Difference between placebo and excipients for parenteral formulations
In this regard, it has been shown that SC injection of smaller volumes of rhGH preparations is less painful and improves patient convenience 89 — In a study by Chantelau et al. Another study evaluated the severity of pain inflicted by SC injection of different volumes of 0. The results showed that an injection volume in the range of 0. One approach to reducing the injection volume is to increase hGH concentration. However, as mentioned previously, highly concentrated hGH formulations have higher viscosity and thus a higher risk of aggregate or insoluble particulate formation, compromising product stability and safety.
Hansen and colleagues studied the effect of hGH concentration and injection volume on ISP and concluded that hGH concentration was directly associated with pain perception following SC injection. The injection volume is determined based on product concentration and dosing regimen. Hence the average dose for adults with GHD is estimated to be 0. It should be noted that the initial dose for GHD patients is gradually increased by 0.
In this case, higher injection volumes might be needed. Dosing frequency and antimicrobial preservatives Low stability and relatively short plasma half-life of rhGH demand frequent injections In addition, it has been shown that daily hGH injection has a superior growth-promoting effect compared to administering the same dose over injections per week 54 , However, it can be expected that patient non-adherence will increase with dosage frequency due to repeated ISP.
McNamara et al. Parenteral rhGH products are available as single- or multi-dose preparations. The single-dose formulations are used for a single injection in a single patient. Due to the disposable nature of these preparations, they usually do not contain antimicrobial preservatives. On the other hand, multi-dose vials or cartridges can be used more than once and require additional preservatives to prevent microbial contamination after the first use.
Antimicrobial preservatives have been associated with ISP in parenteral biopharmaceuticals, including rhGH products. Phenol, m-Cresol, and benzyl alcohol are the most commonly used preservatives in multi-dose rhGH products. According to research conducted on patients with GHD who received SC rhGH injections for one year, m-Cresol was associated with higher local pain compared to 0.
In another study, Bridges and colleagues performed a double-blinded, randomized, cross-over trial on 31 children to compare pain sensation following SC injection of rhGH formulations reconstituted with benzyl alcohol 0. Based on their results, the m-Cresol injection was more painful compared to benzyl alcohol, while no significant difference was observed between injection of 0.
Subcutaneous injection of phenol 4. Similar reactions were previously reported for the m-Cresol component of commercial insulin as well Another study by Svendsen and Carstensen showed local toxic effects of high concentrations of benzyl alcohol, m-Cresol, and phenol upon 1 mL IM injection in rabbits.
Based on these data, it can be concluded that m-cresol injection induces more pain and local toxicity compared to phenol and benzyl alcohol. Another strategy for reducing the ISP is to add a local anesthetic agent to the parenteral formulation The local anesthetic effect of benzyl alcohol upon SC injection has been shown previously , According to their results, SC injection of benzyl alcohol-containing multi-dose formulation was less painful compared to the benzyl alcohol-free single-dose form In a series of three randomized, double-blinded, cross-over trials on the ISP for different QS adjuvant formulations, it was observed that the addition of benzyl alcohol 0.
It can be expected that the anesthetic effect of benzyl alcohol may be, in part, responsible for the observed lower ISP. Injection of hypertonic preparations has been associated with increased local pain and discomfort , Buffers are commonly used for maintaining the pH in biopharmaceutical formulations. Buffer type, strength, and concentration affect the local pain following SC injection. Table 2 presents commonly used buffering agents in parenteral rhGH products. As shown previously, subcutaneous injection of citrate buffer is more painful than normal saline and phosphate buffer — It has been established previously that infusion of acidic formulations is painful.
The difference between the pH of the formulation and the injection-site tissue is responsible for pain sensation. The increased number of H ions upon SC injection of a formulation with an acidic pH compared to the physiological pH of the injection-site tissue activates nociceptors, which are responsible for pain sensation upon SC injection of preparations with non-physiological pH Yang and Lai have recently provided mechanistic insight regarding the contribution of acids and citrate in ISP They showed how acids stimulate and citrate potentiates acid-sensing ion channel 1 ASIC1.
These findings can explain painful injections of slightly acidic formulations containing low citrate concentrations. They suggested that the addition of ASIC1 inhibitors to citrate-containing preparations can decrease ISP without the need to eliminate citrate.
The manufacturers might prefer to produce parenteral protein formulations in non-physiological pH due to stability issues. In this case, using buffers with lower strength is recommended to decrease the ISP. In a study by Fransson et al.
Among these, 10 mM phosphate buffer and pH 7. They showed that increasing buffer concentration at non-physiological pH 50 mM phosphate and pH 6. To minimize the ISP, it has been suggested that the maximum concentration of citrate and phosphate buffers in parenteral preparations should be limited to 7. As mentioned previously, the addition of strong buffers such as citrate to the formulation will increase pain due to radical pH changes within the SC tissue following injection Accordingly, it has been observed that low-strength buffers such as histidine are less painful compared to phosphate and citrate in the SC injection of rhGH formulations Laursen and colleagues studied the dispensing solutions from two commercially available parenteral rhGH products regarding ISP following SC injection In this study, 54 healthy volunteers were injected with 0.
They observed that the citrate-buffered formulation induced higher ISP, while the histidine-buffered formulation did not imply more pain compared to normal saline. Meanwhile, Shi and colleagues reported that ISP following SC injection of citrate- and histidine-buffered formulations were not significantly different It should be noted that, unlike Laursen et al.
In addition, citrate concentration has been directly associated with the severity of injection pain. Shi and colleagues showed that SC injection of 20 mM citrate solution was more painful compared to 5 and 10 mM solutions They also reported that the injection of histidine buffer with a slightly acidic pH 6.
As presented in Table 3 the pH of commercial parenteral rhGH products ranges from 5. The liquid rhGH dosage forms are formulated at slightly acidic conditions compared to the freeze-dried forms. Based on a study by Ward et al. However, the reported discomfort was described as slight to moderate despite the significant pH difference between the albumin preparation and SC tissue They suggested that the low concentration of glycine buffer 20 mM was responsible for minimizing the ISP despite the significant pH difference between the SC tissue and the parenteral albumin As mentioned previously, using weak buffers is recommended in formulations with non-physiological pH.
They suggested that the low glycine concentration minimized the ISP by allowing the rapid pH change of albumin preparation towards the physiological pH of the SC tissue upon injection Perhaps the most comprehensive study regarding the effects of different buffering agents and excipients on ISP has been recently conducted by Shi and colleagues They studied various buffered formulations with different concentrations and pH in combination with commonly used tonicity adjusting excipients.
Their results confirmed the substantial effect of buffer on ISP. In line with previous studies, they also found citrate and histidine to increase ISP. Higher buffering capacity and concentrations were also associated with increased ISP. These sustained protons can induce pain via activating ASICs and transient receptor potential ion channels, which is in line with the results reported by Yang et al.
Since buffer strength and concentration are actively involved in pain sensation following SC injection of parenteral drugs, the development of buffer-free formulations can minimize ISP. In this regard, citrate-free Adalimumab formulation has been reported to be less painful compared to the conventional citrate-buffered preparation Shi and colleagues also supported this by showing that citrate- and phosphate-free formulations were substantially less painful A study by Gharia and Sudhakar showed that SC injection of a succinate-buffered Adalimumab biosimilar was considerably less painful compared to the citrate-buffered form Surfactants Non-ionic surfactants are widely used in parenteral biopharmaceutical products to avoid protein aggregation.
Tween 20 polysorbate 20 or PS20 and poloxamer P or pluronic F68 are commonly used non-ionic surfactants in parenteral hGH products. Despite their protective role, both PS20 and P are susceptible to auto-oxidation producing reactive species that can induce protein degradation or injection-site reactions ISR , including injection-site pain. They suggested that using high-quality raw materials and optimizing shipping and storage conditions can minimize PSs-induced ISR Jewell et al.
They also observed that the injection of Pcontaining micro-emulsified formulation was more painful It has been suggested that sugar-based surfactants such as alkylglucosides can be used as alternatives to polysorbates Other excipients Non-isotonic formulations can increase ISP via activating stretch receptors According to Shi and colleagues, the contribution of NaCl in the ISP is more pronounced compared to sugars and polyols including sucrose, trehalose, and mannitol.
Sorbitol and mannitol are two isomeric sugar alcohols used in rhGH products, providing stability and tonicity adjustment. As mentioned previously, incorporating excipients with local anesthetic effects has been associated with reduced ISP. In addition to the local anesthetic effect of mannitol in combination with lidocaine which has been shown previously , , antinociceptive properties of SC mannitol injection in synergism with diphenhydramine have also been reported recently The rationale behind this phenomenon relies on the activating effect of a lower formulation temperature on the nociceptors following SC injection — Allowing the parenteral product to reach room temperature before injection can reduce the ISP , Discussion Despite recent advances in the field of formulation development, limited or conflicting data are available in the literature on the effect of formulation components on ISP.
In addition, the mechanisms by which each of the formulation components may contribute to injection pain remains elusive. Another issue arises from the fact that a large number of reports regarding injection pain are conducted on animals which makes it difficult to translate these findings to human subjects. Another problem with the existing studies that may in part explain their inconsistent results is using different approaches for quantifying and assessment of pain in tested subjects.
The lack of comprehensive studies regarding the impact of different formulation variables on ISP may be due to the high cost associated with conducting various clinical trials for pharmaceutical companies and the difficulty in studying the complicated interdependent interactions of these formulation parameters on ISP and identifying the exact mechanism by which they affect injection pain. Our investigation suggests that complex interactions between the formulation variables should be considered in addition to the individual contribution of each variable in ISP.
Formulation components in injectable preparations should be selected cautiously. In addition, using high-quality excipients with no residual contamination can inhibit protein and excipients degradation as well as subsequent ISR including injection pain. Using molecular dynamics simulation before formulation design has been suggested in a recent study for easier assessment of the interactions between different formulation components These are used in combination with lubricants as they have no ability to reduce wall friction.
Examples include silica gel , fumed silica , talc , and magnesium carbonate. However, some silica gel glidants such as Syloid R FP and Syloid R XDP are multi-functional and offer several other performance benefits in addition to reducing interparticle friction including moisture resistance, taste, marketing, etc. Lubricants[ edit ] Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine.
Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Lubricants are agents added in small quantities to tablet and capsule formulations to improve certain processing characteristics. While lubricants are often added to improve manufacturability of the drug products, it may also negatively impact the product quality. For example, extended mixing of lubricants during blending may results in delayed dissolution and softer tablets, which is often referred to as "over-lubrication".
Therefore, optimizing lubrication time is critical during pharmaceutical development. Anti-adherent role: Prevent sticking to punch faces or in the case of encapsulation, lubricants.
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Contrary to the past, safety of excipients needs to be well established in order for their use in the pharmaceutical formulations. Therefore, careful consideration should be given while selecting an excipient. This review article provides an overview of the excipients used exclusively in small molecule and biological parenteral products including solutions, suspensions, and lyophilized formulations, information on the possible drug-excipient and drug-packaging interactions and the regulatory requirements for the use of pharmaceutical excipients.
The readers will be able to have a comprehensive understanding of the excipients used in parenteral formulations. Keywords: Parenterals; drug-excipient interactions; excipients; lyophilized pharmaceuticals; regulatory consideration of excipients. Ethanol is miscible with water, glycerine, propylene glycol, and polyethylene glycol It is used as a primary solvent for many organic compounds. Water—alcohol mixtures can be very effective in solubilizing poorly soluble drugs.
Glycerin, USP Glycerol as a solvent This is a clear, colourless, odourless, viscous, hygroscopic liquid with sweet taste, approximately 0. It is a triol alcohol without the central nervous system depressant activity of ethanol. Glycerin is miscible with water, alcohol, propylene glycol, and polyethylene glycol As a solvent, the solubilizing properties of glycerin are comparable to alcohol but because of its viscosity, solutes are slowly soluble in it unless it is rendered less viscous by heating.
Also, the increased viscosity imparted to the final product may be an undesired outcome of the use of this solvent. Glycerol is used in both internal and external preparations. It serves as an excellent solvent for a range of substances such as alkalis, neutral salts, tannins etc. Propylene Glycol as a solvent Propylene glycol USP is a clear, colourless, viscous, practically odourless liquid, with a sweet, slightly acrid taste resembling that of glycerin.
It is a diol and like glycerin, it has no central nervous system activity. Propylene glycol has become widely used as a solvent, extractant and preservative in a variety of pharmaceutical formulations. It is used more often in modern formulations, possibly replacing glycerin as it dissolves a wide variety of materials, such as corticosteroids, phenols, sulpha drugs, barbiturates, vitamins A and D , most alkaloids, and many local anaesthetics.
Polyethylene Glycol as a solvent Polyethylene glycol PEG is a low-molecular-weight grade of polyethylene glycol. It is a clear, colourless, viscous liquid. PEG is a liquid at room temperature, and it is the most common polyethylene glycol used in drug product formulations. Like glycerin and propylene glycol, PEG is miscible with water and alcohol. Co-solvents Co-solvents are primarily liquid components often used to increase the water solubility of drugs which do not contain ionisable group s and whose solubility can thus not be increased by pH adjustment.
They work by reducing the interfacial tension between predominantly aqueous solutions and hydrophobic solutes. The selection of a co-solvent depends on a number of factors, including the solubility and stability of drug substance in the vehicle and toxicity of the vehicle.
Difference between placebo and excipients for parenteral formulations buffett rules of investing
Panel on Excipient and Formulation Considerations
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