Research ArticlePharmaceutics, Drug Delivery and Pharmaceutical TechnologyIn Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery
Introduction
Enteric coatings (EC) were invented in 1950's by Röhm & Haas GmbH1 and are a great asset in the drug delivery toolbox. The use of enteric coatings allows formulation scientists to target the intestine and helps to protect sensitive compounds from the harsh environment of the stomach. This is important to allow oral delivery of peptides for which a low chemical stability is commonly observed. The principle is to coat the dosage form with a polymer that is insoluble in acidic environments such as the stomach, but soluble at intestinal pH of 5.5 and above. Consequently, the use of EC relies on the assumption of an acidic stomach environment for proper function. While this holds true for healthy volunteers, this is not the case for all patient populations. Hypochlorhydria can be caused by chronic atrophic gastritis or H. pylori infection, both of which are common among the elderly.2,3 Another common cause of hypochlorhydria is pharmacological treatment with proton pump inhibitors or H2-receptor antagonists. In populations with elevated gastric pH, an alternative to enteric coatings may be beneficial if the compound needs to be released in the small intestine. Furthermore, enteric coated dosage forms show a large variability in the time of drug release, as seen in the study by Wilding et al.,4 where the disintegration time after gastric emptying varied from 11 to 134 min in the fasted state and from 27 to 140 min in the fed sate. This variability leads to drug release taking place in different parts of the intestine, making targeting to the upper part of the small intestine (i.e. the duodenum and proximal jejunum) challenging when enteric coating is used. This is particularly problematic for drugs with narrow absorption windows, where the drug is mainly absorbed in the upper regions of the small intestine. In a previous clinical study this was indeed observed for octreotide, an octapeptide and potent inhibitor of growth hormone, glucagon and insulin, which had higher absorption from the jejunum than the ileum.5,6
Lately there has been a growing interest in oral delivery of peptides and other macromolecules. Several strategies have been proposed to enable macromolecules to reach the systemic circulation. The most studied and perhaps the most successful strategy so far, is the use of permeation enhancers (PE).7, 8, 9 The current understanding of permeation enhancers is that a sufficiently high local concentration of the enhancer and active pharmaceutical ingredient (API) is needed in order to achieve increased absorption of the macromolecule.8,10 Exactly how high the local concentration need to be, and for how long such a high local concentration need to be maintained, is still unclear and will likely depend on the PE and API used. EC are often used for formulations containing macromolecules and PEs. The main reasons to use EC is to protect against the acidic gastric environment, enzymatic drug degradation in the stomach and to avoid dilution of the permeation enhancer and API prior to reaching the site of absorption.10,11 Enteric coated dosage forms typically dissolve in 10–30 min when measured in a USP II dissolution apparatus. However, this time can be longer in vivo as shown by gamma scintigraphy.4 A higher release rate could allow for higher luminal concentrations of both the PE and the API, which may be advantageous for intestinal absorption of macromolecules.
In addition to pH-sensitive coatings, electrolyte-dependent, osmotically active or time-dependent release systems are also used in pharmaceutical products.12 Another trigger for controlling the release of active substances from dosage forms is the use of physiological, gastrointestinal pressures. Previously Wilde et al. developed pressure sensitive dosage forms that were designed to break from the pressures related to gastric emptying. One dosage form used a brittle glyceryl tristearate capsule filled with paracetamol formulated as a hydroxyethyl cellulose gel.13 Another design was based on drug-containing spheres consisting of hard fat (Witespol W32) or polyethylene glycol 1000. The spheres were coated with a brittle cellulose acetate coating that broke at predefined pressures.14 The hard fat or polyethylene glycol melts at body temperature, generating liquid filled capsules in the stomach, allowing the brittle coating to break. Takada et al. developed a “pressure-controlled colon delivery capsule” that also uses pressure as a trigger for drug release.15, 16, 17
In order to investigate new drug delivery concepts and produce new dosage forms, conventional production techniques may not be the most appropriate. One alternative employed in the current work is the use of rapid prototyping techniques based on 3D printing. For example, 3D printing has already been used by formulation scientists to produce oral dosage forms with complex geometries that cannot be produced using conventional manufacturing techniques.18, 19, 20
Krause et al. designed a 3D printed pressure sensitive capsule aiming to release its content in the antropyloric region of the GI tract in response to the high-pressure event of transit through the pylorus, or the MMC phase III contractions pressing the capsule against the closed pylorus.21 The brittle capsule was designed to shatter into pieces when exposed to a pressure higher than 300 mbar, instantaneously delivering its content. This trigger pressure was chosen based on GI pressure data22, 23, 24 and defined to allow the capsule to maintain its integrity in the stomach while being crushed when exposed to the higher pressure in the antropyloric region related to gastric emptying. The release mechanism enables the possibility of achieving high local concentrations upon drug release. The potentially added control over site of release within the GI tract, together with a potential to achieve high local concentrations may be advantageous for oral delivery of peptides, both in terms of enhanced bioavailability and reduced absorptive variability.
The primary aim of the study was thus to investigate if the pressure sensitive capsules, designed to achieve high local concentrations of drug and permeation enhancer in the upper GI tract by virtue of their instantaneous release mechanism, could achieve a higher peptide bioavailability than traditional enteric coated dosage forms which are known to display variable in vivo release profiles. The pressure sensitive capsules were compared with traditionally enteric coated (Eudragit L) hard gelatin capsules and enteric coated tablets for their drug delivery efficiency in dogs. The synthetic octapeptide octreotide with a molecular weight of 1019 Da was chosen as model drug. Furthermore, the highly soluble and highly permeable BCS class I compound paracetamol was included in the formulations to facilitate evaluation of dosage form performance.25 The permeation enhancer sodium caprate (C10) was included in all dosage forms to enable absorption of the peptide.
Section snippets
Materials
Paracetamol, fluorescein-sodium, sodium chloride, trifluoroacetic acid, formic acid and acetonitrile were purchased from Sigma-Aldrich (St. Louis, MO, USA). Phosphate buffered saline (PBS) was purchased from Life Technologies Limited (Paisley, UK, USA). Hydrochloric acid and tri-sodium phosphate dodecahydrate was purchased from Merck KGaA (Darmstadt, Germany). Sodium caprate was purchased from Finar chemicals (Ahmedabad, India). Octreotide was purchased from Polypeptide Laboratories (Ambernath,
Breaking Pressure Measurement of the Pressure Sensitive Capsules
The investigated dosage forms showed no drug release within the first 60 min when no pressure was applied. After applying a pressure of 200 mbar, no coloring of the dissolution medium was observed. The applied pressure was increased in steps by 50 mbar. After applying pressures of 500 mbar, four of the five tested pressure sensitive capsules broke, which led to an immediate discoloration of the release medium. After increasing the applied pressure up to 550 mbar, the last remaining capsule
Conclusions
In this study the pressure sensitive capsules that did release drug performed similarly as the traditional enteric coated dosage forms in terms of octreotide bioavailability and Cmax. However, the pressure sensitive capsules did not release drug in 50% of the subjects which merits further attention. It is possible that a trigger pressure for release of less than 300 mbar is needed for optimal in vivo performance in dogs. This work confirms the usefulness of paracetamol as a well absorbed marker
Conflicts of Interest
There are no conflicts to declare.
Data Availability
The data generated and analyzed during this study are available from the corresponding author upon reasonable request.
Acknowledgment
This study is part of the science program of the Swedish Drug Delivery Forum (SDDF). Financial support from Vinnova (Dnr 2017–02690) is gratefully acknowledged.
References (49)
- et al.
Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials
Adv Drug Deliv Rev
(2016) - et al.
Intestinal permeation enhancers for oral peptide delivery
Adv Drug Deliv Rev
(2016) - et al.
Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic
Adv Drug Deliv Rev
(2009) - et al.
Development of a pressure-sensitive glyceryl tristearate capsule filled with a drug-containing hydrogel
Int J Pharm
(2014) - et al.
Development of pressure-sensitive dosage forms with a core liquefying at body temperature
Eur J Pharm Biopharm
(2014) - et al.
New preparation method of intestinal pressure-controlled colon delivery capsules by coating machine and evaluation in beagle dogs
J Contr Release
(1998) - et al.
Evaluation of intestinal pressure-controlled colon delivery capsule containing caffeine as a model drug in human volunteers
J Control Release
(1998) - et al.
Effect of geometry on drug release from 3D printed tablets
Int J Pharm
(2015) - et al.
3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release
J Contr Release
(2017) - et al.
Stereolithographic (SLA) 3D printing of oral modified-release dosage forms
Int J Pharm
(2016)
Design and characterization of a novel 3D printed pressure-controlled drug delivery system
Eur J Pharm Sci
Intragastric pH and pressure profiles after intake of the high-caloric, high-fat meal as used for food effect studies
J Control Release
Resolving the physiological conditions in bioavailability and bioequivalence studies: comparison of fasted and fed state
Eur J Pharm Biopharm
Characterization of the GI transit conditions in Beagle dogs with a telemetric motility capsule
Eur J Pharm Biopharm
Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses
Eur J Pharm Biopharm
Gastric pH profiles of beagle dogs and their use as an alternative to human testing
Eur J Pharm Biopharm
Fed and fasted gastric pH and gastric residence time in conscious beagle dogs
J Pharm Sci
Gastric pH and gastric residence time in fasted and fed conscious beagle dogs using the Bravo pH system
J Pharm Sci
Intestinal absorption of the octapeptide SMS 201-995 visualized by fluorescence derivatization
Gastroenterology
Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate
J Pharm Sci
Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs
Eur J Pharm Sci
Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption
Adv Drug Deliv Rev
Food effect projections via physiologically based pharmacokinetic modeling: predictive case studies
J Pharmaceut Sci
Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport
Int J Pharm
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