyglycolide-lactide, 1 to 3 parts of antibacterial agent, 2 to 5 parts of modified toughening agent, 1 to 4 parts of nano mineral filler, 0.5 to 2 parts of cross-linking agent and 2 to 5 parts of plasticizer, the preparation method comprises the following steps: reacting protocatechuic acid with ethanolamine to generate an intermediate 1; and reacting the intermediate 1 with 5, 10, 15, 20-tetra (4-carboxyl phenyl) porphyrin to generate the antibacterial agent. The prepared absorbable suture line containing the silk protein has good mechanical performance, self-repairing performance and antibacterial performance.

The invention provides an L-lactide purification device and an L-lactide purification method. The L-lactide purification device comprises a crystallization unit, an evaporation unit, a condensation unit and an extraction unit, the crystallization unit is at least used for crystallizing, sweating and melting the raw materials to form L-lactide and crystallization raffinate; the inlet of the evaporation unit is communicated with the crystallization residual liquid outlet of the crystallization unit, and the evaporation unit is at least used for evaporating the crystallization residual liquid to form evaporation gas; an inlet of the condensation unit is communicated with a gas phase outlet of the evaporation unit, and the condensation unit is at least used for condensing the evaporation gas to form condensate; a liquid phase inlet of the extraction unit is communicated with a liquid phase outlet of the condensation unit, and the extraction unit is at least used for extracting condensate to form a first component containing L-lactide; the outlet of the extraction unit is communicated with the crystallization unit, so that the crystallization unit adopts the first component as a raw material for crystallization. According to the embodiment of the invention, the yield of the L-lactide can be improved, and the L-lactide with high chemical purity and high optical purity can be obtained.

The present application relates to the field of biological glass, in particular to a kind of composite biological glass and its preparation method and application.The present application uses rhBMP-2, doped antibacterial ion 45S5 bioactive glass and polyethylene glycol-lactide-glycolide polymer compound preparation slow-release antibacterial biological glass, the rhBMP-2 can occur synergistic effect with doped antibacterial ion 45S5 bioactive glass, compared with homologous growth factor can play more optimal synergy with antibacterial ion, so as to have higher antibacterial property and osteogenesis, while having longer slow-release effect in polyethylene glycol-lactide-glycolide polymer.The composite biological glass provided by the present application overcomes the pain points of the prior art for the treatment of oral bone defect, improves the treatment effect, reduces the amount of antibiotic use, and reduces the risk of infection.

Provided are compositions that include a histone deacetylase inhibitor (HDACi) encapsulated in and / or otherwise associated with a nanoparticle. In some embodiments, the HDACi is romidepsin, vorinostat, belinostat, panobinostat, and / or chidamide. In some embodiments, the nanoparticle is a poly(D,L-lactide)-PEG-methyl ether (mPEG-PDLLA) nanopolymer. Also provided are methods for treating diseases, disorders, and / or conditions associated with sensitivity to histone deacetylase inhibitors, such as but not limited to tumors and / or cancers; and methods for inhibiting the growth, proliferation, and / or metastasis of a tumor and / or a cancer associated with sensitivity to histone deacetylase inhibitors by administering an effective amount of a composition as disclosed herein, which methods can optionally include administering at least one additional therapeutically active agent, such as but not limited to a chemotherapeutic agent.

The invention provides a degradable fiber temporary plugging agent and a preparation method thereof, and belongs to the technical field of oil-gas field development. The temporary plugging agent is composed of polylactic acid-polyurethane block copolymer fibers, and the preparation method of the temporary plugging agent comprises the steps that S1, lactide and an initiator containing dihydroxyl are subjected to ring opening polymerization under the action of a first catalyst, and a hydroxyl-terminated prepolymer is formed; s2, reacting the prepolymer with diisocyanate under the action of a second catalyst to synthesize a polylactic acid-polyurethane block copolymer; s3, preparing fibers through a melt spinning or electrostatic spinning process; the degradation rate and the mechanical property of the fiber can be regulated and controlled by regulating and controlling the initiator type, the diisocyanate type, the isocyanato index R value and the catalyst dosage, so that the fiber is suitable for the wide-temperature-range reservoir conditions of 45-120 DEG C, and the technical problems of contradiction between the strength and the degradability, narrow temperature adaptability, secondary damage to the reservoir and the like of a traditional temporary plugging agent are effectively solved.

The invention belongs to the technical field of block copolymers, and particularly relates to an amphiphilic block copolymer, a stereocomplex and a preparation method and application of the amphiphilic block copolymer and the stereocomplex. The amphiphilic block copolymer contains a polyester block and a water-soluble polymer block, and by forming a monomer of the polyester block, on the premise that raw materials such as D, L-lactide serve as first monomers, a second monomer with stereoregularity is introduced, so that the stability of the amphiphilic block copolymer can be improved, and meanwhile, the water solubility or self-dispersity of the amphiphilic block copolymer is still kept; and micelle or nano-particles are formed, and high drug loading capacity is maintained.

The invention relates to a separation qualitative and quantitative detection method for L-lactide, D-lactide and Meso-lactide, and belongs to the field of lactide optical purity detection.The separation qualitative and quantitative detection method comprises the following steps that firstly, various lactide standard curves of different configurations are established respectively, the concentration range of the standard curves is 10-1000 mg / L, and the concentration range of the standard curves is 10-1000 mg / L; the plurality of lactides with different configurations comprise one or more of L-lactide, D-lactide and Meso-lactide; and the lactide with different configurations comprises one or more of the L-lactide, the D-lactide and the Meso-lactide. 2, detecting by using a gas chromatograph-mass spectrometer, and quantitatively calculating a lactide substance to be detected, wherein the concentration range of the lactide substance to be detected is 200-1000mg / L; according to the invention, separation and quantitative detection of three lactide optical isomers are realized by using an analysis method; the influence of impurities in the to-be-detected substance of lactide on the accuracy of the quantitative result of lactide is reduced; qualitative and semi-quantitative information of the impurities in the to-be-detected substance is provided.

The invention discloses a degradable antibacterial anti-inflammatory polyurethane sponge and a preparation method thereof. The preparation method of the polyurethane sponge comprises the following steps: preparing caprolactone / lactide copolymer diol by taking epsilon-caprolactone, DL-lactide and 1, 4-butanediol as raw materials under the action of an organic zinc catalyst ZCAT-T50, and then preparing the polyurethane sponge by taking polyethylene glycol and the caprolactone / lactide copolymer diol as raw materials and 4, 4 '-dicyclohexylmethane diisocyanate as a cross-linking agent under the action of the organic zinc catalyst ZCAT-T50. And finally, sequentially adding an organic zinc catalyst ZCAT-T50, a chitosan oligosaccharide emulsion and a budesonide ethanol solution into the polyurethane prepolymer, and carrying out chain extension, foaming and curing, so as to prepare the budesonide-modified polyurethane composite material. The polyurethane sponge prepared by the invention has excellent mechanical properties, degradability and antibacterial and anti-inflammatory properties, is suitable for making medical hemostatic sponge, and has remarkable economic value and social benefit.

The invention discloses a lumepirone long-acting microsphere sustained-release preparation without a release stagnation period in an early stage, which comprises a lumepirone active ingredient and a medicinal polymer auxiliary material in a mass ratio of (1: 4)-(1: 1), the medicinal polymer auxiliary material is at least one of glycolide-lactide copolymers with the weight-average molecular weight of 5000-150000 Da, and the molar ratio of lactic acid units to glycolic acid units of the glycolide-lactide copolymers is (50: 50)-(95: 5). The lumepirone long-acting microsphere sustained-release preparation without a release arrest phase in the early stage is obtained by specially limiting drying conditions in liquid and medicinal polymer auxiliary materials, the release of the lumepirone long-acting microsphere sustained-release preparation can be maintained for 2 weeks to 1 month without oral administration of the long-acting sustained-release microspheres of lumepirone capsules, the safety and effectiveness of the medicine are met, and the sustained-release preparation is suitable for clinical application. Meanwhile, the problems of early-stage long-time stagnant release and early-stage burst release of the long-acting microsphere preparation can be solved, the compliance can be effectively improved, convenience is provided for patients to the maximum extent, and the economic cost is reduced.

The invention belongs to the technical field of algal polysaccharide extraction, and discloses a modification extraction method of algal asparagus polysaccharide and a method for preparing a lutein coating by using the algal asparagus polysaccharide. The modified extraction method comprises the following steps: extracting gracilaria lemaneiformis powder with a weak base solution, enabling lactide and polysaccharide to be subjected to grafting reaction through a redox initiation system under the assistance of ultrasonic waves, and then separating out a first polysaccharide component with high emulsibility and a second polysaccharide component with high gel property through graded alcohol precipitation. The two obtained functional components are used for coating xanthophyll, specifically, the first polysaccharide component emulsifies a xanthophyll oil phase to form a pre-emulsion, the second polysaccharide component is compounded with gelatin, a composite coacervate is formed on an oil drop interface by adjusting the pH value, and finally drying and curing are conducted. According to the method, two modified polysaccharides with definite functions can be synchronously obtained, the prepared xanthophyll coating is high in encapsulation efficiency, good in storage and processing stability and excellent in water dispersibility, and the problems that xanthophyll is unstable and difficult to apply are effectively solved.

This disclosure relates to crystalline forms of 3-acyl-buprenorphine derivatives and sustained release injectable pharmaceutical compositions for treatment of opioid dependence, pain or depression, including an aqueous suspension of crystalline 3-acyl-buprenoprhine, or a pharmaceutically acceptable salt thereof, wherein the composition does not include an organic solvent, a polylactide polymer, a polyglycolide polymer, or a copolymer of polylactide and polyglycolide. This disclosure also includes 3-acyl-buprenoprhine or a pharmaceutically acceptable salt thereof prepared in a controlled release matrix, including poly(lactide-co-glycolide), sucrose acetoisobutyrate, lecithin, diolein and a combination of two or more thereof.

The application discloses polylactic acid polyol as well as a preparation method and application thereof, and the preparation method comprises the following steps: preparing an in-situ catalyst by heating reaction of a zinc salt, an organic ammonium salt and bis(ethylene carbonate) ether; the anion of the organic ammonium salt is selected from any one of bromide, chloride and iodide; and a lactide monomer is added to obtain polylactic acid polyol through a polymerization reaction. The polylactic acid polyol prepared by the application has a flexible chain segment, can provide better flexibility, and can be applied to preparation of polyurethane materials.

This invention discloses a lactide-Nisin solid dispersion and its preparation method. The method includes preparing a mixture of lactide and a hydrophobic solvent; dispersing Nisin in the mixture obtained in the previous step to obtain a multi-component mixture; and cold-treating the multi-component mixture to obtain a solid mixture containing lactide and Nisin. This invention fully utilizes the binding properties of lactide and Nisin, effectively enhancing the stability of Nisin in complex environments, further expanding the application potential of the prepared antibacterial agent, and providing a new approach for developing multifunctional green food preservatives.

The present invention belongs to the technical field of patch materials and relates to a double-layer composite patch with a healing and repairing function and a preparation method thereof. The double-layer composite patch is composed of an oriented fiber layer and a random dense layer composited up and down; the components of the oriented fiber layer are synthetic polymers and natural polymers, the synthetic polymer is polylactic acid, poly (L-lactide-caprolactone) or poly (lactic acid-glycolic acid copolymer), and the natural polymer is insoluble type I collagen; during preparation, the oriented fiber membrane obtained by electrospinning is first cut and pre-tensioned and placed in a bidirectional clamping device, and then the bidirectional clamping device is placed in a vacuum oven for annealing treatment, and finally the random dense membrane obtained by electrospinning and the oriented fiber membrane after annealing treatment are composited by ultrasonic welding to obtain the double-layer composite patch. The double-layer composite patch of the present invention has both anti-inflammatory and repair functions while achieving the synergy of "exogenous efficient barrier" and "endogenous precise guidance" functions; the preparation method is simple.

The application provides a degradable material, which comprises poly(lactic acid-amino acid) / polycaprolactone microspheres; the poly(lactic acid-amino acid) / polycaprolactone microspheres are prepared by blending poly(lactic acid-amino acid) and polycaprolactone; the proportion of poly(lactic acid-amino acid) and polycaprolactone in the poly(lactic acid-amino acid) / polycaprolactone microspheres is (1-10):(1-10); the polymerization monomers of the poly(lactic acid-amino acid) comprise lactide and amino acid, and the proportion of the lactide and the amino acid is (2-10):1; the median particle size D50 of the poly(lactic acid-amino acid) / polycaprolactone microspheres is 30-300 mu m, and the particle size distribution is less than 1.0. The poly(lactic acid-amino acid) / polycaprolactone microspheres provided by the application solve the problems of slow degradation rate, poor hydrophilicity and mechanical property of the existing degradable material by introducing the hydrolysis bond group in the amino acid, and have good degradation performance and stability.

Disclosed herein is a polysialic acid (PSA)-polymer conjugated compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein P is a poly (lactide-co-glycolide)-poly (ethylene glycol) copolymer (PLGA-PEG) and p is an integer from 4 to 200; nanoparticles comprising the same; and methods of treating ophthalmic diseases using the same. (I)

The invention discloses a composite material for oral bone repair and a preparation method and application thereof, and the composite material comprises the following components in parts by mass: 40-60 parts of a polymer matrix and 40-60 parts of a reinforcing filler dispersed in the polymer matrix; wherein the polymer matrix comprises a multi-arm polycaprolactone-lactide copolymer, and the reinforcing filler comprises hydroxyapatite of which the surface is modified with hydrophobic molecules. According to the invention, the composite material for repairing the oral cavity bone, which is moldable and anti-collapsing and has a degradation rate matched with bone growth, and the preparation method and the application of the composite material can be provided.

The invention discloses a beta-ketimine type binuclear aluminum complex and a preparation method thereof. The binuclear aluminum complex can be used for catalyzing ring opening polymerization of caprolactone, lactide, glycolide, valerolactone, butyrolactone or ethylene carbonate. The invention further discloses a preparation method and application of the binuclear aluminum complex. The preparation method is simple, the reaction condition is mild, the prepared beta-ketimine type binuclear aluminum complex is used as a catalyst, the catalytic activity is high, the stability is good, the service life is long, the molecular weight distribution of the obtained polymerization product is narrow, and the beta-ketimine type binuclear aluminum complex can be well applied to the ring-opening polymerization reaction of cyclic ester.

The invention relates to a preparation method of polylactic acid. Lactide is subjected to a polymerization reaction under the action of a catalyst, polylactic acid is prepared, the structural formula of the catalyst is shown in the formula (1), in the formula (1), R1, R2 and R3 are independently selected from-H or C1-C10 alkyl groups, x and y meet the condition that the algebraic sum of positive and negative valences in the structural formula is 0, and M is selected from metal elements of the IA group, the IIA group, the IIIA group, the IVA group, the IB group or the IIB group. According to the invention, by adding the catalyst with the synergistic catalysis effect of ring-opening polymerization and racemization of lactide, the ring-opening polymerization reaction of lactide is effectively promoted, and the racemization reaction of lactide is controlled, so that the ratio of L-lactic acid to D-lactic acid units in a polylactic acid product is controlled, the melting point of polylactic acid is adjusted, the production cost is reduced, and the product quality is improved. The limitation of raw materials is eliminated, so that the prepared polylactic acid product can be suitable for more application fields.

The present invention provides a preparation method for lactide, and direct lactide and depolymerized lactide. The preparation method comprises: carrying out a prepolymerization reaction on lactic acid to obtain a prepolymerized product; demonomerizing the prepolymerized product; the components separated from the prepolymerized product after demonomerization including direct lactide; and carrying out a depolymerization reaction on the remaining prepolymerized product after demonomerization to obtain depolymerized lactide. The preparation method of the present invention involves a simple process, and lactide having high optical purity can be obtained without melt crystallization.

The invention provides a pure PLA fabric, production equipment and a process, and relates to the technical field of chemical fiber production. The pure PLA fabric production equipment comprises polymerization equipment, a discharge pump, a granulator, spinning equipment, fiber processing equipment, negative pressure equipment, protective gas supply equipment and weaving equipment. According to the invention, the organic guanidine catalyst, the D-lactide and the L-lactide are stirred and uniformly mixed by the stirrer and then form a continuous fluid on the reaction tank through the nozzle in the spray head, the continuous fluid flows through the dead weight of the fluid and then forms a film shape, and the film-shaped fluid can accelerate the separation of internal water vapor in the reaction process, so that the reaction efficiency is improved. The dip angle of the reaction tank can be controlled by driving the cam to rotate through the first motor, so that the flowing speed of fluid on the reaction tank can be conveniently controlled, the reaction time can be accurately controlled, and when a mixture is sprayed out through the spray head, multiple cutting and mixing actions are formed through the metal net, so that the dispersion degree of a catalyst is further improved; and the condition of catalyst agglomeration is avoided.

The invention discloses a guanidyl zinc / aluminum complex as well as a preparation method and application thereof, and relates to the technical field of polymerization catalysts. The guanidyl zinc / aluminum complex prepared by the invention has a single catalytic activity center, and accurate control on the structure and molecular weight of a polymer can be realized by regulating and controlling a ligand structure, metal types and polymerization conditions. The catalyst has the remarkable advantages of low toxicity, low cost, simplicity in synthesis, high catalytic activity, stable performance and the like, and is suitable for lactone ring-opening polymerization reaction. Under the protection of inert gas, the polycaprolactone has excellent activity when catalyzing polymerization of lactide, caprolactone and other lactone monomers, the molecular weight of the obtained polycaprolactone is up to 219.2 kg / mol, and an effective way is provided for preparation of high-molecular-weight polyester. In addition, the catalyst can still keep high activity and stability under simulated industrial conditions, and has wide industrial application prospects.

The invention discloses a skin implant, the skin implant is a freeze-drying agent, the freeze-drying agent is prepared from the following components in parts by weight: 2-15 parts of a PEG-PLA copolymer and 0.05-4.0 parts of hyaluronate, the PEG-PLA copolymer is prepared from a single-terminal hydroxyl polyethylene glycol compound and lactide through a polymerization reaction, and the hyaluronate is prepared from the following components in parts by weight: 1-10 parts of a cross-linking agent, 1-10 parts of a cross-linking agent, 1-10 parts of a cross-linking agent and 1-10 parts of a cross-linking agent. The mass ratio of the single-end hydroxyl polyethylene glycol to the lactide is (2.0-8.5): 1, and the molecular weight of the hyaluronate is 10-100 WDa. The skin implant provided by the invention has an excellent redissolution speed and can be quickly redissolved within 10 minutes, and the quick redissolution characteristic of the freeze-drying agent greatly facilitates clinical operation and shortens the preoperative preparation time.

This invention discloses a biomass hot melt adhesive and its preparation method, belonging to the field of environmentally friendly adhesive technology. Addressing the industry pain points of existing biomass hot melt adhesives, such as difficulties in melt processing and the inability to simultaneously achieve both bonding performance and environmental friendliness, this invention uses a modified lignin graft copolymer prepared by a ring-opening grafting reaction of lignin sulfonate with L-lactide and ε-caprolactone as the matrix, compounded with nano-cellulose whiskers, cashew phenol-based plasticizers, composite crosslinking agents, and bio-based antioxidants to construct a fully biomass formulation system. The product is obtained through a solvent-free melt reaction blending process. The product of this invention is completely biodegradable, possesses excellent hot melt processability, bonding strength, water resistance, and storage stability, and the preparation process is green and environmentally friendly, suitable for large-scale industrial production, and can replace traditional petroleum-based hot melt adhesives.

The invention belongs to the field of high polymer materials, and discloses a method for efficiently catalytically synthesizing polylactic acid, which is characterized by comprising the following steps: adding lactide, a tin catalyst and an initiator into a reactor, quickly heating to 180 + / -20 DEG C under the protective atmosphere and stirring, and carrying out polymerization reaction for more than 10 minutes to obtain high-molecular-weight polylactic acid; the initiator is hydroxy acid and is monobasic acid. The lactide polymerization rate is greatly improved, the polymerization reaction can be completed within more than ten minutes, the lactide conversion rate is 94% or above, the molecular weight is 2.17 * 10 < 5 > Da or above, and the lactide reaches the level of commercial polylactic acid. Compared with a tin catalyst and a tin catalyst / alcohol composite catalytic system, the catalytic system has the advantages that the polymerization rate at the initial reaction stage is increased by 20-30%, and the reaction time is shortened by more than 80%. The catalytic system is applied to a process for synthesizing polylactic acid through reactive extrusion, and the production efficiency of an extruder can be remarkably improved.