A client is interested in developing a generic oral dosage form for a fixed dose combination of two antihypertensive agents: ACEI (20mg) + thiazide diuretic (25mg) in adults. Another liquid formulation of the same drugs is also needed for patients with a swallowing difficulty. Suggest a suitable dosage form, a full formulation design and packaging for each product. You should include a rationale for the nature and quantity for each ingredient in the suggested formulations. The answer should be based on your knowledge of formulation sciences as well as the recommendations of regulatory bodies.
An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London
Introduction
Hypertension is a significant global public health concern. It was the cause of an estimated 7.6 million deaths and 92 million disability-adjusted life years (DALYs) in 2001 alone. It has been understood as a significant issue in the developed world and is becoming increasingly problematic in the African sub-continent and Asia-Pacific regions of the developing world (Addo, Smeeth and Leon, 2007).
Research on ACE Enzyme Inhibitors (ACEI) use for treating hypertension, found a moderate effect on lowering blood pressure while finding no difference in efficacy between the different ACEI tested (Heran et al., 2008). ACEI are thought to work by inhibiting angiotensin I and therefore decreasing circulating levels of angiotensin II and the vaso-constrictor aldosterone (Duchin et al., 1988).
Thiazide diuretics are recommended as the first-line agents in the treatment of hypertension under Canadian, American and The Eight Joint National Committee guidelines (Roush and Sica, 2016). Furthermore, a Cochrane systematic review shows that thiazides achieve a greater blood pressure reduction than ACEI alone (Musini et al., 2014). They are thought to act by inhibiting the renal reabsorption of sodium alongside the increases in sodium and chloride urinary excretion. It increases the volume of urine produced which in turn, lowers blood pressure (Shah, Khatri and Freis, 1978). For the purpose of this assignment, I will be using the Thiazine Diuretic, hydrochlorothiazide (HCTZ) and the generic ACEI captopril.
All excipients and ingredients listed have been checked against the British Pharmacopia’s product monographs and the British National Formulary to ensure acceptability and compliance with UK regulations.
Solid Formulation Design
The solid formulation design will comprise of tablets, produced by direct compression as this is relatively easy inexpensive method and has advantage of better weight uniformity, faster dissolution and drug release when compared to other methods I.e. wet granulation (Reza, Mohiuddin & Mohiuddin, 2002, Meeus 2011). Tablets have been formulated to be 100mg each.
Tablet Coating – Film
The proposed drug form will have a polymer coating consisting of water-soluble cellulose acetate. This has been selected due to its ease of application and fast dissolution (Wheatley, 2007). The role of the film will be simply as a protective layer to the tablet and to taste mask the tablet contents. The polymer will be blended with titanium dioxide to act as an opacifier and white colourant in order to ensure a uniform appearance for all the tablets. Titanium dioxide is very stable in light which is important in the prevention of oxidation of the active drug and excipients (Béchard, Quraishi and Kwong, 1992).
Biphasic delivery system
Captopril is water soluble and stable in strongly acidic pH. As the environment becomes more alkaline, captopril is known to degrade due to instability of the chemical structure (Cheng, Wang and Lin, 2008). As a result of this it can be inferred that captopril will degrade in the intestinal region and the gastric region should be the primary site for captopril action. Controlled delivery systems for captopril have been extensively discussed in the literature. Methods to facilitate tablet floating are a major area of discussion. In this way, the tablet is less affected by gastric emptying and has a longer residence time in the stomach. However, many of these models suggest the use of sodium bicarbonate. This causes the released of carbon dioxide gas which causes the tablet to float. There appears to be some issues with this method, aside from the obvious discomfort that may occur for the patient, as the evolved carbon dioxide may interfere with the diffusion pathway, affecting absorption of the drug (Jiménez-Martínez, Quirino-Barreda and Villafuerte-Robles, 2008).
Studies into a bilayer tablet that incorporates a gastric-floating layer in the treatment of diabetes by He et al., (2014) are of interest. In this study, a layered tablet is produced for one drug product to be released immediately, while a second experiences a sustained release through a buoyancy mechanism. However, again sodium bicarbonate is used to promote floating. An alternative may be to produce a layer that is less dense than the stomach fluids. The Jiménez-Martínez, et al., (2008) study suggests the use of metolose in place of sodium bicarbonate however, these tablets must be compacted with a pressure of 55 MPa in order to achieve buoyancy in the gastric fluid. This low pressure is far from ideal for a solid dosage form that is likely to experience significant turbulence in transport and storage.
It might be possible though careful selection of polymers to achieve the same effect with less complications. It was found that a captopril tablet can be produced by direct-compression and coated with gastric dispersible HCTZ layer. In this case, the polymer ethylcellulose is used as a matrix former while the disintegrant croscaramellose sodium is used in the HCTZ shell resulting in a floating tablet core and a quick disintegrating shell (Babu, Babu and Sirisha, 2014). The added benefit of this model is that a timed release of these two drugs are thought to exhibit a synergistic effect, improving drug efficacy for the patient (He, et al., 2014).
The proposed solid dosage formulation of this drug product is the biphasic release tablet comprising of the HCTZ coat and Captopril core, blended with ethylcelluose in order to give it the desired sustained-release properties.
Excipients
Alongside the active ingredients of 20mg ACEI and 25mg thiazide diuretic, the tablet will require several excipients in order to be made into an appropriate, stable and pharmacologically active dosage form.
Microcrystalline Cellulose (MCC)
MCC has been selected primarily, as a binder and diluent (Osei-Yeboah, et al., 2014). It has important roles in adsorption, anti-adherence, disintegration and is indicated for use as a glidant (Omray & Omray, 1986).
Notable incompatibilities concern the consideration of MCC. It is incompatible with strong oxidising agents (Wu et al., 2009) impurities present in the MCC formulations have been shown to cause oxidation, care must be taken to ensure the MCC is as pure as possible (Wu et al., 2011). MCC has been indicated in a potential interaction with Magnesium Stearate affecting the strength of tablets due to internal film-formation (Zuurman, Van der Voort Maarschalk and Bolhuis, 1999).
Spherically-granulated anhydrous dicalcium phosphate (SGADP) may overcome this issue (Hentzschel, Sakmann and Leopold, 2011), however, the use of dicalcium phosphate is problematic due to granule abrasion and possible interactions of high surface pH reducing drug stability (Schmidt and Herzog, 1993).
The MCC form proposed is therefore the spherical-shaped grade. This allows dry layering (Luhn et al., 2012) and may minimise the impact of magnesium stearate interactions due to it similar morphology to SGADP.
Anhydrous Magnesium Stearate (AMS)
Magnesium Stearate is used as a lubricant. It reduces die wall friction and may prevent the adhesion to the punch. The proposed usage of the anhydrous form is due to its ability to convert into trihydrate at relative humidity ~50-70% (Bracconi, Andrès and Ndiaye, 2003). This will hopefully prevent water vapour in the air from hydrating the rest of the dosage form, providing a level of ‘environmental protection’ for the tablet.
Physical properties of AMS can differ widely between suppliers and even batches from the same vendor (Barra and Somma, 1996). The quality of AMS must be thoroughly checked prior to its inclusion in formulation.
AMS may negatively impact on tablet dissolution. This is thought to be due to its conversion to stearic acid when in acidic media (Ariyasu, Hattori and Otsuka, 2016)and the observed hydrophobicity (Hussain, York and Timmins, 1992). This issue of hydrophobicity is seen again during the production of the tablets where the research seems to suggest that AMS tends to coat the granules and in this way, impacts on dissolution. This effect was markedly seen in HCTZ which is of clear concern for the proposed drug formulation. The same paper suggests the use of sodium stearyl fumarate as an alternative (Desai et al., 1993). However, the moisture absorption properties and the potential offsetting of the decreased dissolution properties with the use of a swelling disintegrant make this uncompelling.
Lactose Monohydrate (LM)
LM is used as both a binder and diluent for tablet formation, it has a further useful role in lyophilisation, which can aid cohesion in the formula (Zuurman et al., 1994, Baheti, Kumar and Bansal 2016).
As the proposed method of tablet formation is direct-compression, the α-lactose monohydrate form is required. This form allows for tablet production without requiring a granulation stage (MedicinesComplete, nd).
There are important considerations to be made in the sue of lactose. In the case of patients with lactose intolerance, this drug may not be suitable for them. The usual suggestion of taking this excipient with food is not valid and this medication must be taken in the fasted state (Singhvi et al., 1982). Evidence seems to suggest that the amount of lactose present in medication should pose no risk. For example, studies have been carried out which suggest 12g of lactose would be needed to elicit negative effects of dietary intolerance (Di Rienzo, et al 2013). Given tablets are proposed to be 100mg total, the lactose content does not seem to pose any risk.
However, demonstrated incompatibilities with ACEI lisinopril is of concern and warrant further attention. Studies suggest the cause of the incompatibility is in the reducing properties of lactose on the free, primary amino group present on the lisinopril molecule (Eyjolfsson, 1998). While Captopril does not have a free amino group, this potential incompatibility should still be avoided.
LM can be co-processed with MSS and has been shown to exhibit good action when combined in tablets formed by direct compression (Michoel, Rombaut and Verhoye, 2002). This further supports the use of LM in this formulation.
Pregelatinised Starch (PGS)
Starch can be used as disintegrant in solid dosage forms (Mattsson and Nyström, 2001). PGS has the advantage of improved flow and compression traits in addition to its appropriateness in direct-compression production methods (Iskandarani, Shiromani and Clair, 2001). PGS has shown improved dissolution compared to a simple starch disintegrant (Alebiowu and Itiola, 2002). This same paper proposed the use of white trifoliate yam as the starch source as this showed greater dissolution when compared the standard corn-based PGS.
PGS acts as a self-lubricant although the combination of AMS may impact this. The concentration of AMS is important to control (MedicinesComplete, nd). Due to this potential interaction, stearic acid is suggested as an alternative however, stearic acid has many more incompatibilities with common drugs, like NSAIDs (Botha and Lötter, 1990) this reduces its suitability as a drug form excipient. Further, stearic acid may negatively impact tablet film-coating (Rowe and Forse, 1983) which must be minimised in order to keep the dosage form intact and improve shelf-life and durability.
The effect of PG as a disintegrant will be enhanced using other excipients for this function.
Croscarmellose Sodium (CCS)
CCS is another is an important substance to include in the solid dosage form (Yassin et al., 2015). It is considered a superdisintegrant and its fast dissolution is well established (Desai et al., 2014). Its mode of action helps the dissolution of insoluble, hygroscopic products (Ferrero et al., 1997), which is important for this medication.
Whilst its efficacy when utilised in direct-compression tablet formation, especially with hygroscopic excipients, has been elucidated (Johnson et al., 1991), its use alongside other disintegrants should alleviate this issue. The incompatibility with basic materials (Bindra et al., 2013) should not be relevant for the proposed, acidic formulation.
AMS has been shown to hinder the otherwise, very high swelling rate of CSS when in an acid medium (Rojas, Guisao and Ruge, 2012). This is something that must be noted and provides further reasoning for the use of a combination of disintegrants.
Sodium Starch Glycolate (SSG) - Type B
SSG is a well-established excipient that acts as a disintegrant in solid dosage forms (Gebre-Mariam, Winnemiekker and Schmidt, 1996). It is indicated for use in direct-compression tablet formation techniques (Sharma et al., 2015), which supports its inclusion in this drug formulation.
The selection of SSG is of particular use as has been shown to increase dissolution in gastric fluids (Ali, Mukherjee and Bandyopadhyay, 2012), which is important for this dosage form. It has a similar mode of action to CCS in that it exhibits significant swelling in order to bring about the disintegration of the tablet (Rojas, Guisao and Ruge, 2012). Similarly, to CSS it is unaffected by hygroscopic products (Mahapatra, Sameeraja and Murthy, 2014).
Type B SSG is crosslinked with sodium trimetaphosphate which gives it better action at low pH (Bolhuis, Zuurman and te Wierik, 1997).
Sodium Metabisulfite (SM)
Sodium Metabisulfite will be used as an antioxidant. Ascorbic acid cannot be used for this formulation as it is incompatible with SSG (Botha, Lötter and Du Preez, 1987). Propyl Gallate has been shown to be a highly effective antioxidant (Celestino, et al 2012), but has shown cytogenic effects on mouse ovary cells (Tayama & Nakagawa, 2001) and may result in adverse effects of contact dermatitis (Golightly et al., 1988). Despite its approval for use by the Cosmetic Ingredient Review (CIR) (CIR, 2003) there is clearly a preference to use an antioxidant without these potential problematic effects.
Summary of solid formulation
The following table shows a summary of all constituents included in the solid formulation, suggested quantity and role.
Table 1 – Table to summarise excipient use, role and quantity in solid dosage formulation. Suggested quantities have been sourced from (MedicinesComplete, nd) unless otherwise stated.
Table 1 – Table to summarise excipient use, role and quantity in solid dosage formulation.
Package Design
FDA regulations require product labels to display boxed warnings, information on product indications and usage, dosage guidance, contraindications as well as warning and precautions that patients should be aware of (FDA, 2013)
The EU Packaging and Packaging Waste Directive, 94/62 applies to pharmaceutical products. This regulation has the aim to “prevent or reduce [packaging waste’s] impact on the environment”. Care must be taken to ensure that packaging selected is reasonable for its use and not superlative (Data.europa.eu, 2015).
The EMA have provided further guidance and state that excipients with a known effect must be declared on the label. In the case of the proposed formulation, the following excipients must be stated:
Pregelatinised Starch – if containing gluten Lactose Sodium metabisulphite - E223 (EMA, 2017)
The use of blister pack has been shown to improve patient adherence due to its ease of use (Braun-Münker and Ecker, 2016). While Polyvinyl chloride is often used due to its easy and cheap production however, disposal issues mean this will be unsuitable for the solid dosage form (Korab 1999).
Aluminium foil blister packaging was found to be the most effective as reducing moisture and oxygen ingress (Allinson, Dansereau and Sakr, 2001). The suggested package design is therefore an aluminium on aluminium blister pack. This should have a silica gel packet included in the box to further protect from humidity. The Patient Information Leaflet and SmPC should be included, and drug label should be present on the blister pack and external box packaging.
Liquid Formulation Design
Alternative considerations must be made with regards to the liquid formulation. Stability and interaction between drugs are likely to be issues that are more present in this medium as a result of the kinetics of particles in the liquid phase. Further, the introduction of microbial agents is more likely and must be accounted for. Additionally, appearance and taste must be considered much more greatly than in the solid dosage form as well as ensuring uniform dosing for patients.
On the other hand, ingredients such as glidants, adherents, lubricants and polymer films are not required.
Colourants have not been identified as the liquid formulation developed is for use in adults. Potential interactions with products are of the utmost concern and as colourants are not necessary; they will not be discussed.
The literature on liquid dosage forms of captopril and HCTZ are limited and often contradictory however, a liquid formulation can be recommended as follows.
Purified Water (USP)
Xantham-gum appears to be the most common base of oral suspension used however, there are significant stability issues observed, whereby the product degrades after only 7 days which is clearly insufficient for a marketed product (Pabari et al., 2012). Although a study by Sathapanapitagkit et al (2015) suggests the use of syrup, additional studies have shown aqueous formulations to be more stable (Pramar, Gupta and Bethea, 1992) and health impacts of high-sugar solutions should be considered.
Long-term stability of an aqueous product has been identified. In this case, the product remained viable up to 1 year (Nahata, Morosco and Hipple, 1994).
A further study by Escribano, Torrado and Torrado (2005) found purified water the preferable aqueous vehicle as it displayed greater stability than other forms of water (tap or mineral) This is not surprising given distilled water will contain fewer dissolved substances. Water has the obvious advantage of being non-toxic as well as plentiful and cheap.
HCTZ has been shown to be sparingly soluble in water and has a high stability in aqueous media. There should be no interactions between the two active drugs because HCTZ is likely to be held in a stable suspension (Baka, Comer & Takács-Novák, 2008).
Poly(ethylene glycol) 200 (PEG200)
Glycerol would be a suitable co-solvent due to it miscibility in water and sweet taste, however it has been implicated in the degradation of captopril in aqueous formulation (Kristensen et al., 2008). As a result the suggested co-solvent is Poly(ethylene glycol) 200 (PEG200), due to its low molecular weight. Although liquid PEG200 may have a bitter taste (Panahi-Azar et al., 2015) this should be easily masked using saccharin.
A co-solvent is required due to the poor solubility of hydrochlorothiazide in water (Yalkowsky, 2019). To this end 20% PEG200 will be used as this should ensure complete dissolution of the diuretic in the liquid formulation.
Edetate Calcium Disodium (ECD)
The Kristensen et al (2008) study, the addition of Edetate Calcium Disodium (ECD) had a dramatic effect on product stability and this is therefore included in the suggested liquid formulation. Even allowing for the successful storage of a captopril solution for up to 1 year at 36°C. This exceeds the requirement laid out by WHO (2001) of 30°C (+/- 2°C).
Sodium Ascorbate
Sodium Ascorbate is an important antioxidant has been shown to significantly stabilise aqueous solutions of captopril for up to 56 days when refrigerated (Haywood and Glass, 2013). The combination of this with ECD should provide suitable stability for this liquid formulation. This is supported by findings from Nahata, Morosco and Hipple (1994).
Citric Acid
Studies have shown a captopril aqueous solution to be most stable at low pH (Sathapanapitagkit et al, 2015, Liu, Chan and Ho, 1999). Additionally, HCTZ has been demonstrated to remain un-ionised at acidic pH ranges.
Citric Acid has been selected as a pH buffer for the formulation. It has an ideal pH to keep the liquid in acidic conditions. Citric Acid can be utilised as a flavouring agent as well as, increasing stability of the active drugs and its action as a preservative (Pubchem.ncbi.nlm.nih.gov, 2019).
Saccharin Sodium
The negative impact of sugars in hastening the degradation of captopril is clear (Liu, Chan and Ho, 1999, Kristensen et al 2008). Care must be taken not to include products of this nature in the liquid formulation. The flavour profile of the liquid formulation is likely to be unpleasant as so, flavourants must be added to make the final product palatable.
Gee, S. C., & Hagemann (2007) ostensibly studied the flavour acceptance in paediatric products however, participants in the study were all adults. They found a slight taste preference to sucrose compared to other sweeteners however, this was only slight. This study shows sorbitol as being next preferred sweetener over sucrose however, sorbitol has quite a high laxative effect and may cause gastrointestinal discomfort in some users.
For these reasons, the alternative sweetener of saccharin will be selected. It should have no impact on blood sugar levels and is calorie free therefore it is a useful product to include.
Sodium Chloride
The literature shows that in adults, sodium can mask the flavour profile of bitter tastes (Mennella and Bobowski, 2015). Sodium chloride should be included in the liquid formulation for this function. Thiazide diuretics can increase sodium levels in the blood, as a result of their mechanism of action, so care should be taken to ensure sodium added is at the absolute minimum level required.
Palatability is a very important consideration for adherence to recommended dosing programmes and this importance demonstrates to role of sodium in the product formulation.
Strawberry Flavouring
Gee & Hagemann (2007) compared a range of common pharmaceutical products for taste and tanked them. Out of the top 3 preferred products all contained strawberry as their primary flavourant. There is a suggestion that the strawberry flavouring may consist of more powerful odorants which might explain this effect (Zhu et al., 2004).
Hydroxyethylcellulose (HEC)
HEC will be used to enhance the viscosity of the formulation. This is important as the aqueous formulation will be difficult to dose appropriately if it is not sufficiently viscous. It is non-ionic and water-soluble as so should blend well with the aqueous medium (Pubchem.ncbi.nlm.nih.gov, 2019).
Hydroxybenzoic Acid (HBA)
Preservatives like alkyl esters of HBA can be formulated to provide a blend of both methyl and propyl HBA forms. This improves antimicrobial action, giving it a broader spectrum of efficacy and therefore has an important role in ensure the liquid formulation are free from microbes (Cho et al., 1998). Greatest effect is seen at acidic pH which is suitable for this formulation (MedicinesComplete, nd).
Summary of liquid formulation
The following table shows a summary of all constituents included in the liquid formulation, suggested quantity and role. A bottle size of 22ml is selected to provide some leeway for occasional wastage or incorrect dosing and allows for 13.33 ‘full dosages’. Assumed to result in 10 ‘real’ doses.
Table 2 – Table to summarise excipient use, role and quantity in liquid formulation. Suggested quantities have been sourced from (MedicinesComplete, nd) unless otherwise stated.
Packaging Design
EU Packaging and Packaging Waste Directive, 94/62 guidelines still apply to liquid formulation and these must equally be considered (Data.europa.eu, 2019).
FDA regulations require product labels to display boxed warnings, information on product indications and usage, dosage guidance, contraindications as well as warning and precautions that patients should be aware of (FDA, 2013)
The EMA have provided further guidance and state that excipients with a known effect must be declare don the label. In the case of the prosed formulation the following excipients must be stated:
Poly(ethlylene) Glycol – as Propylene glycol (E1520) and esters of propylene glycol Hydrobenzoic Acid – as Benzoic acid (E 210) and benzoates (EMA, 2017).
Glass is highly unreactive and impermeable and is an ideal material for liquid formulations. Type II soda-lime-silica glass is ideal for acidic aqueous preparations and therefore, should be used. If amber coloured glass is used, it will reduce possible photo-instability issues. Further, the glass bottles should be produced form “tubular glass cane” as this will give them stability in temperature changes (Campbell and Vallejo, 2015), that are likely to occur when these bottles are refrigerated.
In studies on cough syrup, it was found that plastic was just as effective as glass however, the flavouring tended to degrade at higher temperatures (Singh and Gupta, 2007). While this is not an overt concern for this formulation, this potential issue coupled with the societal shift away from plastic use and concerns over release of microplastics further justifies the selection of amber glass as the container material.
Product labels should be placed directly on the bottle and outer packaging and patient information leaflet should be inserted and packaged alongside the bottle.
A graduated metering spoon should be included to assist in appropriate and uniform dosing. A suggestion of 15ml liquid dosage to provide 20mg and 25mg of ACEI and Thiazide Diuretic respectively, from a 200ml bottle is previously made.
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An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London