Soft Elastic Gelatin Research Articles

Chewable Gelatin Emulsions for Oral Lipid Delivery: Elimination of Gastric Coalescence with κ‐Carrageenan

AbstractGelatin‐based chewable emulsions can be a convenient vehicle for oral delivery of oils or lipid soluble bioactive components. Gelatin‐stabilized emulsions do, however, rapidly flocculate and gradually coalesce in gastric fluids. This destabilization is caused by the combined action of pepsin and mucin and is most significant at pH 3, followed by pH 2, then pH 4. Through in vitro lipolysis experiments it is shown that this destabilization leads to a decrease in emulsion lipolysis rate after incubation in simulated gastric fluids (SGFs). In this paper a potential solution to this gastric instability is suggested: inclusion of 1 wt% sodium‐κ‐carrageenan (κ‐CGN) of intermediate Mw into the gelatin emulsions. The κ‐CGN used has minimal impact on gelatin gelled emulsion properties, preserving the soft elastic gelatin texture. When these gelled emulsions disintegrate in gastric fluids, electrostatic interactions between the gelatin and κ‐CGN occur. While these interactions lead to heavy flocculation, they also protect the gelatin from pepsin action, providing full stability against emulsion coalescence during at least 2 h in SGF at pH 2–4. When the pH is neutralized upon mixing with intestinal fluids, the emulsion fully deflocculates and the rate of in vitro lipolysis is not affected by gastric residence time.Practical applications: Avoiding gastric coalescence in gelatin emulsions may lead to more reliable oral delivery of lipids or lipophilic components in gelatin‐based chewable supplements or functional foods. Keeping the emulsion droplet size stable and small until reaching the intestine may lead to more rapid and efficient intestinal lipolysis, potentially advantageous in regards to bioavailability of slowly digested oils (e.g., omega‐3 concentrate) or for people suffering from impaired lipid digestion. These findings may also be applicable to emulsion systems stabilized by other proteins.

Development of novel spray coated soft elastic gelatin capsule sustained release formulations of nifedipine

Nifedipine release from coated commercially available immediate release soft elastic gelatin capsules was investigated. Capsules were spray coated using two different polymeric combinations, ethylcellulose and hydroxypropylmethylcellulose or pectin, at different coating loads. In vitro drug release studies were conducted in three different dissolution media: with gastric pretreatment, without gastric pretreatment, and in water to investigate the pH effect on nifedipine release. Convolution of in vitro dissolution data for selected formulations and commercially available sustained release nifedipine formulations showed that the tested formulations provided release profiles of nifedipine that are very promising in terms of desirable sustained release formulations.

Detection of Formaldehyde-Induced Crosslinking in Soft Elastic Gelatin Capsules Using Near-Infrared Spectrophotometry

ABSTRACTThe purpose of this research was to monitor the migration of formaldehyde from a polyethylene glycol (PEG) fill into the gelatin shell of a soft elastic gelatin capsule (SEGC) using near-infrared (NIR) spectrophotometry. SEGCs were filled with five solutions of aqueous formaldehyde in PEG (0, 0.05, 0.10, 0.20, and 0.40v/v%), stored at ambient conditions for 48 hr, emptied, and scanned in NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the empty capsules. Good correlation was established (r2 = 0.988) when actual concentrations of formaldehyde in the PEG fill of the capsules were regressed against the principal component (PC) values from NIR spectra of the emptied and washed capsules. The loadings of the first PC describe a baseline shift in the spectra that arises from a change in water concentration. Lower PC loadings reveal the presence of signals at 1780 and 2200 nm that are not due to water absorbance, confirming the hypothesis that chemical bonds are formed during the formaldehyde-induced crosslinking of the gelatin in SEGCs. Gelatin crosslinking, initiated by formaldehyde migration from the PEG fill into the shell of an SEGC, was detected by NIR spectrophotometry. When NIR was coupled to principal component analysis, a linear relationship was found between the NIR spectra of empty SEGCs and the amount of crosslinking induced by concentrations of formaldehyde in the original fill material.

Preparation and In-Vitro Evaluation of Powder Solution Tablets of Valproic Acid

AbstractA tablet dosage form of liquid valproic acid (VPA) was formulated using powder solution technology as an alternative to the manufacturing of soft elastic gelatin capsules (SEGs). Mixing of liquid VPA with suitable adsorbents followed by blending with other excipients resulted in a non-adherent, free flowing powder. Tableting was achieved through standard direct compression. The tablets were acceptable in terms of physical properties. Film coated tablets (FCTs) and sugar coated tablets (SCTs) were also prepared. The in-vitro dissolution rates of these VPA tablets were significantly greater than that of a marketed SEG product. There was no significant change in the dissolution rates of the plain and FCTs after storage under accelerated stability conditions. Powder solution technology was a viable alternative to the commercial preparation of SEGs.

Determination of temazepam and related compounds in capsules by high‐performance liquid chromatography

A reversed-phase, high-performance liquid chromatographic assay method is described for temazepam hard gelatin and soft gelatin capsule analysis. The method is simple, specific, accurate, fast, and stability indicating. A reversed-phase octylsilane (C8) column with a mobile phase composed of methanol:1% acetic acid and detection at 254 nm separated sulfanilamide (internal standard), temazepam, synthetic precursor, and possible degradation products. Detector responses showed linearity to temazepam concentrations over the range 0.075–0.60 mg/mL (r = 0.9999). Mean recovery of temazepam added to capsule excipients was 100.3%. Mean assay results for 15- and 30-mg hard gelatin capsules were 101.5 and 101.3%, respectively. Mean assay results for 10- and 20-mg soft elastic gelatin capsules were 101.1 and 101.5%, respectively.

Separation of the stereoisomers of an allenic E-type prostaglandin

Enprostil (I) is a synthetic dehydro-prostaglandin E 2 containing a chiral allene moiety which is unresolved relative to the four remaining chiral centers. The relative configuration of the four remaining chiral centers is consistent with that of the naturally occurring E series of prostaglandins. Thus, enprostil exists as enantiomeric pairs of two allenic epimers. An analytical procedure has been developed that separates the four optical isomers present in enprostil. This procedure involves, first, the acid-catalyzed dehydration of enprostil to its corresponding prostaglandin A analogue followed by derivatization with β-naphthylsulfonyl- l-prolyl chloride. The resulting diastereomeric sulfonate esters are separated on an achiral silica gel high-performance liquid chromatographic column. This procedure has been applied to the analysis of both enprostil drug substance and enprostil formulated in a propylene carbonate solution from soft elastic gelatin capsules. An efficient procedure for the recovery of enprostil from the solution formulation is also described.

Dosage form and formulation effects on the bioavailability of vitamin E, riboflavin, and vitamin B-6 from multivitamin preparations

The effects of formulation factors and pharmaceutical dosage form on the bioavailability of RRR-alpha-tocopherol (d-alpha-tocopherol), riboflavin, and pyridoxine hydrochloride were studied after administration of two capsule formulations and a tablet to 12 normal humans. Absorption of RRR-alpha-tocopherol was increased from the Aquabiosorb soft elastic gelatin (SEG) capsule formulation compared with the modified standard-SEG capsule and the commercial tablet. There were no significant differences in bioavailability of riboflavin and pyridoxine hydrochloride between the SEG formulation and the tablet albeit a trend toward consistent absorption was seen from the SEG formulation. The modified-SEG formulation exhibited significantly lower bioavailability for these water-soluble vitamins. The enhanced bioavailability of vitamin E and the trend towards faster and more consistent absorption of riboflavin and vitamin B-6 from the SEG formulation may be related to the surfactant vehicle employed and the attendant wetting properties. The results also suggest ethnic differences in vitamin bioavailability.

Stability-Specific HPLC Analysis of the Antiulcer Prostaglandin, Enprostil, in a Soft Elastic Gelatin Capsule Formulation

Abstract This report describes a reverse-phase HPLC assay for the antiulcer drug, enprostil, formulated as a 0.3 mM solution (in propylene carbonate) filled into soft elastic gelatin capsules. The method uses: a 5 μm C18 column, a ternary (THF-methanol-phosphate buffer) mobile phase and 220 nm spectrophotometric detection to provide a sensitive and specific assay for enprostil and its major degradation products. The method satisfies the usual statistical criteria (recovery efficiency, response linearity, precision, lower quantitation limit) and performs well under various operating conditions as demonstrated by system suitability tests (analyte capacity factor dependence on column type, mobile phase composition, flow rate, and column temperature). We also demonstrate how a diode-array spectrophotometric detector

Multidimensional Column-Switching Liquid Chromatographic Method for Dissolution Testing of Enprostil Soft Elastic Gelatin Capsules

Enprostil (methyl 7-[(1 R*, 2R*, 3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1- butenyl]-5-oxocyclopentyl]4, 5-heptadienoate), an E-type prostaglandin exhibiting anti-ulcer activity, is formulated as a propylene carbonate solution filled into soft elastic gelatin (SEG) capsules. Enprostil SEG capsules were maintained for timed intervals at 50 °C, 30 °C, and room temperature, and the quantity of drug released upon complete capsule dissolution was determined as a function of storage condition. The dissolution test adhered to USP XXI guidelines (paddle method) and used a multidimensional HPLC technique to provide a sensitive and selective enprostil assay. Parallel HPLC assays determined the enprostil concentration in the propylene carbonate fill that was physically expressed from initially manufactured and from aged capsules. This corrected for any enprostil loss via chemical degradation on storage. The study included six different aged samples (six replicates each), and for all six samples, the enprostil recovered from dissolved capsules averaged 104 ± 1.4% of the enprostil physically expressed from the capsules. Similarly, the enprostil recovered from dissolved, aged capsules averaged 103 ± 5% of the enprostil physically expressed from capsules at the initial time point. These findings exclude the possibility that interactions with the SEG capsule wall reduce drug availability during storage under normal conditions. The multidimensional HPLC technique should generally extend to analysis of other noncationic drugs formulated into soft gelatin capsules.

Diastereospecific HPLC Analysis of the Antiulcer Drug, Enprostil, in a Soft Elastic Gelatin Capsule Formulation

Abstract Enprostil, an E-type prostaglandin analog, is formulated as a 0.3 mM propylene carbonate solution filled into soft elastic gelatin capsules. A characteristic structural feature of enprostil is the presence of two unresolved chiral centers, yielding a drug molecule that exists as two diastereomeric pairs of enantiomers. This report describes an HPLC method for quantitatively determining the relative amounts of enprostil diastereomers in soft elastic gelatin capsules. Using a Spherisorb ODS 5 μym, 250 × 4.5 mm column and a mobile phase mixture of 59:40:1 methanol:water:tetrahydrofuran separates the enprostil diastereomeric pairs and also resolves the enprostil diastereomers from potential interferences arising from placebo and drug degradation. The method performs well as evidenced by the usual statistical tests for: response linearity, recovery efficiency, precision, and lower quantitation limit. Also, the demonstrated dependence of chromatographic retention on mobile phase composition and system ...

Reactivity of Enprostil Stereoisomers in Soft Elastic Gelatin Capsules

Enprostil (methyl 7-[(1R*, 2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy-1-butenyl]-5-oxocyclopentyl]-4, 5-hepta-dienoate), a gastric acid secretion inhibitor and potent anti-ulcer drug, is formulated as a propylene carbonate solution which is filled into soft elastic gelatin capsules. The drug molecule features two unresolved asymmetric carbon atoms, and synthesis yields an equimolar mixture of four different optical isomers (two diastereomeric pairs of enantiomers). The objective of this study was to establish the degree to which enprostil does or does not degrade stereoselectively in the soft elastic gelatin capsule formulation. Accordingly, we developed an HPLC method capable of resolving enprostil diastereoisomers and applied the method to determining reaction rates of enprostil in soft elastic gelatin capsules maintained at 40°C. The study included three soft elastic gelatin capsule lots: the first two contained an equimolar mixture of all four enprostil enantiomers; and the third contained an equimolar mixture of two individual diastereoisomers of known optical purity. Comparing enprostil degradation rates in the three capsule lots showed that reactivity ratios in all cases were (within the limits of experimental uncertainty) equal to unity. This observation conclusively excludes the possibility of significant enantioselectivity for enprostil degradation in the soft elastic gelatin capsule formulation. We also report kinetic equations for the general case of relating stereospecific reactivity ratios to drug product shelf life when drug concentrations are monitored with nonstereoselective analytical techniques.

Water Migration from Soft Gelatin Capsule Shell to Fill Material and its Effect on Drug Solubility

The bioavailability of some poorly water-soluble drugs was reported to increase due to a change in dosage form from a tablet to a solution encapsulated in soft gelatin capsules. However, the objective of increasing the bioavailability may be defeated if the drug crystallizes from a solution inside the capsule. In this study, a water-insoluble drug [a-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; REV 5901] was solubilized in both polyethylene glycol 400 (PEG 400) and a 6:1 mixture of Gelucire 44/14:PEG 400. The solutions were then encapsulated in soft elastic gelatin capsules with a fill weight of 700mg (drug, 125mg), and water migration from the capsule shell into the fill material and its effect on the solubility of the drug were investigated. Gelucire 44/14 is a mixture of hydrogenated fatty acid esters with a mp of 44μC; PEG 400 was added to reduce the mp of solution to ˜36°C for easier encapsulation. After equilibration of capsules at ambient condition, the amount of water in the PEG 400 solution was 6.3%. This reduced the solubility of the drug by 45%, resulting in drug crystallization. The solubility decreased exponentially with the increase in water content. The water in the encapsulated Gelucire:PEG solution was only 1.1%, which did not affect the solubility significantly.

Gas Chromatographic Analysis of Chloral Hydrate in Soft Gelatin Capsules

AbstractA simple, rapid and sensitive GC method for the analysis of chloral hydrate in soft elastic gelatin capsules was developed using n-amyl alcohol as the internal standard. The samples were chromatographed using a glass column packed with chromosorb 102 and flame ionization detection. The operating temperatures were 175°, 190°, and 200°C for the column, detector, and injector, respectively. This method was shown to isolate chloral hydrate from its major degradation product chloroform. The method was also compared with compendial and colorimetric procedures. The accuracy, precision, linearity, and applicability to soft elastic gelatin capsules are also presented.

Measurement of Soft Elastic Gelatin Capsule Firmness with a Universal Testing Machine

An indication of the firmness of Soft Elastic Gelatin (SEG) capsules was obtained by measurement in a universal testing machine (Instron, Model 1122). Capsules were packed in both glass and polystyrene containers and then exposed them in closed containers to 25°C and 75% RH, 35°C and 75% RH, and 45°C and 75% RH for a period of 21 weeks. At the end of 2, 12, and 21 week periods, samples were withdrawn from environmental chambers and evaluated them for firmness by subjective as well as objective techniques. The deformation of capsules measured by the universal testing machine appears to be a reliable and sensitive method for measuring firmness of SEG Capsules.

Pharmacokinetics of isotretinoin during repetitive dosing to patients.

The multiple dose pharmacokinetics of isotretinoin and its major blood metabolite, 4-oxo-isotretinoin, were studied in 10 patients with cystic acne and 11 patients with various keratinization disorders. Blood samples were obtained at predetermined times following the first dose, interim doses and the final dose. Blood concentrations of isotretinoin and 4-oxo-isotretinoin were measured by a specific and sensitive HPLC method. A lag time was usually observed prior to the onset of absorption following oral administration of the drug in a soft elastic gelatin capsule. Absorption then proceeded rapidly and maximum blood concentrations usually occurred within 4 h of drug administration. The harmonic mean half-life for the elimination of isotretinoin by the cystic acne patients was approximately 10 h after the initial dose and did not change significantly following 25 days of 40 mg b.i.d. dosing. Steady-state blood concentrations remained relatively constant after the fifth day of dosing. The harmonic mean elimination half-life in the patients with various disorders of keratinization was about 16 h. The results of the 2 studies suggest that no significant changes in the pharmacokinetics of isotretinoin occur during multiple dosing and that the multiple dose pharmacokinetic profile is predictable and can be described using a linear pharmacokinetic model. This suggests that the steady-state concentrations of isotretinoin can be predicted from single dose data.