Allopurinol prodrugs. III. Water-soluble N-acyloxymethyl allopurinol derivatives for rectal or parenteral use

Nine amino acid esters of 1-(hydroxymethyl)allopurinol were synthesized and evaluated as potential water-soluble prodrugs of allopurinol with the aim of developing preparations suitable for parenteral and/or rectal administration. Hydrochloride or hydrobromide salts of all the ₁-acyloxymethyl derivatives exhibited a water-solubility greater than 20%. The kinetics of hydrolysis of the compounds was studied in aqueous solution and in human plasma solutions at 37°C. Complete reversion to allopurinol was observed in all cases, the maximum stability of the derivatives occurring at pH < 4. The susceptibility of the derivatives to undergo enzymatic hydrolysis varied widely, the observed half-lives in 80% human plasma ranging from 3 to 140 min. It was concluded that N₁-acyloxymethyl derivatives of allopurinol containing an amino group in the acyl moiety are potentially useful as parenteral delivery forms of the parent drug. Furthermore, compounds containing a weakly basic amino group (pK_a 6–7.5) may be useful as prodrugs to enhance the rectal absorption of allopurinol as assessed on the basis of the water-solubility and lipophilicity of the derivatives.     

Prodrugs as drug delivery systems. 43. O-acyloxymethyl salicylamide N-Mannich bases as double prodrug forms for amines

Due to their rapid cleavage at physiological pH salicylamide N-Mannich bases have been suggested as prodrug forms for primary and secondary amines. A drawback of the Mannich bases is, on the other hand, their limited stability in vitro, raising some stability-formulation problems. In the present study, blocking of the hydroxyl group of the salicylamide N-Mannich bases by O-acyloxymethylation has been shown to be a potentially useful approach to improve the stability. Various O-acyloxymethylated derivatives of N-(morpholinomethyl)salicylamide were prepared and found to be much more stable in acidic and neutral aqueous solution than the parent salicylamide N-Mannich base and to be readily converted to the latter in the presence of human plasma by enzymatic hydrolysis. In addition to providing an in vitro stabilizing effect the concept of O-acyloxymethylation makes it possible to obtain prodrug derivatives of a given amine drug with varying physicochemical properties of importance for drug delivery such as lipophilicity and water-solubility. This can simply be effected by the selection of an appropriate acyloxymethyl group.     

Prodrugs of 5-fluorouracil. IV. Hydrolysis kinetics,bioactivation and physicochemical properties of various N-acyloxymethyl derivatives of 5-fluorouracil

The kinetics and mechanism of hydrolysis of various 1-, 3- and 1,3-acyloxymethyl derivatives of 5-fluorouracil were studied to assess their potential as prodrugs with the aim of enhancing the delivery characteristics of the parent drug. All the derivatives hydrolyzed to yield 5-fluorouracil in quantitative amounts, passing through an unstable N-hydroxymethyl-5-fluorouracil intermediate. The pH-rate profiles obtained revealed the occurrence of specific acid and base catalysis as well as of a water-catalyzed reaction. The rates of hydrolysis were accelerated markedly in the presence of human plasma or rat liver homogenate, suggesting the utility of the derivatives as prodrugs. The derivatives were all more lipophilic than 5-fluoro-uracil as determined by partition experiments in octanol-aqueous buffer systems but the aqueous solubility was only slightly reduced or, for some derivatives, even greater than that of 5-fluorouracil. This behaviour was attributed to differences in the crystal lattice energy, and relationships between melting points, partition coefficients and water-solubilities for these and 11 other prodrug derivatives of 5-fluoro-uracil were established.     

Allopurinol prodrugs. I. Synthesis,stability and physicochemical properties of various N1-acyl allopurinol derivatives

Seven novel N₁-acyl derivatives of allopurinol were synthesized and evaluated as potential prodrugs with the purpose of developing preparations suitable for rectal and parenteral administration. The kinetics of hydrolysis of the derivatives was studied in aqueous solutions at various pH-values and in human plasma solutions at 37° C. All the compounds hydrolyzed to yield allopurinol in quantitative amounts and rate expressions were derived to account for the pH-rate profiles observed. The rates of hydrolysis were accelerated by plasma enzymes, the half-lives of hydrolysis in 80% human plasma solutions at 37°C being 6, 4, 2.5 and 4 min for the N₁-acetyl, N₁-propionyl, N₁-butyryl and N₁-benzoyl derivatives, respectively. These N-acyl derivatives were more lipophilic than allopurinol as determined by partition experiments in octanol-water but the solubility in water was even greater (the N₁-acetyl derivative) or only slightly reduced (the other derivatives) as compared with allopurinol. This behaviour was attributed to a decreased intermolecular hydrogen bonding in the crystal lattice achieved by blocking the 1-NH group by acylation. It is suggested that N₁-acylation may be a promising means of obtaining prodrug forms of allopurinol with the aim of enhancing the rectal delivery characteristics of the drug. This was confirmed in preliminary animal experiments. Two highly water-soluble derivatives, 1-(N,N-dimethylglycyl)allopurinol hydrochloride and 1-(4-N,N-di-methylaminobutyryl)allopurinol hydrochloride, were prepared but found to be less suitable as parenteral delivery forms of allopurinol due to a very limited stability in aqueous solution, arising from intramolecular catalysis by the dimethylamino group in the acyl moiety.     

Water-Soluble,Solution-Stable,and Biolabile N-Substituted (Aminomethyl)benzoate Ester Prodrugs of Acyclovir

Various N-substituted 3- or 4-(aminomethyl)benzoate esters of acyclovir were synthesized and evaluated as water-soluble prodrug forms with the aim of improving the delivery characteristics of acyclovir, in particular its parenteral administration. The esters showed a high solubility in weakly acidic solutions and, as demonstrated with the 3-(N,N-dipropylaminomethyl)benzoate ester, a high stability in such solutions, allowing storage for several years. The esters combine these properties with a high susceptibility to undergo enzymatic hydrolysis in plasma. The half-lives of hydrolysis in 80% human plasma ranged from 0.8 to 57 min, the rate being highly dependent on the position (3 or 4) of the aminomethyl group relative to the ester moiety. All esters were more lipophilic than acyclovir in terms of octanol–pH 7.4 buffer partition coefficients. These properties make N-substituted (aminomethyl)-benzoate esters a promising new prodrug type for acyclovir to enhance its delivery characteristics.     

Prodrugs of 5-fluorouracil. III. Hydrolysis kinetics in aqueous solution and biological media,lipophilicity and solubility of various 1-carbamoyl derivatives of 5-fluorouracil

The kinetics of hydrolysis of five 1-carbamoyl-5-fluorouracil derivatives (methyl-, ethyl-, butyl-, phenyl- and N,N-dimethylcarbamoyl derivatives) was studied in aqueous solution of pH 1–14, human plasma solutions and in the presence of rat liver homogenate at 37°C. All the derivatives hydrolyzed to yield 5-fluorouracil in quantitative amounts. The decomposition rates in aqueous solution (pH 1–10) showed a sigmoid pH-dependence which could be ascribed to water-catalyzed or spontaneous hydrolysis of the neutral and anionic forms (pK_a 6.1–6.7). The greater reactivity observed for the anionic form of the derivatives was attributed to intramolecular general base catalysis. The half-lives of hydrolysis of the 1-alkylcarbamoyl derivatives at pH 7.40 and 37°C were 8–11 min and that of the 1-phenyl-carbamoyl derivative 5 s, whereas the N,N-dimethylcarbamoyl derivative proved to be highly stable. The hydrolysis was not catalyzed by rat liver homogenates, and human plasma surprisingly showed a pronounced inhibition. This deceleration of the hydrolysis rate was attributed to a non-productive binding to or inclusion of the compounds by plasma proteins. The derivatives were more lipophilic than 5-fluorouracil as determinded by partition experiments in octanol-aqueous buffer systems and possessed a lower water-solubility.     

Pro-drugs as drug delivery systems XIII. Kinetics of decomposition of N-Mannich bases of salicylamide and assessment of their suitability as possible pro-drugs for amines

The kinetics of decomposition of various N-Mannich bases of salicylamide in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for amino compounds. The decomposition, yielding salicylamide, amine and formaldehyde in stoichiometric amounts, showed bell-shaped pH-rate profiles which could be accounted for by assuming spontaneous decomposition of both neutral and protonated Mannich base and unreactivity of the derivatives in the anionic form. For the Mannich bases with the amines piperidine, α-alanine, methylamine and morpholine, the half-lives of decomposition at pH 7.40 and 37°C were 14, 17, 28 and 41 min, respectively, suggesting that salicylamide N-Mannich bases are possible candidates as pro-drugs for compounds containing a primary or secondary amino group. N-Amidomethylation of the amines with salicylamide resulted in a pronounced lowering of their basicity corresponding to 3–4 pK_a units which may be of potential utility for the application of N-Mannich bases as pro-drug forms for amines.     

Prodrugs as drug delivery systems. XXX. 4-Imidazolidinones as potential bioreversible derivatives for the α-aminoamide moiety in peptides

The hydrolysis kinetics of five 4-imidazolidinones derived from acetone and the dipeptides Ala-Gly, Ala-Ala, Phe-Leu, Leu-Gly and Asp-Phe methyl ester were studied to assess their suitability as prodrug forms for the α-aminoamtde moiety occurring in peptides. The imidazolidinyl peptides were found to undergo a complete hydrolysis in the pH range 1–10 at 37°C and most of them showed a sigmoidal pH-rale profile with maximum rates at pH > 4. The stability of the derivatives varied widely, the following half-lives being obtained at pH 7.40 and 37°C: 0.9 h (Asp-Phe methyl ester), 3.4 h (Phe-Leu), 24.6 h (Ala-Ala). 410 h (Ala-Gly) and 530 h (Leu-Gly). The major structural factor influencing the stability appeared to be the stcric properties within the C-terminal amino acid residue. The 4-imidazolidinones are much weaker bases (pK_a about 3.1) than the parent dipeptides and, as determined by partition experiments in octanol-aqueous buffer systems with the Phe-Leu derivative, they are more Hpophilic than the parent compounds. It is suggested that 4-imidazolidinone formation in principle may Become a useful approach to bioreversible dehvatization of dipeptides or other peptides containing an α aminoamide function with the aim of solving delivery problems fur peptide drugs.     

Prodrugs as drug delivery systems. Part 42. 2-Hydroxymethylbenzamides and 2-acyloxymethylbenzamides as potential prodrug forms for amines

Several 2-hydroxymethylbenzamides derived from various primary and secondary amines were prepared and evaluated as potential prodrug models for the amino group occurring in several drugs. The hydroxy-amides were found to undergo a quantitative cyclization in aqueous solution to phthalide and the parent amine. The lactonization was specific acid- and base-catalyzed as well as subject to buffer catalysis. The structural factor being predominantly responsible for the different reactivities of the hydroxy-amides was found to be the steric properties of the amines, the amine basicity being only of minor importance. The cyclization proceeded only slowly at pH 7.4 and 37°C and in order to be a useful prodrug principle it may be necessary to accelerate the reaction rate, e.g. by introducing sterically or catalytically accelerating substituents in the hydroxy-amide moiety. Acylation of the hydroxymethyl group was shown to block the lactonization and hence to stabilize the hydroxy-amides. However, in the presence of human plasma the ester grouping was readily hydrolyzed yielding the parent 2-hydroxymethylbenzamide. Such cascade latentiation may thus be a particularly useful prodrug principle affording at the same time adequate in vitro stability and in vivo lability.     

Allopurinol prodrugs. IV. Improved rectal and parenteral delivery of allopurinol using the prodrug approach as evaluated in rabbits

Various N₁-acyl and N-acyloxymethyl prodrug derivatives of allopurinol were evaluated as parenteral and rectal delivery forms of the parent drug. The rectal and parenteral absorption characteristics of twelve derivatives and of allopurinol were assessed in rabbits. Whereas the rectal absorption of allopurinol was less than 3%, the various prodrug derivatives showed a bioavailability ranging from 11 to 94%. The most promising prodrug candidates were N₁-acyloxymethyl derivatives containing a weakly basic amino group in the acyl moiety e.g. 1-(N,N-diethylglycyloxy-methyl)allopurinol hydrochloride. Such compounds are highly soluble in water and possess an adequate lipophilicity at physiological pH. The varying extent of rectal absorption of the derivatives was discussed in relation to the water-solubility and lipophilicity, as expressed in terms of octanol-aqueous buffer partition coefficients.     

Synthesis,in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery

New glycosyl derivatives of ibuprofen (I, II, III, and IV) were synthesized in order to overcome the ineffective delivery of ibuprofen across the blood–brain barrier owing to its low permeability, using d-glucose as a drug targeting agent. Ibuprofen was linked directly to the C-2, C-3, C-4, and C-6 positions of glucose via ester bonds. Furthermore, in vitro stabilities of the four ester derivatives were evaluated to determine both their stability in aqueous medium and their feasibility to undergo enzymatic cleavage by esterase in biological samples to regenerate the original drug. From the obtained results, compounds I–IV appeared to be moderately stable in pH 7.43 buffer solution, rat plasma, and brain tissue extracts. In vivo experiments showed that the AUC_0–t of ibuprofen in plasma after the injection of prodrugs is several times higher than that of AUC_0–t after the injection of ibuprofen. In addition, the maximal concentration of ibuprofen in brain after the administration of ester IV was three fold higher than that of the control group. Also, the concentration of ibuprofen was kept stable in brain for about 4?h for four esters, which was beneficial for the treatment of Alzheimer’s disease and highlighted the possibility of brain drug delivery of ibuprofen using prodrug strategies.     

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

Abstract

The highly organized structure of the stratum corneum provides an effective barrier to the drug delivery into or across the skin. To overcome this barrier function, penetration enhancers are always used in the transdermal and dermal drug delivery systems. However, the conventional chemical enhancers are often limited by their inability to delivery large and hydrophilic molecules, and few to date have been routinely incorporated into the transdermal formulations due to their incompatibility and local irritation issues. Therefore, there has been a search for the compounds that exhibit broad enhancing activity for more drugs without producing much irritation. More recently, the use of biomaterials has emerged as a novel method to increase the skin permeability. In this paper, we present an overview of the investigations on the feasibility and application of biomaterials as penetration enhancers for transdermal or dermal drug delivery systems.     

Self-assembled drug delivery systems 2. Cholesteryl derivatives of antiviral nucleoside analogues: synthesis, properties and the vesicle formation

Self-assembled drug delivery systems (SADDS) are defined as the self-aggregates of amphiphilic prodrugs. Prodrug, molecular self-assembly and nanotechnology are involved in SADDS manufacturing. But the knowledge of the self-assembly of amphiphilic prodrugs and the formation rules of SADDS is very limited. In this paper, five cholesteryl derivatives of antiviral nucleoside analogues were synthesized, involving antiviral acyclovir, didanosine and zidovudine, and the different acyl linkers, succinyl, adipoyl and phosphoryl. The derivatives are typical amphiphiles with nucleosides as polar heads and long-chained lipids as hydrophobic tails. The derivatives showed the similar soluble behavior, and the solubility highly depended on the types of solvents. Two forces, hydrogen bonding and hydrophobic interaction in alcohol solutions could improve the derivatives dissolving. However, the molecular self-assembly of derivatives could prefer to happen in the noncompetitive solvents including chloroform and tetrahydrofuran (THF) based on the intermolecular hydrogen bonding between nucleobase moieties, which could greatly increase their solubility. The derivatives formed nanosized vesicles based on hydrophobic interaction after injecting their THF solutions into water. The volume ratios of polar heads and hydrophobic tails of amphiphiles could determine the vesicle size, and the amphiphiles with large ratios would prefer to form small vesicles. The self-assembled vesicles would likely become SADDS.     

Physicochemical characterization of colloidal drug delivery systems such as reverse micelles, vesicles, liquid crystals and nanoparticles for topical administration.

Topical administration of cosmetics and pharmaceuticals involves a variety of different formulations of which colloidal drug carrier systems are currently of particular interest. After a short introduction of reverse micellar solutions, liquid crystals, vesicles and nanoparticles, appropriate methods of physicochemical characterization are introduced including X-ray diffraction, laser light scattering, electron microscopy, and differential scanning calorimetry. Emphasis is laid on topical applications of the colloidal drug delivery systems (DDS) covered, with the main objective of both sustained drug release and improved stability of DDS.     

Testosterone solid lipid microparticles for transdermal drug delivery. Formulation and physicochemical characterization

Purpose: The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system.

Methods: Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5?mg TS?g^?1. Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24?h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated.

Results: The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7–95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM?<?5% GD?<?5% SA?<?5% GB?<?2.5% GM?<?2.5% SA?<?10% GD?<?10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB–2.5?mg TS?g^?1 SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB–2.5?mg TS?g^?1 stored at 5°C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation.

Conclusions: The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.     

Atomic force microscopy: a tool to study the structure,dynamics and stability of liposomal drug delivery systems

Much work has been done during the past few decades to develop effective drug delivery systems (DDS), many of which are based on nanotechnology science. Liposomes are the most attractive lipid vesicles for drug delivery. The multifunctional properties of liposomes have a key role in modifying the bioavailability profile of a therapeutic agent. Different analytical techniques can be used to describe liposomes, not least applied scanning probe microscopy (SPM) techniques. Atomic force microscopy (AFM) seems to be one of the most effectively applied SPM techniques. This review article outlines the applications of AFM in evaluating the physical characteristics and stability of liposomal DDSs. Other well-known microscopy techniques used in evaluating liposome physical characteristics are also mentioned, and the contribution of AFM to evaluating liposomal stability is discussed. Among the advantages of AFM in examining the physicochemical properties of liposomal DDSs is its ability to provide morphological and metrology information on liposome properties. AFM thus appears to be a promising tool in technological characterization of liposomal DDSs.     

Lipid nanocarriers as skin drug delivery systems: Properties,mechanisms of skin interactions and medical applications

During the past decades, lipid nanocarriers are gaining momentum with their multiple advantages for the management of skin diseases. Lipid nanocarriers enable to target the therapeutic payload to deep skin layers or even to reach the blood circulation making them a promising cutting-edge technology.Lipid nanocarriers refer to a large panel of drug delivery systems. Lipid vesicles are the most conventional, known to be able to carry lipophilic and hydrophilic active agents. A variety of lipid vesicles with high flexibility and deformability could be obtained by adjusting their composition; namely ethosomes, transfersomes and penetration enhancer lipid vesicles which achieve the best results in term of skin permeation. Others are designed with the objective to perform higher encapsulation rate and higher stability, such as solid lipid nanoparticles and nanostructured lipid nanocarriers.In this review, we attempted to give an overview of lipid based nanocarriers developed with the aim to enhance dermal and transdermal drug delivery. A special focus is put on the nanocarrier composition, behavior and interaction mechanisms with the skin. Recent applications of lipid-based nanocarriers for the management of skin diseases and other illnesses are highlighted as well.     

Poly(ethylene-co-methyl acrylate) membranes as rate-controlling barriers for drug delivery systems: characterization, mechanical properties and permeability

Poly(ethylene-co-methyl acrylate) (EMA) membranes with different amounts of methyl acrylate (MA) content were studied in terms of the thermal and mechanical properties, swelling and drug permeation. The increase in MA content in the copolymer significantly increased the percentage of elongation and decreased the tensile strength and modulus of elasticity of the membranes. The degree of swelling of the EMA membranes increased with the ethanol composition and MA content. The contact angle of a sessile drop (10 μL of ethanol/water solution) decreased with an increase in the ethanol fraction suggesting that the membrane wettibility increased with the ethanol content. The flux of diltiazem hydrochloride increased from 0.012 to 0.018 mg cm⁻² h⁻¹ with an increase in the MA content from 16.5 to 29.0%. By increasing the ethanol fraction from 0.4 to 1.0, the flux of diltiazem hydrochloride into the membranes with 29.0% MA, increased from 2.56 (±0.09)×10⁻³ to 18.38 (±0.62)×10⁻³ mg cm⁻² h⁻¹. The permeability coefficient increased from 5.85×10⁻⁶ to 3.53×10⁻⁴ cm h⁻¹ with an increase in the ethanol fraction. The flux can also be correlated with the drug solubility in the membrane and ethanol. For example, the solubilities of diltiazem hydrochloride, paracetamol and ibuprofen were 0.64, 6.68 and 504.48 mg cm⁻³ in the membrane, respectively. Under the same conditions, the flux for the above mentioned drugs was 0.08 (±0.01), 0.53 (±0.01) and 45.11 (±2.00) mg cm⁻² h⁻¹.     

Phytantriol and glyceryl monooleate cubic liquid crystalline phases as sustained‐release oral drug delivery systems for poorly water‐soluble drugs II. In‐vivo evaluation

Objectives Lipid‐based liquid crystals formed from phytantriol (PHY) and glyceryl monooleate (GMO) retain their cubic‐phase structure on dilution in physiologically relevant simulated gastrointestinal media, suggesting their potential application as sustained‐release drug‐delivery systems for poorly water‐soluble drugs. In this study the potential of PHY and GMO to serve as sustained‐release lipid vehicles for a model poorly‐water‐soluble drug, cinnarizine, was assessed and compared to that of an aqueous suspension formulation. Methods Small‐angle X‐ray scattering was used to confirm the nanostructure of the liquid‐crystalline matrix in the presence of the selected model drug, cinnarizine. Oral bioavailability studies were conducted in rats, and disposition of lipid and drug in segments of the gastrointestinal tract was determined over time. Differences in the digestibility and stability of formulations under digestion conditions were investigated using an in‐vitro lipolysis model. Key findings The oral bioavailability of cinnarizine using the PHY formulation was 41%, compared to 19% for the GMO formulation and 6% for an aqueous suspension. The PHY formulation provided a T_max for cinnarizine of 33 h, with absorption apparent up to 55 h after administration. In contrast, the T_max for the GMO formulation was only 5 h. The PHY formulation was retained in the stomach for extended periods of time, with 56% of lipid remaining in the stomach after 24 h, in contrast to less than 1% of the GMO formulation after 8 h, suggesting that gastric retention was a key aspect of the prolonged period of absorption, which correlated with the formulations' relative susceptibility to in‐vitro lipolysis and degradation. Conclusions PHY provides a dramatic sustained‐release effect for cinnarizine on oral administration, which is linked to gastric retention of the formulation and its ability to resist digestive processing. Poorly digested liquid crystal lipid formulations therefore offer a novel class of sustained‐release matrices for oral administration.