Hard Gelatin Capsules Research Articles

HPMC AS CAPSULE SHELL MATERIAL: PHYSICOCHEMICAL, PHARMACEUTICAL AND BIOPHARMACEUTICAL PROPERTIES

The most common instability problem of gelatin capsules arises from negative impact of extremes of temperature and especially atmospheric relative humidity on the mechanical integrity of the capsule shells with adverse effect extended even to the fill material. Moreover, choice of fill materials is highly restricted either due to their specific chemical structure, physical state or hygroscopicity. Additional reports of unpredictable disintegration and dissolution of filled hard gelatin capsules in experimental studies have prompted the search for a better alternative capsule shell material. The present review aims to provide an overview on the physicochemical, pharmaceutical and biopharmaceutical properties of hydroxypropyl methylcellulose (HPMC) as capsule shell material and perform comparative evaluation of HPMC and gelatin in terms of in vitro/in vivo performance and storage stability. HPMC capsule provides a highly flexible and widely acceptable platform capable of solving numerous challenges currently facing the pharmaceutical and nutraceutical industries and expands the possibilities for selection of different types of fill materials. The current topic introduces a new section on influence of various factors on in vitro dissolution of HPMC capsules. Delayed in vitro disintegration/dissolution of HPMC capsules in aqueous medium does not produce any negative effect in vivo. However, advancements in the processes of production and filling of HPMC capsule shells and detailed studies on effects of various parameters on their in vitro/in vivo dissolution would establish their supremacy over hard gelatin capsules in future.

Atovaquone oral bioavailability enhancement using electrospraying technology

Atovaquone in combination with proguanil hydrochloride, marketed as Malarone® tablets by GlaxoSmithKline (GSK), is prescribed for the treatment of malaria. High dose and poor bioavailability are the main hurdles associated with atovaquone oral therapy. The present study reports development of atovaquone nanoparticles, using in house designed and fabricated electrospraying equipment, and the assessment of bioavailability and therapeutic efficacy of the nanoparticles after oral administration. Solid nanoparticles of atovaquone were successfully produced by electrospraying and were characterized for particle size and flow properties. Differential Scanning Calorimetry, X-ray Diffraction, Fourier Transform Infrared Spectroscopy studies were also carried out. Atovaquone nanoparticles along with proguanil hydrochloride and a suitable wetting agent were filled in size 2 hard gelatin capsules. The formulation was compared with Malarone® tablets (GSK) and Mepron® suspension (GSK) in terms of in vitro release profile and in vivo pharmacokinetic studies. It showed 2.9-fold and 1.8-fold improved bioavailability in rats compared to Malarone® tablets and Mepron® suspension respectively. Therapeutic efficacy of the formulation was determined using modified Peter's 4-day suppressive tests and clinical simulation studies using Plasmodium berghei ANKA infected Swiss mice and compared to Malarone®. The developed formulation showed a 128-fold dose reduction in the modified Peter's 4-day suppressive tests and 32-fold dose reduction in clinical simulation studies. Given that only one capsule a day of developed formulation is required to be administered orally compared to 4 Malarone® tablets once a day and that too at a significantly reduced dose, this nanoparticle formulation will definitely reduce the side-effects of the treatment and is also likely to increase patient compliance.

Organic Colouring Agents in the Pharmaceutical Industry

AbstractFood dyes are largely used in the process of manufacturing pharmaceutical products. The aim of such a procedure is not only to increase the attractiveness of products, but also to help patients distinguish between pharmaceuticals. Various dyes, especially organic colouring agents, may in some cases have a negative impact on the human body. They are incorporated into pharmaceutical products including tablets, hard gelatine capsules or soft gelatine capsules, lozenges, syrups, etc. This article provides an overview of the most widely used colouring agents in pharmaceuticals, their characteristics and the EU legislation which regulates their use.

Controlled release properties of zein powder filled into hard gelatin capsules

This study aimed to investigate the relationship between controlled release behaviour, swelling and initial water sorption of zein powder filled into hard gelatin capsules. Release, release rate and dissolution efficiency of various physical mixtures of zein and propranolol HCl filled into capsules were measured by dissolution testing. As the gelatin shell dissolved, zein rapidly formed a matrix, providing prolonged drug release, after an initial drug burst. Drug loading and ionic strength of the medium significantly influenced drug release. Imaging and gravimetric analysis were used to investigate matrix swelling and erosion. Zein matrices swelled like hydrophilic matrices, yet were practically non-erodible. Moreover, a strong significant positive correlation was found between matrix swelling and drug release (Pearson's correlation coefficient, r≥0.9657, p-value≤0.0017), suggesting that the degree of swelling governed drug release. The tensiometry test revealed that the initial ingress of media through the pores of zein powder was significantly limited by a reduction of the capillary radii of these pores, as a result of rapid polymer hydration. In conclusion, the rapid hydration of zein powder could explain the matrix formation and the controlled release observed with the capsules in the dissolution studies. Initial hydration, swelling and release behaviour were dependent on the ionic strength of the medium.

Formulation and modifying drug release from Hard and Soft Gelatin Capsules for Oral drug delivery

Capsule is the most versatile of all dosage forms. Capsules are solid dosage forms in which one or more medicinal and inert ingredients are enclosed in a small shell or container usually made of gelatin. There are two types of capsules, “hard” and “soft”. The hard capsule is also called “two pieces” as it consists of two pieces in the form of small cylinders closed at one end, the shorter piece is called the “cap” which fits over the open end of the longer piece, called the “body”. The soft gelatin capsule is also called as “one piece”. Capsules are available in many sizes to provide dosing flexibility. Unpleasant drug tastes and odors can be masked by the tasteless gelatin shell. The administration of liquid and solid drugs enclosed in hard gelatin capsules is one of the most frequently utilized dosage. This proves the oral bioavailability of poorly soluble compounds, delivery of low and ultra-low doses of a compound using softgel also ensures decreased plasma variability. This has led to the commercial pharmaceutical and nutraceutical industries opting for the development of alternative shell forming materials instead of the traditional capsule shell material gelatin. This review discusses establishment and the ongoing development of the manufacturing technology for liquid and semisolid capsules with focus on progress and challenges of soft and hard gelatin capsules formulation in oral administration for improved solubility and as an absorption-enhancing technique. These considerations form a basis for new applications in oral drug delivery.

FORMULATION AND EVALUATION OF ASPIRIN RELEASE FROM MATRIX PELLETS COMPRESSED INTO MUPS TABLET

MUPS (Multiple Unit Pellets System):
 The oral route of drug administration is the most important and most user-friendly route of administration. In recent years, Multiple Unit Pellet Systems (MUPS) tablets are widely used in solid dosage form design. MUPS is considered to provide pharmacokinetic advantages compared to monolithic dosage forms. Typically, modified release pellets are contained in MUPS tablets. Modified release drug delivery systems have acquired very important role in pharmaceutical research and development.1
 1.1Advantages of Compaction of MUPS over Conventional Modified-Release Tablets and/or Pellet-Filled Capsules and Tablets. 
 
 The compression of multiparticulates into tablets, unlike the hard gelatin capsule, is a tamper-proof dosage form and has greater physicochemical and microbiological stability of pellets as they are embedment in the inert matrix.
 Tablets have less difficulty in esophageal transport than capsules.
 Tablets containing coated subunits can be prepared at a lower cost than these subunits filled into hard gelatin capsules because of higher production rate of the tablet press.
 The expensive control of capsule integrity after filling is also eliminated.
 In addition, tablets containing multiparticulates without losing the controlled-release properties could be scored, which allow a more flexible dosage regimen.

In Vitro Release Study on Capsules and Tablets Containing Enteric - Coated Granules Prepared by Wet Granulation

Wet granulation method was used instead of conventional pan coating or fluidized –bed coating technique to prepare enteric-coated diclofenac sodium granules, using ethanolic solution of EudragitTM L100 as coating, binding and granulating agent .Addition of PEG400 or di-n-butyl phthalate as a plasticizer was found to improve the enteric property of the coat.
 Part of the resulted granules was filled in hard gelatin capsules (size 0), while the other part was compressed into tablets with and without disintegrant.
 The release profile of these two dosage forms in 0.1N HCl (pH 1.2)for 2 hours, and in phosphate buffer (pH 6.8) for 45 minutes as well as the release kinetic were compared with that of the enteric film coated Voltadin (R) SDI tablets.
 The results of this study show that, the prepared dosage forms have a good enteric property, with faster release of drug from encapsulated enteric-coated granules in comparison with compressed tablets.

The study of pharmaco-technological parameters for the standardization of hard gelatin capsules on the base of the substance phenibut

Within the pharmaceutical development is necessary to determine the volume and the order of operations aimed at standardizing of a medicine. In this aspect is important the achieving of standardization conditions at appropriate stages of the production process and conducting the quality control procedures at the release of a medicine. Aim. To study the pharmaco-technological parameters of a medicine in the form of hard gelatin capsules on the base of the substance phenibut. Results. It has been built the control strategy of Bifren medicine, capsules of 250 mg. Taking into account the recommendations of the leadership ICH Q8 there were conducted the works on determination the medicine’s quality target profile. Obtained results was formed the basis of the concept of documentation development for standardization of medicines, particularly, specifications for quality control of the products. The study of pharmaco-technological parameters was consisted in the study of the uniformity content of active ingredient per unit dosage of the medicine, the average weight of the capsule content, the uniformity of the mass of the capsule content, and the disintegration and dissolution of capsules. When carried out the works of assessment of the stability of a medicine there were studied conditions and developed eligibility criteria to include pharmaco-technological parameters in the specification on the stability studying. Conclusions. The results of experimental studies were used in the development of quality control methods for the medicine Phenibut, capsules of 250 mg and specifications for a series of a medicine and to specifications on corresponding intermediate products. A result of conducted complex works were defined permissible limits of pharmaco-technological indicators which characterized more rigid approach to the requirements for intermediate products compared with the standards for the finished product, which is one of the provable elements of the system ensure the quality of medicines in the company “Pharma Start”.

Novel expandable gastro retentive system by unfolding mechanism of levetiracetam using simple lattice design – Formulation optimization and in vitro evaluation

The aim of the present study was to develop and characterize a novel expandable gastro-retentive dosage form (GRDF), based on unfolding mechanism. The dosage form consists of a drug loaded the polymeric patch, folded into a hard gelatin capsule. Gastro retention obtained from unfolding and swelling of the patch and its adhesion to the gastric mucosa. Therefore in this work, a gastro retentive patch of levetiracetam was developed using simple lattice design considering concentration of Hydroxy Propyl Methyl Cellulose, Carbopol 934P and Xanthan gum as independent variables. A response surface plot and multiple regression equations were used to evaluate the effect of independent variables on dependent variables such as mucoadhesive strength (g/cm2) and t90 (h). The prepared patches were evaluated for weight and thickness variation, mechanical properties, in vitro drug release and unfolding behavior. The absence of drug-polymer interaction and uniform drug dispersion in the polymeric patches was revealed by FT-IR, DSC, XRD and SEM. The results indicates, the novel GRDF based on unfolding mechanism can be alternative for other mucoadhesive dosage forms which will provide sustained release for 12h.

Nanoethosomes for transdermal delivery of tropisetron HCl: multi-factorial predictive modeling, characterization, and ex vivo skin permeation

Objective: The aim of the present work is to exclusively optimize and model the effect of phospholipid type either egg phosphatidylcholine (EPC) or soybean phosphatidylcholine (SPC), together with other formulation variables, on the development of nano-ethosomal systems for transdermal delivery of a water-soluble antiemetic drug. Tropisetron HCl (TRO) is available as hard gelatin capsules and IV injections. The transdermal delivery of TRO is considered as a novel alternative route supposing to improve BAV as well as patient convenience.Methods: TRO-loaded ethanolic vesicular systems were prepared by hot technique. The effect of formulation variables were optimized through a response surface methodology using 3 × 22-level full factorial design. The concentrations of both PC (A) and ethanol (B) and PC type (C) were the factors, while entrapment efficiency (Y1), vesicle size (Y2), polydispersity index (Y3), and zeta potential (Y4) were the responses. The drug permeation across rat skin from selected formulae was studied. Particle morphology, drug–excipient interactions, and vesicle stability were also investigated.Results: The results proved the critical role of all formulation variables on ethosomal characteristics. The suggested models for all responses showed good predictability. Only the concentration of phospholipid, irrespective to PC type, had a significant effect on the transdermal flux (p < 0.01). The ethosomal vesicles were unilamellar with a nearly spherical shape. EPC-based ethosomes proved good stability.Conclusion: The study suggests the applicability of statistical modeling as a promising tool for prediction of ethosomal characteristics. The ethanolic vesicles were considered as novel potential nanocarriers for accentuated transdermal TRO delivery.

Randomized double-blinded pilot clinical study of the antidiabetic activity of Balanites aegyptiaca and UPLC-ESI-MS/MS identification of its metabolites

Context: Balanites aegyptiaca Del. (Zygophyllaceae) fruits are traditionally known for the treatment of hyperglycaemia. Several in vitro and in vivo studies proposed some mechanisms of action. However, clinical trials in human beings were never reported to date. Objectives: To investigate the antidiabetic efficacy of the 70% ethanol extract of the pericarps of B. aegyptiaca (BE) within a nutritional intervention in elderly people. Materials and methods: Ultra-performance electrospray ionization-mass spectroscopy (UPLC-ESI-MS/MS) analysis was used for metabolic profiling of BE which was incorporated in hard gelatine capsules (400 mg/day) and tested on 30 type 2 diabetes (T2D) Egyptian patients for 8 weeks. According to sex, age and body mass index participants were divided into two equivalent groups, placebo and treatment. Results: Thirteen compounds were identified in BE using UPLC-ESI-MS/MS analysis among which five steroidal saponins, seven phenolic compounds and a sterol glucoside. At the end of the 8-week treatment, the treated group showed 26.88% decrease in 2 h postprandial plasma glucose relative to 2.6% increase in the placebo group, while fasting plasma glucose was reduced to 10.3%. Treatment with BE capsules for 8 weeks produced significant reduction in the plasma triglyceride, total cholesterol and low-density lipoprotein cholesterol by 9.0, 12.76 and 21.35%, respectively, with 29.8% increase in the high-density lipoprotein cholesterol. Plasma alanine transaminase and aspartate transaminase were reduced by 42.6 and 43.3%, respectively. Discussion and conclusion: Administration of the BE capsules to T2D resulted in significant improvements in the glycaemic markers and the lipid profile, without adverse effects or hypoglycaemia.

Ассортиментный контур сегмента российского фармацевтического рынка лекарственных средств в твердых желатиновых капсулах

Ассортиментный контур сегмента российского фармацевтического рынка лекарственных средств в твердых желатиновых капсулах

Review on: New approaches in self micro-emulsifying drug delivery system

Self Micro-Emulsifying drug delivery system is recent and novel approaches have been attracted to considerable interest as an efficient means for improving solubility, dissolution rate and oral bioavailability of API (Active Pharmaceutical Ingredient). Now a day's up to 40% of new drug chemical entities developed and discovered by pharmaceutical industry by recent years such as poorly soluble and highly permeable lipid based drug delivery system (such as lipophilic compound). SMEDDS are most important approaches for improvement of solubility enhancement of lipid based BCS Class II drug delivery system. SMEDDS is isotropic mixture of oil, hydrophilic surfactant and co-surfactant and solubilised drug. This formulation spontaneously from fine oil-in-water microemulsion upon dilution with water. They can be encapsulated in hard or soft gelatin capsule or to form other solid dosage forms by using various recently developed techniques such as spry drying, adsorption to solid carrier, melt granulation, melt extrusion/extrusion speronization and encapsulation in liquid and semisolid dosage forms. Oral delivery of such drugs is complicated for the reason that of their low bioavailability, high intra and inter-subject variability and not have dose linearity. The article gives complete overview of SMEDDS but special attention has been shown to formulation, design, evaluation and application of SMEDDS.

Influence of excipients on mixtures containing high amount of dry extract from Aesculus hippocastanum L.

The aim of this study was to evaluate the influence of the qualitative composition of excipients on formulation technology of hard gelatin capsules containing high amount of dry extract from Aesculus hippocastanum L. (ESAH). The rheological and technological characteristics of ESAH were determined and the influence of pharmaceutical excipients on the properties of mixtures was studied by a 22 factorial design. The dissolution profiles of the capsules containing the best mixtures were obtained using sodium lauryl sulfate aqueous solution 1% (w/v) as medium. The ESAH showed high cohesivity and therefore low flow. Moreover, the ESAH showed lower level of residual moisture and was stable under controlled atmosphere. When considering pre-formulation, the filler/binder materials (microcrystalline cellulose or lactose) and glidant (colloidal silicon dioxide) increased the technological properties of the mixtures in comparison to pure ESAH. In conclusion, the dissolution profiles showed that there was no significant difference between the formulations and the ESAH, which demonstrated totally release after 30 minutes.

DEVELOPMENT AND COMPARISON OF ORALLY INHALABLE SUSTAINED RELEASE FORMULATIONS FOR THREE RESPIRATORY DRUGS FOR ASTHMA

The present work was designed to develop and compare orally inhalable sustained release formulation for salbutamol sulphate (SS), ambroxol hydrochloride (AH) and montelukast sodium (MS).The emulsion solvent evaporation method was used to prepare microparticles with the polymers. The prepared polymer encapsulated microparticles were blended with carrier inhalable lactose and filled in size 3 hard empty gelatin capsule. Formulations T1-T9 were prepared with 1:1 ratio of PLGA (50:50), PLGA (75:25) and Eudragit RS100. The formulation T1 prepared with SS:PLGA (50:50) produces best result when compared with other formulations T2-T9. Formulation T1 gives in vitro release 91.23% at 12 h and having particle size of microparticles (D0.5 µm) 1.94±0.6 and respiratory fraction 34.9± 2.59 %.

Effect of Rheology and Poloxamers Properties on Release of Drugs from Silicon Dioxide Gel-Filled Hard Gelatin Capsules-A Further Enhancement of Viability of Liquid Semisolid Matrix Technology.

The liquid and semisolid matrix technology, filling liquids, semi-solids and gels in hard gelatin capsule are promising, thus, there is a need of enhanced research interest in the technology. Therefore, the present study was aimed to investigate isoniazid (freely soluble) and metronidazole (slightly soluble) gels filled in hard gelatin capsules for the effect of poloxamers of different viscosities on release of the drugs. Gel of each drug (10% w/w, particle size 180-250μm), prepared by mixing poloxamer and 8% w/w hydrophilic silicon dioxide (Aerosil® A200), was assessed for rheology, dispersion stability and release profile. Both the drugs remained dispersed in majority of gels for more than 30days, and dispersions were depended on gels' viscosity, which was further depended on viscosity of poloxamers. A small change in viscosity was noted in gels on storage. FTIR spectra indicated no interactions between components of the gels. The gels exhibited thixotropic and shear-thinning behaviour, which were suitable for filling in hard gelatin capsules without any leakage from the capsules. The release of both drugs from the phase-stable gels for 30days followed first-order kinetics and was found to be correlated to drugs' solubility, poloxamers' viscosity, polyoxyethylene contents and proportion of block copolymer (poloxamers) in the gels. The findings of the present study indicated that release of drugs of different solubilities (isoniazid and metronidazole) might be modified from gels using different poloxamers and Aerosil® A200.

A Review on Self Emulsified Drug Delivery System: A Promising Approach for Drug Delivery of BCS Class II and IV Drugs

Purpose: The oral delivery of drugs having poor aqueous solubility presents a major challenge. Selfemulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and cosolvents/surfactants, can improve the oral absorption of highly lipophilic drug compounds. The current review summarizes the latest research in the field of SEDDS and we emphasize basically the type of excipients used by current researcher. Approaches : SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil- in- water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids. Findings : Lipophilic drug compounds exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible plasma drug profiles. Conclusion : Almost 40% of the new drug compounds are hydrophobic in nature which draws attention towards SEDDS to improve the oral bioavailability of such drugs.

In vitro evaluation of the impact of gastrointestinal transfer on luminal performance of commercially available products of posaconazole and itraconazole using BioGIT

Biorelevant Gastrointestinal Transfer system (BioGIT) has been shown to be useful in reproducing concentrations of drugs in the fasted upper small intestine after their administration in the stomach. In the present investigation, we evaluated the impact of gastrointestinal transfer on luminal performance of commercially available products of two highly lipophilic weak bases, posaconazole (Noxafil® suspension) and itraconazole (Sporanox® hard gelatin capsules and Sporanox® oral solution) by comparing % solid fraction, concentrations and supersaturation in the duodenal compartment of BioGIT with recently reported data in the upper small intestine of healthy adults. BioGIT was useful for estimating the % solid fraction in the upper small intestine, in cases where dissolution during gastric residence was incomplete, i.e. after administration of Noxafil® and Sporanox® capsules, and the precipitated fraction of itraconazole in the upper small intestine after administration of Sporanox® solution; median values in vitro were similar to the luminal values. Based on the values for the area under the concentration vs. time data estimated up to 45min post initiation of the experiment, concentrations in the duodenal compartment of BioGIT were similar to previously measured concentrations in the upper small intestine of healthy adults or they overestimated them by up to 2.5 times. In most cases, supersaturation of contents in the upper small intestine was overestimated, partly due to underestimation of luminal solubility.

Challenge of paediatric compounding to solid dosage forms sachets and hard capsules - Finnish perspective.

The study evaluated the quality of compounded sachets and hard gelatine capsules and their feasibility in paediatric drug administration. Commercial tablets were compounded to sachets and capsules in hospital environment, and the uniformity of content and simulated drug dose were determined. Compounded formulations were successfully obtained for a range of drug substances; dipyridamole, spironolactone, warfarin and sotalol formulations were within acceptable limits for uniformity of content, in most cases. However, some loss of drug was seen. The type and amount of excipients were found to affect uniformity of content; good conformity of capsules was obtained using lactose monohydrate as filler, whereas microcrystalline cellulose was a better choice in sachets. In capsules, content uniformity was obtained for a range of drug doses. If the drug is aimed to be administered through a nasogastric tube, solubility of the drug and excipients should be considered, as they were found to affect the simulated drug dose in administration. Compounded sachets and capsules fulfilled the quality requirements in most cases. In compounding, the choice of excipients should be considered as they can affect conformity of the dosage form or its usability in practice. Quality assurance of compounded formulations should be taken into consideration in hospital pharmacies.

SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEM

&lt;p&gt;ABSTRACT&lt;br /&gt;Oral route is the most convenient route of drug administration in many diseases and till today it is the first way investigated in the development of&lt;br /&gt;new dosage forms. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility,&lt;br /&gt;thereby pretense problems in their formulation. More than 40% of potential drug products suffer from poor water solubility. For the therapeutic&lt;br /&gt;delivery of lipophilic active moieties (biopharmaceutical classification system Class II drugs), lipid-based formulations are inviting increasing&lt;br /&gt;attention. Currently, a number of technologies are available to deal with the poor solubility, dissolution rate, and bioavailability of insoluble drugs.&lt;br /&gt;One of the promising techniques is self-microemulsifying drug delivery systems (SMEDDS). SMEDDS have gained exposure for their ability to increase&lt;br /&gt;solubility and bioavailability of poorly soluble drugs. SMEDDS, which are isotropic mixtures of oils, surfactants, solvents, and co-solvents/surfactants&lt;br /&gt;can be used for the design of formulations to improve the oral absorption of highly lipophilic drug compounds. Conventional SMEDDS are mostly&lt;br /&gt;prepared in a liquid form, which can have some disadvantages. SMEDDS can be orally administered in soft or hard gelatin capsules and form fine&lt;br /&gt;relatively stable oil-in-water emulsions. Solid-SMEDDS are prepared by solidification of liquid/semisolid self-micron emulsifying ingredients into&lt;br /&gt;powders, have gained popularity. This article gives a complete overview of SMEDDS, but special attention has been paid to formulation, design,&lt;br /&gt;evaluation, and little emphasis on application of SMEDDS.&lt;br /&gt;Keywords: Self-microemulsifying drug delivery system, Surfactant, Oil, Co-surfactant, Bioavailability, Lipophilic, Biopharmaceutical classification&lt;br /&gt;system Class II drugs.&lt;/p&gt;