Unlocking the full potential of lipid-based formulations using lipophilic salt/ionic liquid forms.

Lipid-based formulations (LBF) are widely used by industry and accepted by the regulatory authorities for oral drug delivery in the pharmaceutical and consumer healthcare market. Innovation in the LBF field is however needed in order to meet the demands of modern drugs, their more challenging problem statements and growing needs for achieving optimal pharmacokinetics (i.e., no food-effects, low variability) on approval. This review describes a new lipophilic salt / ionic liquid approach in combination with LBF, and how this salt strategy can be used to better tailor the properties of a drug to LBFs. The potential advantages of lipophilic salts are discussed in the context of dose escalation studies during toxicological evaluation, reducing the pill burden, increasing drug absorption of new drugs and in life-cycle management. Commentary on lipophilic salt synthesis, scale-up, LBF design and the regulatory aspects are also provided. These topics are discussed in the broad context of bringing the widely recognized advantages of LBFs to a broader spectrum of drugs.

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations.

Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by 1H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically >10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.

Toward the establishment of standardized in vitro tests for lipid-based formulations. 5. Lipolysis of representative formulations by gastric lipase.

PURPOSE: Lipid-based formulations (LBF) are substrates for digestive lipases and digestion can significantly alter their properties and potential to support drug absorption. LBFs have been widely examined for their behaviour in the presence of pancreatic enzymes. Here, the impact of gastric lipase on the digestion of representative formulations from the Lipid Formulation Classification System has been investigated. METHODS: The pHstat technique was used to measure the lipolysis by recombinant dog gastric lipase (rDGL) of eight LBFs containing either medium (MC) or long (LC) chain triglycerides and a range of surfactants, at various pH values [1.5 to 7] representative of gastric and small intestine contents under both fasting and fed conditions. RESULTS: All LBFs were hydrolyzed by rDGL. The highest specific activities were measured at pH 4 with the type II and IIIA MC formulations that contained Tween®85 or Cremophor EL respectively. The maximum activity on LC formulations was recorded at pH 5 for the type IIIA-LC formulation. Direct measurement of LBF lipolysis using the pHstat, however, was limited by poor LC fatty acid ionization at low pH. CONCLUSIONS: Since gastric lipase initiates lipid digestion in the stomach, remains active in the intestine and acts on all representative LBFs, its implementation in future standardized in vitro assays may be beneficial. At this stage, however, routine use remains technically challenging.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 6: effects of varying pancreatin and calcium levels.

The impact of pancreatin and calcium addition on a wide array of lipid-based formulations (LBFs) during in vitro lipolysis, with regard to digestion rates and distribution of the model drug danazol, was investigated. Pancreatin primarily affected the extent of digestion, leaving drug distribution somewhat unaffected. Calcium only affected the extent of digestion slightly but had a major influence on drug distribution, with more drug precipitating at higher calcium levels. This is likely to be caused by a combination of removal of lipolysis products from solution by the formation of calcium soaps and calcium precipitating with bile acids, events known to reduce the solubilizing capacity of LBFs dispersed in biorelevant media. Further, during the digestion of hydrophilic LBFs, like IIIA-LC, the un-ionized-ionized ratio of free fatty acids (FFA) remained unchanged at physiological calcium levels. This makes the titration curves at pH 6.5 representable for digestion. However, caution should be taken when interpreting lipolysis curves of lipophilic LBFs, like I-LC, at pH 6.5, at physiological levels of calcium (1.4 mM); un-ionized-ionized ratio of FFA might change during digestion, rendering the lipolysis curve at pH 6.5 non-representable for the total digestion. The ratio of un-ionized-ionized FFAs can be maintained during digestion by applying non-physiological levels of calcium, resulting in a modified drug distribution with increased drug precipitation. However, as the main objective of the in vitro digestion model is to evaluate drug distribution, which is believed to have an impact on bioavailability in vivo, a physiological level (1.4 mM) of calcium is preferred.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 4: proposing a new lipid formulation performance classification system.

The Lipid Formulation Classification System Consortium looks to develop standardized in vitro tests and to generate much-needed performance criteria for lipid-based formulations (LBFs). This article highlights the value of performing a second, more stressful digestion test to identify LBFs near a performance threshold and to facilitate lead formulation selection in instances where several LBF prototypes perform adequately under standard digestion conditions (but where further discrimination is necessary). Stressed digestion tests can be designed based on an understanding of the factors that affect LBF performance, including the degree of supersaturation generated on dispersion/digestion. Stresses evaluated included decreasing LBF concentration (↓LBF), increasing bile salt, and decreasing pH. Their capacity to stress LBFs was dependent on LBF composition and drug type: ↓LBF was a stressor to medium-chain glyceride-rich LBFs, but not more hydrophilic surfactant-rich LBFs, whereas decreasing pH stressed tolfenamic acid LBFs, but not fenofibrate LBFs. Lastly, a new Performance Classification System, that is, LBF composition independent, is proposed to promote standardized LBF comparisons, encourage robust LBF development, and facilitate dialogue with the regulatory authorities. This classification system is based on the concept that performance evaluations across three in vitro tests, designed to subject a LBF to progressively more challenging conditions, will enable effective LBF discrimination and performance grading.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations.

PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs. METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases. RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol. CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance.

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 1: method parameterization and comparison of in vitro digestion profiles across a range of representative formulations.

The Lipid Formulation Classification System Consortium is an industry-academia collaboration, established to develop standardized in vitro methods for the assessment of lipid-based formulations (LBFs). In this first publication, baseline conditions for the conduct of digestion tests are suggested and a series of eight model LBFs are described to probe test performance across different formulation types. Digestion experiments were performed in vitro using a pH-stat apparatus and danazol employed as a model poorly water-soluble drug. LBF digestion (rate and extent) and drug solubilization patterns on digestion were examined. To evaluate cross-site reproducibility, experiments were conducted at two sites and highly consistent results were obtained. In a further refinement, bench-top centrifugation was explored as a higher throughput approach to separation of the products of digestion (and compared with ultracentrifugation), and conditions under which this method was acceptable were defined. Drug solubilization was highly dependent on LBF composition, but poorly correlated with simple performance indicators such as dispersion efficiency, confirming the utility of the digestion model as a means of formulation differentiation.