Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To p...Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To prepare the solid dispersions,there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations.Polymer selection is of great importance because it influences the stability,solubility and dissolution rates,manufacturing process,and bioavailability of the ASD.This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers,formulation designs and preparation methods.Furthermore,considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.展开更多
Paracetamol (PCM) is enlisted in the WHO model list as an essential medicine for pain and palliative care, but at overdose, it causes hepatic damage. This study was designed to assess the analgesic efficacy and hepato...Paracetamol (PCM) is enlisted in the WHO model list as an essential medicine for pain and palliative care, but at overdose, it causes hepatic damage. This study was designed to assess the analgesic efficacy and hepatoprotective property of a solid dispersion (SD) loaded with PCM. A number of PCM loaded formulations (PSDs) were fabricated using silica alone or in combination with polyethylene glycol and/or Na-citrate followed by in-vitro dissolution profiling. Selected PSDs with improved dissolution profile were subjected to solid-state characterization (DSC, PXRD, FTIR, and SEM), stability study along with investigation of in-vivo analgesic efficacy and effect on hepatocytes. Among these, PSD10 showed a rapid and significantly higher in-vitro drug release than pure PCM. This improvement was distinct to other PSDs also. Solid-state characterization of PSD10 authenticated the conversion of crystalline PCM to amorphous form upon formulation. Subsequent oral administration of PSD10 in Swiss albino mice showed 1.44-fold greater analgesic efficacy than pure PCM at dose 30 mg/kg. Besides, at acute toxic dose, liver histology of PSD10 mice was comparable with NC mice indicating hepatic protection upon formulation, whereas the PCM mice showed extensive hepatic necrosis which was also endorsed by significantly higher values of SGPT, SGOT, and ALP than PSD10 mice. Finally, an accelerated stability study of PSD10 performed according to the guideline of ICH noticed no remarkable deviation in its dissolution performance as well as crystalline nature. Thus, this newly developed PSD10 may be a safe and promising alternative for pain management and palliative care.展开更多
The objective of this study was to improve the dissolution and bioavailability of silymarin(SM).Solid dispersions(SDs)were prepared using solution-enhanced dispersion by supercritical fluids(SEDS)and evaluated in vitr...The objective of this study was to improve the dissolution and bioavailability of silymarin(SM).Solid dispersions(SDs)were prepared using solution-enhanced dispersion by supercritical fluids(SEDS)and evaluated in vitro and in vivo,compared with pure SM powder.The particle sizes,stability,and contents of residual solvent of the prepared SM-SDs with SEDS and solvent evaporation(SE)were investigated.Four polymer matrix materials were evaluated for the preparation of SM-SD-SEDS,and the hydrophilic polymer,polyvinyl pyrrolidone K17,was selected with a ratio of 1:5 between SM and the polymer.Physicochemical analyses using X-ray diffraction and differential scanning calorimetry indicated that SM was dispersed in SD in an amorphous state.The optimized SM-SD-SEDS showed no loss of SM after storage for 6 months and negligible residual solvent(ethanol)was detected using gas chromatography.In vitro drug release was increased from the SM-SDSEDS,as compared with pure SM powder or SM-SD-SE.In vivo,the area under the rat plasma SM concentration-time curve and the maximum plasma SM concentration were 2.4-fold and 1.9-fold higher,respectively,after oral administration of SM-SD-SEDS as compared with an aqueous SM suspension.These results illustrated the potential of using SEDS to prepare SM-SD,further improving the biopharmaceutical properties of this compound.展开更多
In current study,immediate release solid dispersion(SD)formulation of antiulcer drug lafutidine(LAFT)was developed using hot melt extrusion(HME)technique.Amphiphilic Soluplusused as a primary solubilizing agent,with ...In current study,immediate release solid dispersion(SD)formulation of antiulcer drug lafutidine(LAFT)was developed using hot melt extrusion(HME)technique.Amphiphilic Soluplusused as a primary solubilizing agent,with different concentrations of selected surfactants like PEG 400,Lutrol F127(LF127),Lutrol F68(LF68)were used to investigate their influence on formulations processing via HME.Prepared amorphous glassy solid dispersion was found to be thermodynamically and physicochemically stable.On the contrary,traces of crystalline LAFT not observed in the extrudates according to differential scanning calorimetry(DSC),X-ray diffraction(XRD),scanning electron microscopy(SEM)and Raman spectroscopy.Raman micro spectrometry had the lowest detection limit of LAFT crystals compared with XRD and DSC.Atomic Force microscopy(AFM)studies revealed drugpolymer molecular miscibility and surface interaction at micro level.1HeCOSY NMR spectroscopy confirmed miscibility and interaction between LAFT and Soluplus,with chemical shift drifting and line broadening.MD simulation studies using computational modelling showed intermolecular interaction between molecules.Dissolution rate and solubility of LAFT was enhanced remarkably in developed SD systems.Optimized ratio of polymer and surfactants played crucial role in dissolution rate enhancement of LAFT SD.The obtained results suggested that developed LAFT has promising potential for oral delivery and might be an efficacious approach for enhancing the therapeutic potential of LAFT.展开更多
Nifedipine is a practically water-insoluble drug used therapeutically as a calcium-channel blocker for systemic and coronary vasodilation.Poorly soluble drugs that undergo dissolution rate-limited gastrointestinal abs...Nifedipine is a practically water-insoluble drug used therapeutically as a calcium-channel blocker for systemic and coronary vasodilation.Poorly soluble drugs that undergo dissolution rate-limited gastrointestinal absorption generally show increased bioavailability when dissolution is improved by formulation techniques[1].In solid dispersion system,a drug may exist as an amorphous form in polymeric carriers,and this may result in improved solubility and dissolution rate as compared with crystalline drug.Solid dispersion can be prepared by either fusion or solvent method[2].展开更多
Nimodipine(NMD)is a dihydropyridine calcium channel blocker with selectivity for cerebral blood vessels and the major therapeutic indication of NMD is for the prevention and treatment of delayed ischemic neurological...Nimodipine(NMD)is a dihydropyridine calcium channel blocker with selectivity for cerebral blood vessels and the major therapeutic indication of NMD is for the prevention and treatment of delayed ischemic neurological disorders and other cerebrovascular disorders,such as stroke which is associated with biological rhythm.This study was mainly designed to solve the drawback of conventional NMD solid dosage form,low bioavailability and limited clinical efficacy,by preparing enteric solid dispersion(SD)and the SD was prepared via melting method.The physical state of the dispersed NMD in the polymer matrix was characterized by differential scanning calorimetry(DSC),powder X-ray diffraction(PXRD)and dissolution studies.Compared with pure drug and physical mixture,the dissolution of NMD-SD was enhanced dramatically(about 80%).Furthermore,in consideration of the biological rhythm of stroke,we first obtained a delayed-release tablet containing NMD-SD by a direct powder compression method.As shown in the dissolution studies,the tablet released less than 10%in the artificial gastric acid in the initial 2 h and released 32.1%,75%,more than 90%at 4,10 and 14 h respectively in the artificial intestinal fluid.This investigation has solved the problems of oral solid dosage forms of NMD,and it has the good industry prospect.展开更多
Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API.However,there are inconsistent dissolution performances of solid dispersion reported which entails further...Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API.However,there are inconsistent dissolution performances of solid dispersion reported which entails further investigation.In this study,solid dispersions of ketoprofen in three hydrophilic carriers,i.e.PVP K30,PVPVA 6:4 and PVA were prepared and characterized.Physical characterization of the physical mixture of ketoprofen and carriers shows certain extent of amorphization of the API.This result is coinciding to evaluation of drug-polymer interaction using ATR-FTIR whereby higher amorphization was seen in samples with higher drug-polymer interaction.XRPD scanning confirms that fully amorphous solid dispersion was obtained for SD KTP PVP K30 and PVPVA system whereas partially crystalline system was obtained for SD KTP PVA.Interestingly,dissolution profiles of the solid dispersion had shown that degree of amorphization of KTP was not directly proportional to the dissolution rate enhancement of the solid dispersion system.Thus,it is concluded that complete amorphization does not guarantee dissolution enhancement of an amorphous solid dispersion system.展开更多
The poor dissolution characteristics of water-insoluble drugs are a major challenge for pharmaceutical scientists.Reduction of the particle size/increase in the surface area of the drug is a widely used and relatively...The poor dissolution characteristics of water-insoluble drugs are a major challenge for pharmaceutical scientists.Reduction of the particle size/increase in the surface area of the drug is a widely used and relatively simple method for increasing dissolution rates.The objective of this study was to improve solubility,release and comparability of dissolution of a poorly soluble drug using two different types of formulations(solid dispersions and microspheres).Hydrochlorothiazide was used as a model drug.The solid dispersions and microspheres were prepared by solvent evaporation method using ethyl cellulose,hydroxypropyl methylcellulose in different drug-to-carrier ratios(1:1,1:2 w:w).The prepared formulations were evaluated for interaction study by Fourier transform infrared spectroscopy,differential scanning calorimetry,percentage of practical yield,drug loading,surface morphology by scanning electron microscopy,optical microscopy and in-vitro release studies.The results showed no interaction between the drug and polymer,amorphous state of solid dispersions and microspheres,percentage yield of 42.53%to 78.10%,drug content of 99.60%to 99.64%,good spherical appearance in formulation VI and significant increase in the dissolution rate.展开更多
[Objectives]To investigate the in vitro transdermal effect of curcumin solid dispersion needles prepared with povidone K 30(PVP K30),polyethylene glycol 6000(PEG 6000)and poloxamer 188(block polyether F68,poloxamer 18...[Objectives]To investigate the in vitro transdermal effect of curcumin solid dispersion needles prepared with povidone K 30(PVP K30),polyethylene glycol 6000(PEG 6000)and poloxamer 188(block polyether F68,poloxamer 188,F68)as carrier matrix,respectively.[Methods]Vertical Franz diffusion cell and HPLC method were used to detect the cumulative penetration and skin retention of the microneedles within 12 h.[Results]Within 12 h,the cumulative penetration of PVP K30 microneedles was as high as 7.098μg/cm2,and the skin retention reached 35.28μg/cm2;PEG 6000 and poloxamer 188 microneedles all showed good transdermal effect;while normal curcumin solid dispersion(control)had no obvious transdermal effect.[Conclusions]The transdermal penetration of curcumin is improved after prepared into solid dispersion microneedles,and among different matrixes,PVP K30 is the best choice.展开更多
Introduction:Griseofulvin is an antifungal drug belonging to Biopharmaceutical Classification System(BCS class II)having low solubility.Objectives:To formulate,evaluate and enhance the dissolution of poorly water solu...Introduction:Griseofulvin is an antifungal drug belonging to Biopharmaceutical Classification System(BCS class II)having low solubility.Objectives:To formulate,evaluate and enhance the dissolution of poorly water soluble drug Griseofulvin by using solid dispersion method.Methods:Six formulations were prepared by solid dispersion method using Polyethylene Glycol(PEG 6000)125 mg,0 mg,62.5 mg,100 mg,25 mg,150 mg and superdisintegrants Crospovidone 0 mg,125 mg,62.5 mg,100 mg,25 mg,150 mg in all batches respectively.Findings:Satisfactory results were obtained from evaluation of physical characteristics of Griseofulvin tablets including:carr’s compressibility index(17.5±0.19%to 11.76±0.67%),Hausner ratio(1.21±0.01 to 1.13±0.02)and post compression parameters including:thickness(5.16±0.02 mm to 4.57±0.19 mm),friability(0.024%to 0.322%),hardness(4±0.28 kg/cm^(2)to 5±0.57 kg/cm^(2)),disintegration time(14-870 seconds).Conclusions:F3 was best formulation among all formulated batches with in-vitro drug release 30.05%in 10 minutes,69.21%in 30 minutes and 97.11%in 45 minutes.This indicated that formulation F3 batch with PEG 6000 of 62.5 mg and crospovidone 62.5 mg showed increased dissolution.展开更多
OBJECTIVE:To prepare aloe-emodin solid dispersion(AE-SD)and determine the metabolic process of AE and AE-SD in vivo.METHODS:AE-SD was prepared via solvent evaporation or solvent melting using PEG-6000 and PVP-K30 as c...OBJECTIVE:To prepare aloe-emodin solid dispersion(AE-SD)and determine the metabolic process of AE and AE-SD in vivo.METHODS:AE-SD was prepared via solvent evaporation or solvent melting using PEG-6000 and PVP-K30 as carriers.Thermogravimetric analysis,X-ray diffraction spectroscopy,differential scanning calorimetry,Fourier transform infrared spectroscopy and scanning electron microscopy were used to identify the physical state of AESD.Optimal prescriptions were screened via the dissolution degree determination method.Using Phoenix software,AE suspension and AE-SD were subjected to a pharmacokinetic comparison study analyzing the alteration of behavior in vivo after AE was prepared as a solid dispersion.Acute toxicity was assessed in mice,and the physiological toxicity was used as the determination criterion for toxicity.RESULTS:AE-SD showed that AE existed in the carrier in an amorphous state.Compared with polyethylene glycol,polyvinylpyrrolidone(PVP)inhibited AE crystallization,causing the drug to transform from a dense crystalline state to an amorphous form and increasing the degree of drug dispersion.Therefore,it was more suitable as a carrier material for AE-SD.The addition of poloxamer(POL)was more beneficial to the stability of solid dispersions and could reduce the amount of PVP.The dissolution test confirmed that the optimal ratio of AE to the composite vector AE-PVP-POL was 1:2:2,and its dissolution effect was also optimal.Based on the pharmacokinetic comparison,the drug absorption was faster and quickly reached the peak of blood drug concentration in AE-SD compared to AE,the Cmax of AE-SD was greater than that of AE,and t1/2 and mean residence time of AE-SD were less than AE.The results showed that the drug metabolism in AE-SD was better,and the residence time was shorter.The toxicology study showed that both AE and AE-SD had no toxicity.CONCLUSION:This paper established that the solubility of the drug could be increased after preparing a solid dispersion,as demonstrated by in vitro dissolution experiments.In vivo pharmacokinetics studies confirmed that AE-SD could improve the bioavailability of AE in vivo,providing a new concept for the research and development of AE preparations.展开更多
The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling,affecting molecular mobility,crystallinity,particle size and finally,the drug dissolution rate.As ...The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling,affecting molecular mobility,crystallinity,particle size and finally,the drug dissolution rate.As the stability of these metastable systems depend on both formulation and process variables,the aim of this study was to assess for the first time,the impact that the polymer load and the rotational speed applied upon high energy ball milling could have on the performance of binary co-milled solid dispersions composed of tadalafil(a hydrophobic crystalline drug)and Soluplus(an amphiphilic,hygroscopic amorphous polymer).Each of these variables was tested at three levels.Scanning electron microscopy,laser diffraction and X-ray powder diffraction were used to analyze morphology,particle size distribution and crystallinity of ball milled formulations respectively.Dissolution studies were also carried out.Advanced tools of applied physics,namely solid state 1H NMR and relaxometry were used to assess the structure and water mobility upon gaseous phase hydration on storage.It was shown that both tested variables determined the particle size of the formulation.When the rotational speed of 400 rpm was used,all solid dispersion were XRD-amorphous,but to ensure the immediate release of tadalafil its micellar solubilization in Soluplus was necessary.While the formulation was exposed to water vapor,the hydration level increased with an increasing polymer load as well.Hence,the rotational speed governed the space available for the adsorption of water molecules and their organization in a monolayer or multilayers.Such behavior may have impact on the kinetics of the amorphous drug recrystallization,and finally deteriorate its dissolution.展开更多
Atorvastatin has low aqueous solubility resulting in low oral bioavailability(12%)and thus presents a challenge in formulating a suitable dosage form.To improve the aqueous solubility,a solid dispersion formulation of...Atorvastatin has low aqueous solubility resulting in low oral bioavailability(12%)and thus presents a challenge in formulating a suitable dosage form.To improve the aqueous solubility,a solid dispersion formulation of atorvasta tin was prepared by lyophilization utilising skimmed milk as a carrier.Six different formulations were prepared with varying ratios of drug and carrier and the corresponding physical mixtures were also prepared.The formation of a solid dispersion formulation was confirmed by differential scanning ca lorimetry and X-ray diffraction studies.The optimum drug-to-carrier ratio of 1:9 en hanced solubility nearly 33-fold as compared to pure drug.In vitro drug release studies exhibited a cumulative release of 83.69% as compared to 22.7% for the pure drug.Additionally,scanning electron microscopy studies suggested the conversion of crystalline atorvastatin to an amorphous form.In a Triton-induced hyperlipidemia model,a 3-fold increase in the lipid lowering potential was obtained with the reformulated drug as compared to pure drug.These results suggest that solid dispersion of atorvastatin using skimmed milk as carrier is a promising approach for oral delivery of atorvastatin.展开更多
The solid dispersion has become an established solubilization technology for poorly water soluble drugs.Since a solid dispersion is basically a drug-polymer two-component system,the drug-polymer interaction is the det...The solid dispersion has become an established solubilization technology for poorly water soluble drugs.Since a solid dispersion is basically a drug-polymer two-component system,the drug-polymer interaction is the determining factor in its design and performance.In this review,we summarize our current understanding of solid dispersions both in the solid state and in dissolution,emphasizing the fundamental aspects of this important technology.展开更多
The objective of the study was to prepare solid dispersions containing a thermally unstable drug by hot-melt extrusion(HME).Carbamazepine(CBZ)was selected as model drug and combinations of Kollidon VA64(VA64),Soluplus...The objective of the study was to prepare solid dispersions containing a thermally unstable drug by hot-melt extrusion(HME).Carbamazepine(CBZ)was selected as model drug and combinations of Kollidon VA64(VA64),Soluplus(SOL)and Eudragit EPO(EPO)were utilized as carriers.Preformulation was conducted to identify the suitability of polymer combinations based on solubility parameters,differential scanning calorimetry(DSC),hot stage microscopy and thermogravimetric analysis.Physicochemical properties of solid dispersions were determined by DSC,X-ray diffraction,fourier transform infrared spectroscopy,dissolution and accelerated stability testing.The results show that drug-polymer miscibility at temperatures below the melting point(Tm)of CBZ was improved by combining EPO with VA64 or SOL.With 30%drug loading in a solid dispersion in SOL:EPO(1:1,w/w),CBZ was mainly present in an amorphous form accompanied by a small amount of a microcrystalline form.The dissolution rate of the solid dispersion was significantly increased(approximately 90%within 5 min)compared to either the pure drug(approximately 85%within 60 min)or the corresponding physical mixture(approximately 80%within 60 min)before and after storage.The solid dispersion in SOL:EPO(1:1,w/w)was relatively stable at 401C/75%RH under CBZ tablet packaging conditions for at least 3 months.In conclusion,polymer combinations that improve drug-polymer miscibility at an HME processing temperature below the Tm of a drug appear to be beneficial in the preparation of solid dispersions containing thermally unstable drugs.展开更多
Amorphous solid dispersions(ASDs)are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs.Various approaches have been employed to produce ASDs and novel techniques are emerging.This ...Amorphous solid dispersions(ASDs)are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs.Various approaches have been employed to produce ASDs and novel techniques are emerging.This review provides an updated overview of manufacturing techniques for preparing ASDs.As physical stability is a critical quality attribute for ASD,the impact of formulation,equipment,and process variables,together with the downstream processing on physical stability of ASDs have been discussed.Selection strategies are proposed to identify suitable manufacturing methods,which may aid in the development of ASDs with satisfactory physical stability.展开更多
Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug.The solid dispersions were characterized by diff...Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug.The solid dispersions were characterized by differential scanning calorimetry(DSC),hot stage polarized optical microscopy(HSPM),infrared spectroscopy(FTIR)and stability studies.The solid dispersion significantly enhanced the stability of calcitriol,which could be attributed to the high antioxidant activity of the solid lipid dispersion.The rapid dissolution rate from the solid dispersion was attributed to the amorphous or solid solution state of drug with improved specific surface area and wettability than the drug crystals.Therefore,solid dispersion of calcitriol with D-a-tocopheryl polyethylene glycol 1000 succinate(TPGS)offers a good approach to modify the release and enhance stability of calcitriol.The influence of lipophilic solid dispersion on drug bioavailability needs further investigation.展开更多
The purpose of this study was to improve the dissolution rate and anti-inflammatory effect of ibuprofen by a solid dispersion(SD)method.Initial screening was developed based on drug solubility in carriers in the liqui...The purpose of this study was to improve the dissolution rate and anti-inflammatory effect of ibuprofen by a solid dispersion(SD)method.Initial screening was developed based on drug solubility in carriers in the liquid state to select a suitable water-soluble carrier system for the preparation of SDs.The dissolution of ibuprofen in urea was higher than in PEG4000 or mannitol.Thus,urea was selected as the carrier for the preparation of SDs.SDs were characterized in terms of dissolution,differential scanning calorimetry(DSC),X-ray diffraction(XRD),scanning electron microscopy(SEM),and Fourier transform infrared(FTIR)spectroscopy.Solid dispersionbased(SDBT)and conventional(CT)tablets were prepared by the wet granulation method.The antiinflammatory effect of SDBT was evaluated using the mouse ear edema test with xylene.In vitro release results indicated that the ibuprofen dissolution rate was improved by the SD.SD characterization results suggested that ibuprofen partly precipitates in crystalline and amorphous forms after SD preparation and that ibuprofen and urea do not interact.SDBT displayed more significant anti-inflammatory effects than CT.The dissolution rate and anti-inflammatory effect of ibuprofen were significantly enhanced by the ibuprofen-urea SD.展开更多
Objective:The current investigation aimed to determine the appropriate dosage form by comparing solid dispersion and liposome to achieve the purpose of improving the solubility and bioavailability of linarin.Methods:L...Objective:The current investigation aimed to determine the appropriate dosage form by comparing solid dispersion and liposome to achieve the purpose of improving the solubility and bioavailability of linarin.Methods:Linarin solid dispersion(LSD)and linarin liposome(LL)were developed via the solvent method and the thin film hydration method respectively.The Transwell chamber model of Caco-2 cells was established to evaluate the absorption of drug.The pharmacokinetics of linarin,LSD and LL in rats after ig administration were carried out by high performance liquid chromatography(HPLC)method.Results:The solubility of LSD and LL was severally 3.29 times and 3.09 times than that of linarin.The permeation coefficients of LSD and LL were greater than 10^(-6),indicating that the absorption of LSD and LL were both better than linarin.The bioavailability of the LSD was 3.363 times higher than that of linarin,and the bioavailability of LL was 0.9886 times higher than that of linarin.Conclusion:The linarin was more suitable for making solid dispersion to enhance its solubility and bioavailability.展开更多
A low cost,rapid and sensitive preparation method of silica gel supported ionic liquid(SGSIL)combined with matrix solid phase dispersion(MSPD)followed by high performance liquid chromatography(HPLC)with ultraviolet de...A low cost,rapid and sensitive preparation method of silica gel supported ionic liquid(SGSIL)combined with matrix solid phase dispersion(MSPD)followed by high performance liquid chromatography(HPLC)with ultraviolet detection(UV)is proposed,and it was applied to determine the seven active compounds in Salvia Miltiorrhiza herb.SGSIL and ionic liquid[BMIM]BF4 were used as the adsorbent and the green elution reagent in the MSPD procedure.Several extraction conditions including type of filler and elution solvent,the volume of elution solvent,material liquid ratio were optimized.Under the optimum conditions,the SGSIL-MSPD-HPLC method showed a low limit of detection(LOD,S/N=3)of 0.0122-0.8788μg/mL for standard solution,limit of quantification(LOQ,S/N=10)of 0.0406-2.9292μg/mL for standard solution,wide linear range from 1.56 to 2000μg/mL for all compounds for standard solution,correlation coefficients(r)of more than 0.9990,acceptable reproducibility(relative standard deviations,RSDs<3.54%),and precision of RSDs<3.36%for intra-day,RSDs<3.50%for inter-day.The satisfactory recoveries ranged from 96.4 to 102.5,with RSDs less than 3.45%.The developed SGSIL-MSPD method is easier and more suitable for the determination of the seven active compounds in Salvia Miltiorrhiza herb than the traditional ultrasonic extraction.It was an effective and efficient method for the extraction and quantification of the seven active compounds in traditional Chinese herbal samples.展开更多
基金the National Natural Science Foundation of China(No.81872813,22108313,82273880)Natural Science Foundation of Jiangsu Province(No.BK 20200573,BK 20200576)+1 种基金Fundamental Research Funds for the Central Universities(No 2632022ZD16)the Scientific Research Fund of Hunan Provincial Education Department(No.22B0820).
文摘Amorphous solid dispersion(ASD)is one of the most effective approaches for delivering poorly soluble drugs.In ASDs,polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level.To prepare the solid dispersions,there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations.Polymer selection is of great importance because it influences the stability,solubility and dissolution rates,manufacturing process,and bioavailability of the ASD.This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers,formulation designs and preparation methods.Furthermore,considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.
文摘Paracetamol (PCM) is enlisted in the WHO model list as an essential medicine for pain and palliative care, but at overdose, it causes hepatic damage. This study was designed to assess the analgesic efficacy and hepatoprotective property of a solid dispersion (SD) loaded with PCM. A number of PCM loaded formulations (PSDs) were fabricated using silica alone or in combination with polyethylene glycol and/or Na-citrate followed by in-vitro dissolution profiling. Selected PSDs with improved dissolution profile were subjected to solid-state characterization (DSC, PXRD, FTIR, and SEM), stability study along with investigation of in-vivo analgesic efficacy and effect on hepatocytes. Among these, PSD10 showed a rapid and significantly higher in-vitro drug release than pure PCM. This improvement was distinct to other PSDs also. Solid-state characterization of PSD10 authenticated the conversion of crystalline PCM to amorphous form upon formulation. Subsequent oral administration of PSD10 in Swiss albino mice showed 1.44-fold greater analgesic efficacy than pure PCM at dose 30 mg/kg. Besides, at acute toxic dose, liver histology of PSD10 mice was comparable with NC mice indicating hepatic protection upon formulation, whereas the PCM mice showed extensive hepatic necrosis which was also endorsed by significantly higher values of SGPT, SGOT, and ALP than PSD10 mice. Finally, an accelerated stability study of PSD10 performed according to the guideline of ICH noticed no remarkable deviation in its dissolution performance as well as crystalline nature. Thus, this newly developed PSD10 may be a safe and promising alternative for pain management and palliative care.
基金supported financially by the Subject Chief Scientist Program(10XD14303900)from Science and Technology Commission of Shanghai Municipalitythe Specialized Research Fund for the Doctoral Program of Higher Education of China(20123107110005).
文摘The objective of this study was to improve the dissolution and bioavailability of silymarin(SM).Solid dispersions(SDs)were prepared using solution-enhanced dispersion by supercritical fluids(SEDS)and evaluated in vitro and in vivo,compared with pure SM powder.The particle sizes,stability,and contents of residual solvent of the prepared SM-SDs with SEDS and solvent evaporation(SE)were investigated.Four polymer matrix materials were evaluated for the preparation of SM-SD-SEDS,and the hydrophilic polymer,polyvinyl pyrrolidone K17,was selected with a ratio of 1:5 between SM and the polymer.Physicochemical analyses using X-ray diffraction and differential scanning calorimetry indicated that SM was dispersed in SD in an amorphous state.The optimized SM-SD-SEDS showed no loss of SM after storage for 6 months and negligible residual solvent(ethanol)was detected using gas chromatography.In vitro drug release was increased from the SM-SDSEDS,as compared with pure SM powder or SM-SD-SE.In vivo,the area under the rat plasma SM concentration-time curve and the maximum plasma SM concentration were 2.4-fold and 1.9-fold higher,respectively,after oral administration of SM-SD-SEDS as compared with an aqueous SM suspension.These results illustrated the potential of using SEDS to prepare SM-SD,further improving the biopharmaceutical properties of this compound.
基金The author is also thankful to UGC(SAP)for providing the research fellowship and Institute of Chemical Technology,ELITE status(Mumbai,India)for providing all facilities and guidance.The authors are thankful to S.A.I.F.department at Indian Institute of Technology,Mumbai for Raman and 1HeCOSY NMR experimental help and analyses.
文摘In current study,immediate release solid dispersion(SD)formulation of antiulcer drug lafutidine(LAFT)was developed using hot melt extrusion(HME)technique.Amphiphilic Soluplusused as a primary solubilizing agent,with different concentrations of selected surfactants like PEG 400,Lutrol F127(LF127),Lutrol F68(LF68)were used to investigate their influence on formulations processing via HME.Prepared amorphous glassy solid dispersion was found to be thermodynamically and physicochemically stable.On the contrary,traces of crystalline LAFT not observed in the extrudates according to differential scanning calorimetry(DSC),X-ray diffraction(XRD),scanning electron microscopy(SEM)and Raman spectroscopy.Raman micro spectrometry had the lowest detection limit of LAFT crystals compared with XRD and DSC.Atomic Force microscopy(AFM)studies revealed drugpolymer molecular miscibility and surface interaction at micro level.1HeCOSY NMR spectroscopy confirmed miscibility and interaction between LAFT and Soluplus,with chemical shift drifting and line broadening.MD simulation studies using computational modelling showed intermolecular interaction between molecules.Dissolution rate and solubility of LAFT was enhanced remarkably in developed SD systems.Optimized ratio of polymer and surfactants played crucial role in dissolution rate enhancement of LAFT SD.The obtained results suggested that developed LAFT has promising potential for oral delivery and might be an efficacious approach for enhancing the therapeutic potential of LAFT.
文摘Nifedipine is a practically water-insoluble drug used therapeutically as a calcium-channel blocker for systemic and coronary vasodilation.Poorly soluble drugs that undergo dissolution rate-limited gastrointestinal absorption generally show increased bioavailability when dissolution is improved by formulation techniques[1].In solid dispersion system,a drug may exist as an amorphous form in polymeric carriers,and this may result in improved solubility and dissolution rate as compared with crystalline drug.Solid dispersion can be prepared by either fusion or solvent method[2].
基金special construction projects fund which belongs to“Taishan ScholardPharmacy Specially Recruited Experts”.
文摘Nimodipine(NMD)is a dihydropyridine calcium channel blocker with selectivity for cerebral blood vessels and the major therapeutic indication of NMD is for the prevention and treatment of delayed ischemic neurological disorders and other cerebrovascular disorders,such as stroke which is associated with biological rhythm.This study was mainly designed to solve the drawback of conventional NMD solid dosage form,low bioavailability and limited clinical efficacy,by preparing enteric solid dispersion(SD)and the SD was prepared via melting method.The physical state of the dispersed NMD in the polymer matrix was characterized by differential scanning calorimetry(DSC),powder X-ray diffraction(PXRD)and dissolution studies.Compared with pure drug and physical mixture,the dissolution of NMD-SD was enhanced dramatically(about 80%).Furthermore,in consideration of the biological rhythm of stroke,we first obtained a delayed-release tablet containing NMD-SD by a direct powder compression method.As shown in the dissolution studies,the tablet released less than 10%in the artificial gastric acid in the initial 2 h and released 32.1%,75%,more than 90%at 4,10 and 14 h respectively in the artificial intestinal fluid.This investigation has solved the problems of oral solid dosage forms of NMD,and it has the good industry prospect.
基金the financial support received from the short term grant 304/PFARMASI/6313055,Universiti Sains Malaysia in carrying out this work.
文摘Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API.However,there are inconsistent dissolution performances of solid dispersion reported which entails further investigation.In this study,solid dispersions of ketoprofen in three hydrophilic carriers,i.e.PVP K30,PVPVA 6:4 and PVA were prepared and characterized.Physical characterization of the physical mixture of ketoprofen and carriers shows certain extent of amorphization of the API.This result is coinciding to evaluation of drug-polymer interaction using ATR-FTIR whereby higher amorphization was seen in samples with higher drug-polymer interaction.XRPD scanning confirms that fully amorphous solid dispersion was obtained for SD KTP PVP K30 and PVPVA system whereas partially crystalline system was obtained for SD KTP PVA.Interestingly,dissolution profiles of the solid dispersion had shown that degree of amorphization of KTP was not directly proportional to the dissolution rate enhancement of the solid dispersion system.Thus,it is concluded that complete amorphization does not guarantee dissolution enhancement of an amorphous solid dispersion system.
文摘The poor dissolution characteristics of water-insoluble drugs are a major challenge for pharmaceutical scientists.Reduction of the particle size/increase in the surface area of the drug is a widely used and relatively simple method for increasing dissolution rates.The objective of this study was to improve solubility,release and comparability of dissolution of a poorly soluble drug using two different types of formulations(solid dispersions and microspheres).Hydrochlorothiazide was used as a model drug.The solid dispersions and microspheres were prepared by solvent evaporation method using ethyl cellulose,hydroxypropyl methylcellulose in different drug-to-carrier ratios(1:1,1:2 w:w).The prepared formulations were evaluated for interaction study by Fourier transform infrared spectroscopy,differential scanning calorimetry,percentage of practical yield,drug loading,surface morphology by scanning electron microscopy,optical microscopy and in-vitro release studies.The results showed no interaction between the drug and polymer,amorphous state of solid dispersions and microspheres,percentage yield of 42.53%to 78.10%,drug content of 99.60%to 99.64%,good spherical appearance in formulation VI and significant increase in the dissolution rate.
基金2020 National Undergraduate Training Program for Innovation and Entrepreneurship(202010656041).
文摘[Objectives]To investigate the in vitro transdermal effect of curcumin solid dispersion needles prepared with povidone K 30(PVP K30),polyethylene glycol 6000(PEG 6000)and poloxamer 188(block polyether F68,poloxamer 188,F68)as carrier matrix,respectively.[Methods]Vertical Franz diffusion cell and HPLC method were used to detect the cumulative penetration and skin retention of the microneedles within 12 h.[Results]Within 12 h,the cumulative penetration of PVP K30 microneedles was as high as 7.098μg/cm2,and the skin retention reached 35.28μg/cm2;PEG 6000 and poloxamer 188 microneedles all showed good transdermal effect;while normal curcumin solid dispersion(control)had no obvious transdermal effect.[Conclusions]The transdermal penetration of curcumin is improved after prepared into solid dispersion microneedles,and among different matrixes,PVP K30 is the best choice.
基金This research received no specific grant from any funding agency in public,commercial,or not-for-profit sectors.
文摘Introduction:Griseofulvin is an antifungal drug belonging to Biopharmaceutical Classification System(BCS class II)having low solubility.Objectives:To formulate,evaluate and enhance the dissolution of poorly water soluble drug Griseofulvin by using solid dispersion method.Methods:Six formulations were prepared by solid dispersion method using Polyethylene Glycol(PEG 6000)125 mg,0 mg,62.5 mg,100 mg,25 mg,150 mg and superdisintegrants Crospovidone 0 mg,125 mg,62.5 mg,100 mg,25 mg,150 mg in all batches respectively.Findings:Satisfactory results were obtained from evaluation of physical characteristics of Griseofulvin tablets including:carr’s compressibility index(17.5±0.19%to 11.76±0.67%),Hausner ratio(1.21±0.01 to 1.13±0.02)and post compression parameters including:thickness(5.16±0.02 mm to 4.57±0.19 mm),friability(0.024%to 0.322%),hardness(4±0.28 kg/cm^(2)to 5±0.57 kg/cm^(2)),disintegration time(14-870 seconds).Conclusions:F3 was best formulation among all formulated batches with in-vitro drug release 30.05%in 10 minutes,69.21%in 30 minutes and 97.11%in 45 minutes.This indicated that formulation F3 batch with PEG 6000 of 62.5 mg and crospovidone 62.5 mg showed increased dissolution.
文摘OBJECTIVE:To prepare aloe-emodin solid dispersion(AE-SD)and determine the metabolic process of AE and AE-SD in vivo.METHODS:AE-SD was prepared via solvent evaporation or solvent melting using PEG-6000 and PVP-K30 as carriers.Thermogravimetric analysis,X-ray diffraction spectroscopy,differential scanning calorimetry,Fourier transform infrared spectroscopy and scanning electron microscopy were used to identify the physical state of AESD.Optimal prescriptions were screened via the dissolution degree determination method.Using Phoenix software,AE suspension and AE-SD were subjected to a pharmacokinetic comparison study analyzing the alteration of behavior in vivo after AE was prepared as a solid dispersion.Acute toxicity was assessed in mice,and the physiological toxicity was used as the determination criterion for toxicity.RESULTS:AE-SD showed that AE existed in the carrier in an amorphous state.Compared with polyethylene glycol,polyvinylpyrrolidone(PVP)inhibited AE crystallization,causing the drug to transform from a dense crystalline state to an amorphous form and increasing the degree of drug dispersion.Therefore,it was more suitable as a carrier material for AE-SD.The addition of poloxamer(POL)was more beneficial to the stability of solid dispersions and could reduce the amount of PVP.The dissolution test confirmed that the optimal ratio of AE to the composite vector AE-PVP-POL was 1:2:2,and its dissolution effect was also optimal.Based on the pharmacokinetic comparison,the drug absorption was faster and quickly reached the peak of blood drug concentration in AE-SD compared to AE,the Cmax of AE-SD was greater than that of AE,and t1/2 and mean residence time of AE-SD were less than AE.The results showed that the drug metabolism in AE-SD was better,and the residence time was shorter.The toxicology study showed that both AE and AE-SD had no toxicity.CONCLUSION:This paper established that the solubility of the drug could be increased after preparing a solid dispersion,as demonstrated by in vitro dissolution experiments.In vivo pharmacokinetics studies confirmed that AE-SD could improve the bioavailability of AE in vivo,providing a new concept for the research and development of AE preparations.
基金Sonata Bis (grant no.DEC-2019/34/E/NZ7/00245)financed by the National Science Centre in Polandsupport (grant no.7150/E-338/M/2017)financed by the Polish Ministry of Science and Higher Educationthe equipment purchased thanks to the financial support of the European Regional Development Fund in the framework of the Polish Innovation Economy Operational Program (contract no.POIG.02.01.00-12-023/08).
文摘The presence of residual water may deteriorate the performance of amorphous solid dispersions prepared by ball milling,affecting molecular mobility,crystallinity,particle size and finally,the drug dissolution rate.As the stability of these metastable systems depend on both formulation and process variables,the aim of this study was to assess for the first time,the impact that the polymer load and the rotational speed applied upon high energy ball milling could have on the performance of binary co-milled solid dispersions composed of tadalafil(a hydrophobic crystalline drug)and Soluplus(an amphiphilic,hygroscopic amorphous polymer).Each of these variables was tested at three levels.Scanning electron microscopy,laser diffraction and X-ray powder diffraction were used to analyze morphology,particle size distribution and crystallinity of ball milled formulations respectively.Dissolution studies were also carried out.Advanced tools of applied physics,namely solid state 1H NMR and relaxometry were used to assess the structure and water mobility upon gaseous phase hydration on storage.It was shown that both tested variables determined the particle size of the formulation.When the rotational speed of 400 rpm was used,all solid dispersion were XRD-amorphous,but to ensure the immediate release of tadalafil its micellar solubilization in Soluplus was necessary.While the formulation was exposed to water vapor,the hydration level increased with an increasing polymer load as well.Hence,the rotational speed governed the space available for the adsorption of water molecules and their organization in a monolayer or multilayers.Such behavior may have impact on the kinetics of the amorphous drug recrystallization,and finally deteriorate its dissolution.
文摘Atorvastatin has low aqueous solubility resulting in low oral bioavailability(12%)and thus presents a challenge in formulating a suitable dosage form.To improve the aqueous solubility,a solid dispersion formulation of atorvasta tin was prepared by lyophilization utilising skimmed milk as a carrier.Six different formulations were prepared with varying ratios of drug and carrier and the corresponding physical mixtures were also prepared.The formation of a solid dispersion formulation was confirmed by differential scanning ca lorimetry and X-ray diffraction studies.The optimum drug-to-carrier ratio of 1:9 en hanced solubility nearly 33-fold as compared to pure drug.In vitro drug release studies exhibited a cumulative release of 83.69% as compared to 22.7% for the pure drug.Additionally,scanning electron microscopy studies suggested the conversion of crystalline atorvastatin to an amorphous form.In a Triton-induced hyperlipidemia model,a 3-fold increase in the lipid lowering potential was obtained with the reformulated drug as compared to pure drug.These results suggest that solid dispersion of atorvastatin using skimmed milk as carrier is a promising approach for oral delivery of atorvastatin.
基金This work was supported by the National Natural Science Foundation of China(Grant No.50873056 to Y.H.).
文摘The solid dispersion has become an established solubilization technology for poorly water soluble drugs.Since a solid dispersion is basically a drug-polymer two-component system,the drug-polymer interaction is the determining factor in its design and performance.In this review,we summarize our current understanding of solid dispersions both in the solid state and in dissolution,emphasizing the fundamental aspects of this important technology.
文摘The objective of the study was to prepare solid dispersions containing a thermally unstable drug by hot-melt extrusion(HME).Carbamazepine(CBZ)was selected as model drug and combinations of Kollidon VA64(VA64),Soluplus(SOL)and Eudragit EPO(EPO)were utilized as carriers.Preformulation was conducted to identify the suitability of polymer combinations based on solubility parameters,differential scanning calorimetry(DSC),hot stage microscopy and thermogravimetric analysis.Physicochemical properties of solid dispersions were determined by DSC,X-ray diffraction,fourier transform infrared spectroscopy,dissolution and accelerated stability testing.The results show that drug-polymer miscibility at temperatures below the melting point(Tm)of CBZ was improved by combining EPO with VA64 or SOL.With 30%drug loading in a solid dispersion in SOL:EPO(1:1,w/w),CBZ was mainly present in an amorphous form accompanied by a small amount of a microcrystalline form.The dissolution rate of the solid dispersion was significantly increased(approximately 90%within 5 min)compared to either the pure drug(approximately 85%within 60 min)or the corresponding physical mixture(approximately 80%within 60 min)before and after storage.The solid dispersion in SOL:EPO(1:1,w/w)was relatively stable at 401C/75%RH under CBZ tablet packaging conditions for at least 3 months.In conclusion,polymer combinations that improve drug-polymer miscibility at an HME processing temperature below the Tm of a drug appear to be beneficial in the preparation of solid dispersions containing thermally unstable drugs.
基金supported,in whole or in part,by the Bill&Melinda Gates Foundation[No.OPP1159809,USA]supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award(No.R01AI132681,USA)
文摘Amorphous solid dispersions(ASDs)are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs.Various approaches have been employed to produce ASDs and novel techniques are emerging.This review provides an updated overview of manufacturing techniques for preparing ASDs.As physical stability is a critical quality attribute for ASD,the impact of formulation,equipment,and process variables,together with the downstream processing on physical stability of ASDs have been discussed.Selection strategies are proposed to identify suitable manufacturing methods,which may aid in the development of ASDs with satisfactory physical stability.
基金The work was supported by the National Natural Science Foundation of China(No 81173002)National Science and Technology Support Program(No 2012BAI35B02)International Science and Technology Cooperation and Exchange Projects(No 2008DFA31080).
文摘Solid dispersion of calcitriol with lipophilic surfactants and triglycerides was developed by melt-mixing method to modify the release and enhance stability of the drug.The solid dispersions were characterized by differential scanning calorimetry(DSC),hot stage polarized optical microscopy(HSPM),infrared spectroscopy(FTIR)and stability studies.The solid dispersion significantly enhanced the stability of calcitriol,which could be attributed to the high antioxidant activity of the solid lipid dispersion.The rapid dissolution rate from the solid dispersion was attributed to the amorphous or solid solution state of drug with improved specific surface area and wettability than the drug crystals.Therefore,solid dispersion of calcitriol with D-a-tocopheryl polyethylene glycol 1000 succinate(TPGS)offers a good approach to modify the release and enhance stability of calcitriol.The influence of lipophilic solid dispersion on drug bioavailability needs further investigation.
基金International S&T Cooperation Program of China(ISTCP,No.2011DFA31270)National Natural Science Foundation of China&Korea Science and Engineering Foundation(NSFC-KOSEF,No.40911140282)the Fundamental Research Funds for the Central Universities(Nos.841111042 and 201213006)for their financial support.
文摘The purpose of this study was to improve the dissolution rate and anti-inflammatory effect of ibuprofen by a solid dispersion(SD)method.Initial screening was developed based on drug solubility in carriers in the liquid state to select a suitable water-soluble carrier system for the preparation of SDs.The dissolution of ibuprofen in urea was higher than in PEG4000 or mannitol.Thus,urea was selected as the carrier for the preparation of SDs.SDs were characterized in terms of dissolution,differential scanning calorimetry(DSC),X-ray diffraction(XRD),scanning electron microscopy(SEM),and Fourier transform infrared(FTIR)spectroscopy.Solid dispersionbased(SDBT)and conventional(CT)tablets were prepared by the wet granulation method.The antiinflammatory effect of SDBT was evaluated using the mouse ear edema test with xylene.In vitro release results indicated that the ibuprofen dissolution rate was improved by the SD.SD characterization results suggested that ibuprofen partly precipitates in crystalline and amorphous forms after SD preparation and that ibuprofen and urea do not interact.SDBT displayed more significant anti-inflammatory effects than CT.The dissolution rate and anti-inflammatory effect of ibuprofen were significantly enhanced by the ibuprofen-urea SD.
基金financed by Natural Science Foundation of Henan Province(Grant No.182300410348)。
文摘Objective:The current investigation aimed to determine the appropriate dosage form by comparing solid dispersion and liposome to achieve the purpose of improving the solubility and bioavailability of linarin.Methods:Linarin solid dispersion(LSD)and linarin liposome(LL)were developed via the solvent method and the thin film hydration method respectively.The Transwell chamber model of Caco-2 cells was established to evaluate the absorption of drug.The pharmacokinetics of linarin,LSD and LL in rats after ig administration were carried out by high performance liquid chromatography(HPLC)method.Results:The solubility of LSD and LL was severally 3.29 times and 3.09 times than that of linarin.The permeation coefficients of LSD and LL were greater than 10^(-6),indicating that the absorption of LSD and LL were both better than linarin.The bioavailability of the LSD was 3.363 times higher than that of linarin,and the bioavailability of LL was 0.9886 times higher than that of linarin.Conclusion:The linarin was more suitable for making solid dispersion to enhance its solubility and bioavailability.
基金This research was supported by Special Research Fund for Young Doctors of Qiqihar Medical University(QMSI2020B-03,hosted by Wenjing Li).
文摘A low cost,rapid and sensitive preparation method of silica gel supported ionic liquid(SGSIL)combined with matrix solid phase dispersion(MSPD)followed by high performance liquid chromatography(HPLC)with ultraviolet detection(UV)is proposed,and it was applied to determine the seven active compounds in Salvia Miltiorrhiza herb.SGSIL and ionic liquid[BMIM]BF4 were used as the adsorbent and the green elution reagent in the MSPD procedure.Several extraction conditions including type of filler and elution solvent,the volume of elution solvent,material liquid ratio were optimized.Under the optimum conditions,the SGSIL-MSPD-HPLC method showed a low limit of detection(LOD,S/N=3)of 0.0122-0.8788μg/mL for standard solution,limit of quantification(LOQ,S/N=10)of 0.0406-2.9292μg/mL for standard solution,wide linear range from 1.56 to 2000μg/mL for all compounds for standard solution,correlation coefficients(r)of more than 0.9990,acceptable reproducibility(relative standard deviations,RSDs<3.54%),and precision of RSDs<3.36%for intra-day,RSDs<3.50%for inter-day.The satisfactory recoveries ranged from 96.4 to 102.5,with RSDs less than 3.45%.The developed SGSIL-MSPD method is easier and more suitable for the determination of the seven active compounds in Salvia Miltiorrhiza herb than the traditional ultrasonic extraction.It was an effective and efficient method for the extraction and quantification of the seven active compounds in traditional Chinese herbal samples.
