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Formulation and analysis of topical propranolol gel
Research Proposal
Summary
The use of oral propranolol for severe infantile haemangiomas has been used off licence for several years. But this is not without its problems, therefore topical treatments have been trialled. Topical propranolol has shown effective but again this is an unlicensed treatment, with no standardized formulation method. Consequently, there is a need for a standardised formulation method. Different methods of formulating a topical propranolol will be used, including the cold method, direct swelling method or forming a microemulsion based hydrogel. The gel produced will need to be tested and analysed by HPLC and the analytical method used will need to be validated. The validation will be in accordance with the International Conference on Harmonisation’s validation of analytical procedures: text and methodology Q2(R1).
Background
Infantile haemangiomas (IH) are benign vascular tumours that appear between four to six weeks of an infant’s life. They are the most common form of soft tissue tumour present in children, with an incidence between 4-10% of the population (Price et al., 2018). Most will not require treatment and will eventually disappear as the child grows, some are complicated and can be disfiguring or life threatening (Tang et al., 2015). There is currently no UK guidance on the treatment of IH, most hospital trusts will have their own guidelines on what treatment is to be used and the need to treat is assessed using the haemangioma severity scale (HSS). This measures the risk of an IH without treatment. It includes: the size of the tumour; the location; whether there is any risk of structural abnormalities; complications (including infection, ulceration and airway involvement); pain and risk of disfigurement (Mull et al., 2017). HSS is commonly used to decide if a patient is to be started on oral propranolol treatment and at what dose this is to be given. There has been a small number of positive studies on the use of oral propranolol, with all studies reviewed showing an improvement (Starkey and Shahidullah, 2011). Starkey and Shahidullah go on to state that more evidence is needed to make a fully informed decision about use of oral propranolol. They also mention possible adverse effects linked to oral propranolol including: hypoglycaemia, GI upset, drowsiness and sleep disturbance.
Topical applications of beta blockers have also proved effective, with the National Institute for Health and Care Excellence (NICE) producing an evidence summary on the use of topical timolol. This advises that timolol eye drops can be used as a topical treatment, but it is unlicensed (NICE, 2015). Evidence of positive outcomes using a novel timolol gel have also been published (Zheng and Li, 2018). There is no form of topical propranolol in production but there are studies using locally prepared topical treatments published. These reports show that it is an effective and safe treatment for small haemangiomas if the benefits of oral propranolol are outweighed by the risks of treatment (Price et al., 2018). This systematic review also stated that in the studies selected and reviewed, there were no systemic side effects due to the low plasma concentrations. It also suggests that oral propranolol is a quicker and more effective treatment for complicated, high risk IH. Therefore, it is recommended that topical treatment is given to patients whose tumours are small and superficial and where oral treatment is not recommended (Price et al., 2018).
But, using this data isn’t without its problems. For each trial of topical propranolol, a different formulation is used, therefore the evidence is inconsistent. The formulations in the studies varied heavily from a tablet crushed in petroleum jelly to actual gel, cream or ointment formulations (Padula et al., 2018). There are no commercial or industrial medicinal products available to standardize these trials. Therefore, there is a large requirement for the formulation of a standardized method of formulation to ensure that data produced by these trials is correct.
When formulating a topical application for IHs retention in the skin is probably just as important as permeability (Padula et al., 2018). The epidermis will act as a reservoir and the drug will still be present and functioning even after removal of the topical application (Casiraghi et al., 2016). Using the results from the Padula study the most effective semi solid preparation is a lipophilic cream prepared with olive oil. They also suggest problems with a gel formulation, including the risk of systemic side effects for significant absorption. They also have limited skin retention, which as previously mentioned is important in the treatment of IHs. This also reinforces the idea that all studies previously carried out testing topical treatments are not fully valid due to different formulations used.
Another challenge faced is the lack of a validated analysis procedure. According to the British Pharmacopeia (BP) “Validation is performed in order to show that the result(s) generated by a particular analytical procedure are reliable and accurate” (British Pharmacopeia, 2018). This provides another reason why the previously mentioned studies regarding propranolol gels are not fully trustworthy. Therefore, alongside formulating a topical preparation a validated analysis procedure is required. In order to validate an analytical procedure, certain characteristics need to be considered. These are accuracy, precision (both repeatability and intermediate precision), specificity, detection limit, quantitation limit, linearity and range (International Conference on Harmonisation, 2005). Accuracy shows the closeness between a reference value and the value attained. This may be shown by testing a known quantity of a compound and then calculating the measured against actual amounts. The repeatability of an analytical procedure can be determined by preparing a 100% concentration of the active compound. This will then be diluted and six separate, but identical determinations of the solution will be analysed. This shows the precision of a procedure using the same conditions over a short period of time. The intermediate precision shows the variations within an individual lab, for example, different days, operators or machines. This is tested by the same dilution analysed as per the analytical procedure on different days with different analysts. Specificity is done to assess the identity of the analyte whilst in the presence of impurities (including solvents and excipients). This is done by carrying out purity tests with stressed solutions alongside a test with all the ingredients of the preparation without an active ingredient. Then the active ingredient (propranolol) can be identified amongst the impurities. The detection limit is the smallest amount of active ingredient that can be identified by the analytical procedure, but not shown as having an exact value. This is done by creating a calibration curve. Can also be demonstrated by analysing low concentrations of active ingredient and showing that a response is obtained. The quantitation limit is the lowest amount of active ingredient that can be shown as having an exact value. This is also demonstrated with a calibration curve. Linearity is the capacity an analytical procedure has to obtain results that are directly proportional to the amount of active ingredient in the sample. This is also achieved by creating a calibration curve. The range is the interval between the lowest and highest amounts of active ingredient, where there is a suitable level of precision, accuracy and linearity.

Method
This project will comprise of two parts. The formulation of the topical gel and the validation of an analytical procedure. The formulation of the gel could be done in many ways. Possibly the simplest method is the cold method. A poloxamer gel is formed by adding poloxamer 407 to a cooled water solution of propranolol hydrochloride under stirring. Then left in a refrigerator overnight (Padula et al., 2018). Another method that could be used is the direct swelling method. This allows for permeation enhancers to be added. HPMC is dispersed in glycerine and water is added with continuous stirring. This is then left for 24 hours to swell. Propranolol hydrochloride is then dissolved in water and ethylparaben is dissolved in a few drops of ethanol and mixed with tween 60. At this stage a terpene permeation enhancer can also be added. All the solutions are mixed together and made up to a total volume with water (Zhou et al., 2014). The final process that could be used is a microemulsion based hydrogel. Propranolol hydrochloride is dissolved under stirring to propylene glycol monocaprylate, polyoxyl castor oil (PEG 40) and propylene glycol. Water is then added drop by drop with continuous stirring. An acrylate cross polymer (Carbopol EDT 2020 was used by Olariu et al) is dispersed slowly into the microemulsion under stirring to form a gel (Olariu et al., 2014). These methods are using processes outlined by different research articles, therefore the materials used may vary to the ones available for this project. But the basic principles are the same.
The gel formulated will then need to be tested. There are multiple parameters that could be used in order to test the formulation prepared. The first test will be an observational assessment of the formulation produced. Assessing the colour, appearance and viscosity. The total concentration of drug in the formulation will also need to be tested. This will be done using a HPLC analysis. A drug permeation analysis could also be completed using Franz diffusion cells.
The drug concentration analysis technique using HPLC will need to be validated. This will be done using the International Conference on Harmonization (ICH) validation of analytical procedures: text and methodology Q2(R1). The first step will be to establish a calibration curve of propranolol hydrochloride ranging from 20%-120% of active compound. This is done using dilutions of the active ingredient. An internal standard will also be added. This will show the linearity of the analytical procedure. Stressed samples can also be run, including a blank sample of excipients but no active ingredient. Other samples include acid and alkaline or samples degraded by oxidation, light or heat. This is testing the specificity of the procedure. Next, the range will be analysed. Concentrations of API are spiked into the formulation and analysed, this will be performed in triplicate. When testing the precision six replicate dilutions will be analysed in succession for the repeatability. For the intermediate precision, dilutions of the finished product will be prepared on separate days and analysed on different machines. A calibration curve made with much smaller quantities than those used for the linearity will need to be established. The slope and standard deviation of this calibration curve can be used to identify the quantification limit and the detection limit. The robustness of the sample is assessed by changing certain parameters (mobile phase composition, temperature, flow rate and column) and recording the results. Finally, the system suitability will need to be assessed by using a previously recorded chromatogram. This will be used to define certain parameters including retention time, theoretical plates and resolution. This will be done with two peaks, the active compound (propranolol hydrochloride) and an impurity.
Aim:
To formulate a topical gel preparation of propranolol and to produce a validated analytical procedure for this product.
Objectives:
• Research a suitable formulation for topical propranolol and formulate a method
• Produce a suitable gel formulation of topical propranolol
• Create an analytical procedure using HPLC
• Validate this analytical procedure

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