Pathways of paracetamol absorption from layered excipient suppositories: artificial intelligence approach.

When studying paracetamol availability after rectal administration, the differences between slower and faster release suppositories were discovered. Approach with modelling and simulation of compartment-based models was used to explore the differences. A study of paracetamol from layered excipient suppositories shows that many different mechanisms are involved in the drug pharmacokinetics. There is also a large number of articles, each dealing with only one or with a few of the mechanisms. However, there is little information available on how the mechanisms interact in the organism and thus govern the pharmacokinetics of the drug, which means that systemic view in the expert knowledge is missing. In the case of paracetamol rectal availability the use of partially fuzzyfied model allowed systemic combination of all described mechanisms found in the literature and measured data. In spite of non-identifiability, the model showed that patterns that explained differences in bioavailabilities of the two formulations of suppositories could be found. Results of modelling and simulation show that "in vivo" there is practically no difference in cumulative release profiles between the two formulations. However, due to higher content of mono-di-glycerides in a slower release formulation, the extent of absorption is augmented both by absorption-enhancing effect of mono-di-glycerides and the liver bypass mechanism via diminished viscosity.     

Layered excipient suppositories: The possibility of modulating drug availability

The release rate of a drug dose from suppositories is affected by characteristics of the excipient (melting temperature and rate, viscosity at rectal temperature, hydro-lipophilic characteristics). Release kinetics from excipients commonly available do not always respond to clinical requirements, even after the introduction of auxiliary agents. Release curves which were differentiated and adaptable to therapeutic conditions were obtained by vehicling a drug in suppositories of two superimposed layers of lipophilic excipients with different characteristics and hence with a difference in drug availability. The two distinct excipient layers release the drug from these suppositories contemporaneously but independently. The amount of drug released in the time course is the sum of the single amounts individually released by the two suppository layers. By previously mixing the two excipients, release rate becomes uniform in the suppository body overall and is conditioned only by the assumed characteristics of the mixture. The release mechanism for superimposed layer suppositories is confirmed by the good agreement between experimental and calculated curves. By using a pair of excipients with different characteristics in superimposed layers between which the drug is distributed, it is possible to modulate drug release kinetics by regulating the reciprocal ratio between the two suppository fractions.     

Effect of temperature on drug release and drug absorption in mixed type diclofenac sodium suppositories

New types of diclofenac sodium suppositories known to control a drug release function for hospital preparations were developed based on a concept of the drug delivery system. Hard fat (Witepsol) used as a base of the suppository consists of a mixture of triglycerides, diglycerides and monoglycerides, and each Witepsol is characterized by its physicochemical properties. Authors disclosed that the amount of drug release measured in the commercially available diclofenac sodium suppositories decreased at a low temperature (36 degrees C). Mixed types of diclofenac sodium suppositories consisting of Witepsol W35 and Witepsol E85 as a base were also prepared and their drug release functions investigated in vitro and in vivo. The in vitro drug release properties changed with the mixing ratios of the two bases and with the temperature of the fluid tested. The amount of released diclofenac sodium increased with increases of both the ratio of Witepsol W35 in the suppository and the temperature of the test fluid. Moreover, several processes causing these phenomena were evidenced by the image analysis. The in vivo absorption of diclofenac sodium was found to be also influenced by these factors. Consequently, it is predicted that such factors as the ratio of Witepsol W35 in the suppository and the temperature will influence the drug absorption and the pharmacological effect of diclofenac sodium suppositories.     

Effects of surfactant characteristics on drug availability from suppositories

The addition of surfactants to suppository formulations is referred to in the scientific literature, but their effects on drug availability remain uncertain. Surfactants are reported to improve drug dispersion into hard fatty excipients, to increase the spreading of the melted suppository on the rectal mucosa leading to a greater contact surface, to reduce the viscosity of the molten mass and to reduce the pathway of drug particles to the interface. In the present study a systematic investigation based on tensiometric and rheological methods was carried out to evaluate the effects of nonionic surfactants with different HLBs (hydrophilic-lipophilic-balance) on drug availability and to clarify the possible mechanisms involved in the release process. The relationship between the melted suppositories and a membrane simulating the rectal barrier were investigated in the course of the in vitro release test by measuring their energy characteristics. At the same time, the potential influences of such interactions on drug release were investigated in suppositories formulated with different kinds and concentrations of surfactant additives. Drug availability was influenced not only by the interaction between the suppository and the rectal membrane but also by the interaction between surfactant, lipophilic excipient and suspended drug particles. Such interactions appear to greatly influence drug release from suppositories, which, in turn, is the main parameter determining drug availability.     

Effect of the surfactant on the availability of piroxicam as a poorly hydrosoluble drug from suppositories

The use of surfactants in suppository formulations has been suggested to improve availability of poorly soluble drugs. In the present study, different kinds of surfactants have been investigated to clarify the influence on piroxicam release from suppositories formulated with both lipophilic and hydrophilic bases. Two hydrophilic glucose-derivate surfactants, and a polyoxylglyceride amphiphilic surfactant, all with high HLB values, were investigated for their use in improving drug availability. The two glucose derivate surfactants reduced drug availability from both lipophilic suppositories and hydrophilic formulations, according to longer disintegration times and drug micellization. The more complex surfactant, a lauroyl macrogolglyceride, showed an increase in piroxicam availability from lipophilic suppositories at the higher tested concentrations (15% and 20%). Otherwise, when used in hydrophilic formulations, it was less effective in promoting drug release and even reduced drug availability.     

Effects of absorption enhancers in chloroquine suppository formulations: I. In vitro release characteristics.

The need to develop chloroquine suppository formulations that yield optimal bioavailability of the drug has been emphasized. This study demonstrates the effects of incorporation of known absorption-enhancing agents (nonionic surfactants and sodium salicylate) on the in vitro release characteristics of chloroquine from polyethylene glycol (1000:4000, 75:25%, w/w) suppositories. The release rates were determined using a modification of the continuous flow bead-bed dissolution apparatus for suppositories. Results showed that the extent of drug release from suppositories containing any of three surfactants (Tween 20, Tween 80 and Brij 35) was 100%, whereas 88% release was obtained with control formulation (without enhancer) (P<0.05). However, Tween 20 was more effective than Brij 35 and Tween 80 in improving the drug release rate. There was a concentration-dependent effect with Tween 20, and 4% (w/w) of this surfactant was associated with the highest increase in the rate of drug release from the suppositories. Sodium salicylate at a concentration of 25% (w/w) also significantly enhanced the drug release rate, but a higher concentration of the adjuvant markedly reduced both the rate and extent of drug release. Combined incorporation of Tween 20 and sodium salicylate did not significantly modify (P0.05) the rate of drug release when compared to the effect of the more effective single agent. Due to their effects in improving the drug release profiles coupled with their intrinsic absorption-promoting properties, it is suggested that incorporation of 4% (w/w) Tween 20 and/or 25% (w/w) sodium salicylate in the composite polyethylene glycol chloroquine suppository formulations, may result in enhancement of rectal absorption of the drug. This necessitates an in vivo validation.     

Evaluation of mucin as a release enhancer for rectal delivery of glibenclamide

In this work mucin was evaluated as a release and absorption enhancer for glibenclamide from rectal glycerogelatin suppository. Glycerogelatin suppositories containing different ratios of glibenclamide to I-mucin (insoluble), S-mucin (soluble) and sodium salicylate respectively, were formulated using the fusion method. The suppositories were evaluated using standard parameters. Release studies were carried out in phosphate buffer (pH 7.6). The pharmacodynamic (PD) evaluation of the formulations was carried out on normoglycaemic albino rats. The results of the physical tests showed that the suppositories possessed high resistance to rupture and had uniformity of weight and drug contents. The erosion times of the suppositories with I-mucin, S-mucin and sodium salicylate were shorter than glycerogelatin suppositories BP without any release enhancer (control). Analysis of the release data showed that the release pattern was bi-phasic with initial fast release and subsequent slow release of the glibenclamide from the suppositories. The release mechanism followed first order kinetics. All the suppositories containing either S-mucin, I-mucin or sodium salicylate showed better glibenclamide release than the control without any release enhancer (p < 0.05). The pharmacodynamic studies showed that the overall glucose lowering effect in rats was greater in S-mucin suppositories than in sodium salicylate and I-mucin suppositories. The results of this study indicated that mucin extracted from Bovine spp. could be used to enhance the release and subsequent absorption of glibenclamide from rectal glycerolgelatin suppositories.     

Evaluation of paracetamol suppositories by a pharmacopoeial dissolution test--comments on methodology.

Ph.Eur. and BP have introduced a dissolution apparatus for suppositories. Suitability of the apparatus for quality control of paracetamol suppositories was evaluated and the effect of experimental conditions on dissolution profiles was studied. Paracetamol suppositories containing 80-500 mg of the drug, on fatty base, were obtained from four manufacturers (A, B, C, D). The diffusion cell was modified by incorporation of an in-built thermoprobe and large difference (up to 1.7 degrees C) between temperature in the water-bath and in the dissolution chamber was observed. This effect was avoided by increasing the length of tubing immersed in the thermostat at the inlet of the cell. The most reproducible results were observed for A and C suppositories, however from suppository C the total dose of paracetamol was released after 3.5-4.5 h while the release from suppository A was slow with only 40-87% of the total dose liberated during 6 h. Suppositories B did not melt at 37 degrees C and less than 5% of the drug was released. Fast release was observed after melting when the temperature was elevated to 39.5 degrees C. The results demonstrate clearly that essentially complete melting of a suppository in the dissolution chamber is required for an appropriate dissolution of paracetamol in vitro. Disintegration time, softening time, drop point and particle size of the suspended drug were measured and the relevance of these parameters for dissolution behaviour of the preparations was discussed.     

Preparation and In vitro Evaluation of Naproxen Suppositories

The aim of this work was to develop the best formulations for naproxen suppositories. The effects of different bases and surfactants on the physicochemical characteristics of the suppositories were determined by several tests such as weight variation, melting point, assay, hardness, and release rate. All formulations met the standard criteria for tested physicochemical parameters; weight variation (97-112%), content uniformity (97-105%), melting point (4.66-8.7 min) and hardness tests (>5400 g). Based on release rate studies, hydrophilic, and lipophilic bases without surfactants were not suitable bases for naproxen suppository. Amongst the formulations containing surfactants only Witepsol H15 with 0.5% w/w of Tween 80 and Witepsol W35 with 0.5% of cetylpyridinium chloride were suitable and released nearly complete drug during 30 and 60 min, respectively. This study demonstrates the effects of incorporation of known agents on the in vitro release characteristics of naproxen suppository.     

生物粘附性达那唑缓释栓剂的处方筛选与体外释放度考察

目的 :生物粘附性达那唑栓剂的处方筛选 ,并考察其体外释放规律。方法 :以羟丙甲基纤维素 (HPMC)为缓释材料 ,将等量聚乙二醇6000(PEG6000)和聚乙二醇600(PEG600)以熔融法制备含不同HPMC量的缓释栓剂 ,考察释放度与HPMC用量之间的关系。结果 :随着HPMC用量增加 ,栓剂释药减慢 ,当HPMC与PEG的比例为1∶6 5时 ,栓剂中药物在体外12h内缓慢释放 ,符合一级释放规律。结论 :生物粘附性骨架材料HPMC能延缓达那唑从栓剂中释放 ,当HPMC与PEG的比例为1∶6 5时栓剂能达到设计要求。     

In-vitro evaluation and vaginal absorption of metronidazole suppositories in rabbits

Vaginal suppository formulations of metronidazole were prepared using six different bases as Witepsol H15, Cremao, Ovucire WL2944, Ovucire WL3264, PEG 1500, PEG 6000. Three different dissolution methods were used to evaluate the in vitro drug release from the suppositories. The diffusion studies were performed through synthetic (cellophane) and natural membrane (rabbit vagina), but the drug did not show good permeation characteristics from natural membrane. Ovucire WL3264 suppositories of metronidazole labeled with 99mTc (Tecnetium-99m) were used for the vaginal absorption and biodistribution studies in the rabbits. Scintigraphic images were collected after vaginal administration of the labeled suppositories using SPECT gamma fitted with a low energy, high-resolution parallel hole collimator. The labeled drug showed high biodistribution in urine beside vaginal site. The results of this study suggested that the Ovucire WL3264 suppository of metronidazole prepared for vaginal infections could also be effective in the urinary infections.     

Reciprocating dialysis tube method: periodic tapping improved in vitro release/dissolution testing of suppositories.

The reciprocating dialysis tube (RDT) method can be used for in vitro release/dissolution testing of suppositories and has been reported to show good in vitro and in vivo correlation. However, for suppositories with viscous excipients, the result remains variable and generally under-predicts in vivo absorption. The purpose of this study was to assess whether periodic tapping of the closure of the RDT could improve in vitro release testing of suppositories. Two commercially available acetaminophen suppositories (A and B) that showed characteristic release behavior under normal rectal temperatures (37 and 38 degrees C) were chosen as test suppositories. In the absence of tapping, suppository A showed different release profiles at 37 and 38 degrees C, but the difference disappeared with periodic tapping. This finding was consistent with minimum temperature effect in the rectal absorption of suppository A in rabbits. Suppository B showed distinct release profiles at 37 and 38 degrees C irrespective of tapping, and the rectal absorption of suppository B in rabbits was affected by temperature. The test variability (CV% and ranges of release values) was substantially reduced in the presence of tapping. In conclusion, the addition of periodic tapping to RDT method developed in this study could improve in vitro release testing of suppositories.     

Investigation of the relationship between melting-related parameters and in vitro drug release from vaginal suppositories

The effect of temperature on drug release from meteneprost potassium vaginal suppositories was investigated using a dissolution test based on the USP I apparatus. Comparison of the dissolution results with the DSC melting behaviour revealed that drug release was extremely slow until melting of the suppository was essentially complete. The melting behaviour of the meteneprost potassium suppositories was also varied by preparing suppositories from bases with higher and broader melting ranges. The observed dissolution behaviour (at 37 degrees C) confirmed that drug release increased as the melting temperature of a particular suppository decreased. Differential scanning calorimetry, viscosity and dilatometry methods were used to characterize the suppository melting process. The effects of suppository melting range, melt temperature and composition were investigated with respect to in vitro drug release. Methodology for the HPLC determination of meteneprost in suppositories and in dissolution media are also reported.     

温度敏感型布洛芬缓释液体栓的制备与体内外评价

目的:以泊洛沙姆407(P407)和泊洛沙姆188(P188)为组合基质,添加生物黏附剂卡波姆(Cabopol)以及促渗透剂氮酮(Azone)制备温敏型布洛芬(IBU)缓释液体栓剂,考察液体栓释药的体内外相关性。方法:以凝胶温度、凝胶强度、生物黏附力和液体栓剂体外释放度为指标进行体外筛选;经比格犬直肠给药测定动物体内药物释放曲线进行体内筛选;用3P97程序计算药动学参数。结果:布洛芬体外释放结果符合零级模式,R2>0.9时,体内药物释放出现平台,显示了良好的体内外相关性;药动学研究结果表明,体内过程为一室模型,药动学参数为tmax=3.551 h,Cmax=21.483μg.mL-1,t1/2(Ke)=2.740 h,AUC0→∞=210.850μg.mL-1.h,MRT=7.670 h。结论:所制备的布洛芬液体栓剂具有良好的缓控释特征。     

Effect of drug solubility on the in vitro availability rate from suppositories with lipophilic excipients

The factors involved in mechanisms of availability of different drugs from suppositories with lipophilic excipients were studied by using an in vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. The solubility in water of drugs was found to be the fundamental factor influencing the release rate from suppositories. In fact, following the melting of the suppository at body temperature the drug particles can migrate to the interface with the small volume of rectal secretion where they dissolve. Drug molecules can so diffuse until they come into contact with the rectal barrier through which the drug is absorbed. Drug concentration in the intrarectal aqueous phase produces the gradient against the large volume of the plasma phase. This gradient regulates the diffusion rate through the barrier. A drug with a low water solubility saturates the intrarectal phase at low concentration hindering the subsequent dissolution of the drug particles remaining in the melted excipient. This fact maintains the viscosity of the melted suppository at a ligh level, which slows the migration of the particles. On the other hand, a drug with high water solubility quickly leaves the excipient, producing a high concentration in the intrarectal phase which supports a high diffusion rate across the barrier. The results obtained indicate that drugs with low solubility in water result in low availability, while drugs with good solubility can give an intense and rapid drug supply for a rapid and intense therapeutic response with the dose administered almost completely utilised.     

Effect of drug solubility on in vitro availability rate from suppositories with polyethylene glycol excipients

Factors involved in the availability mechanism of different drugs from suppositories with polyethylene glycol (PEG) excipients were studied using an in vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. Different from lipophilic excipients, the drug is released as a consequence of the progressive dissolution of PEG into the intrarectal aqueous phase. Drug concentration in this small intrarectal phase produces the gradient against the large volume of the plasmatic phase, which regulates the diffusion rate through the barrier. As with lipophilic excipients, drug solubility in water was found to be an important factor influencing suppository release rate. Nevertheless, PEG influenced in vitro drug availability considerably, by increasing both drug solubility and dissolution rate. The osmotic effect of PEG in the intrarectal compartment influenced the increase in volume of the aqueous phase. The results, compared with those obtained from suppositories with a lipophilic excipient, show a higher dissolution rate from PEG excipient, but a higher diffusion rate across the barrier did not always correspond. Drugs less soluble in water showed a greater availability from PEG suppositories. On the contrary the more soluble drugs were less available.     

Biopharmaceutical investigation of rectal suppositories. Part 2(1): Pharmaceutical and biological availability of phenobarbital and phenobarbital-sodium

The influence of the suppository base and drug solubility on the release an absorption of phenobarbital and phenobarbital-sodium from model suppositories was investigated. It was established that the pharmaceutical and biological availability of phenobarbital is higher from a hydrophilic base because of its improved solubility. The rate and the degree of release of phenobarbital-sodium are more significant from lipophilic bases. The bioavailability of two drug forms-phenobarbital and phenobarbital-sodium--is almost equal after rectal and oral administration.     

Evaluation of sustained release suppositories prepared with fatty base including solid fats with high melting points

To prepare the sustained release suppositories, solid fats such as polyglycerol ester of fatty acids (PGEFs) or beeswax were utilized with a fatty suppository base, Witepsol H15. PGEFs such as decaglycerol heptabehenate (HB750) and hexaglycerol pentastearate (PS500), and beeswax have relatively high melting points. The addition of PGEFs or beeswax to Witepsol H15 increased the apparent viscosity of suppository bases at 37 degrees C without any large change in the melting point of Witepsol H15. Moreover, the apparent viscosity of a mixed base with HB750, PS500 or beeswax at 37 degrees C was significantly correlated with the amount of each solid fat in a mixed base. The release of acetaminophen (AAP), a model drug, from suppositories was delayed by HB750, PS500 or beeswax, and an excellent correlation was observed between the apparent viscosity of these mixed bases and Higuchi's rate constants in each mixed base suppository, suggesting that these solid fats could regulate the drug release from the mixed base suppositories by changing their viscosity. In the in vivo absorption study in rats, several suppositories made from Witepsol H15-HB750 or Witepsol H15-beeswax mixed bases prolonged the rectal absorption of AAP without reducing AUC. In conclusion, by using solid fats such as HB750 and beeswax with relatively high melting points, it is possible to control the rate of drug release from fatty base suppositories for maintaining the plasma concentration of drugs for longer time periods.     

The role of various surfactants on the release of salbutamol from suppositories

Salbutamol is a selective beta(2)-adrenoreceptor agonist with different pharmacological effects. In this research because of the simplicity of suppository application in elderly and its higher plasma concentration than tablets as well as its particular indication in premature labour, salbutamol suppositories were prepared. The suppositories were formulated containing 10 mg of the drug and Witepsol H15, the oleaginous soluble base using melting method. To optimize the release rate of drug, different surfactants namely, sodium lauryl sulphate (SLS) as an ionic surfactant and Tween 80 as well as Arlacel 60 as non-ionic surfactants with different HLBs were chosen. The effect of surfactant concentration on the release rate of salbutamol from suppositories were also investigated. All prepared formulations fulfilled the specifications set down in British Pharmacopoeia. The results showed that Tween 80 (2%w/w) and SLS (0.75%w/w) caused an increase in dissolution rate of salbutamol from suppositories. As anionic surfactants, such as SLS, cause greater damage on mucosa than non-ionic surfactant, such as Tween 80, this study recommended that Tween 80 could be added in suppository formulation in order to increase the dissolution rate of salbutamol. It was also shown that the release rate of salbutamol altered linearly with the amount of Tween 80 in suppository formulations.     

Feasibility of the Ph.Eur. flow-through cell for dissolution testing of the compounded rectal suppositories containing indomethacin or sodium diclofenac

Ph.Eur. and BP have introduced a dissolution apparatus for suppositories. Suitability of the apparatus for quality control of indomethacin or sodium diclofenac (100 mg) compounded suppositories was evaluated and the effect of the type of suppository base on dissolution profiles was studied. The fastest and most reproducible release profiles were observed for hydrophilic base (macrogols). More than 80% of the drug was released during 60 min, while after 350 min 18.5-50% of the total amount was released from lipophilic bases (Witepsol and Adeps solidus). The results demonstrate that slow and non-reproducible release occurs when the lipophilic suppository base does not melt. The feasibility of the test for the formulations, which do not melt during the procedure, is questionable.