Category: TECHNICAL NOTE

Medicated Chewing Gum Excipient

Chewing gum is popular among consumers, being enjoyed by people of all ages. The first successful formulation of medicated chewing gum products was in the early 1970s when Nicorette was launched by Pfizer for use in smoking cessation.

Since then, directly compressible chewing gum has quickly gained momentum as a readily adaptable platform for delivery pharmaceutical and nutracetical actives. it is currently recognized as a dosage form and defined in pharmacopoeias, including the European Pharmacopoeia.

Aside from their reported health benefits, such as helping boost blood flow to the brain and strengthening tooth enamel, chewing gums offer the following advantages to the pharmaceutical product formulator:

• Chewing gum can help increase patient adherence
• It offers fast onset of action and can improve bioavailability of drugs as some amount of drug is absorbed through the buccal mucosa
• It can also be administered discretely and without the need for water.

Although directly compressed gum excipient systems are widely promoted as relatively trouble-free and amenable on standard tableting equipment, product developers often experience several technical challenges during formulation and evaluation of medicated chewing gum products. This Technical Note provides a quick reference guide on how to handle and trouble-shoot common issues when using this material.

Types of Medicated Chewing Gum and Manufacturing Methods

There are currently two types of medicated chewing gum and manufacturing methods, namely extruded gum and compressed gum.

Extruded gums are produced using a traditional method of manufacture whereby the ingredients are intensively mixed at elevated temperature to produce a matrix. The matrix is then cut into ‘pillows’ and subsequently sprayed with coating agents.

Compressed gums are manufactured by blending active ingredients with the gum base and compressing the obtained mix on a tableting press. The direct compression method is a cool and dry process suitable for a wide range of ingredients. An example of a compressed gum system is the Health in Gum® excipient by CAFOSA SA, part of the MARS WRIGLEY conglomerate.

The Health in Gum® excipient system, the focus of this Technical Note, utilizes a food-grade gum base, polyols, plasticizers and anticaking agents. The active ingredient(s), sweeteners and flavours are added to the base, blended and compressed on standard tableting equipment. Additional processing or adaptations of equipment is not required.

Recommended Procedure for Handling Health in Gum®

1. Break the lumps, if any, with a vibrating sieve (1 mm). Remove any pieces that you cannot break manually.
2. In the selected blender, add the powder gum, the active and any other ingredient in powder form (e.g flavour in powder form, intensive sweeteners and colours) following the suggested formulation. Mixing time will depend on the type of mixer and the batch size. Gentle mixing needs more time but it tends to be better than intensive mixing.
3. Add the liquid flavour so that it distributes homogeneously into the blend (for instance, spraying). If you cannot add the liquid to the mixer, you need to make a premix of the flavour and some of the silicon dioxide.
4. After spraying, add between 0.5% of Silicon Dioxide with high oil absorption capacity (for instance, Sipernat 50S from Evonik or Syloid 244FP from Grace) and mix until you get a dry and free flowing.
5. Add lubricant (2% on the case of Magnesium stearate) into the blender and mix until homogeneous.
6. Sieve again, as some ingredients may agglomerate (liquid flavour and silicon dioxide).
7. Before adding the final mix to the pressing machine, add a small quantity of the selected lubricant to the tablet press and run the machine slowly for a few minutes to allow the lubricant to cover punches. This will reduce the initial stickiness.
8. Start compressing. Standard speeds are between 30k and 40k tablets/hr. Adjust pressure and weight, with final tablet hardness between 7 and 10 mm.

Tips and Suggestions

1. Add silicon dioxide before adding the liquid flavour. The total silica content should however not exceed 2% to give the chewing gum the optimum texture.
2. The liquid flavour should have Triacetin or a suitable oil (e.g Vitamine E) as the solvent to be chewing gum compatible
3. Ensure that the product does not exceed 27ºC during processing. Heating up leads to a loss of fluidity and increases stickiness.
4. Experiment with compression forces as they have different effects on gum texture depending on the formulation ingredients.
5. Some ingredients with acid properties may affect to the texture of the gum. In this case, we suggest changing metallic stearates by stearic acid.
6. Gums should be stored away from excessive heat, in a dry cool area. Keep away from direct light. The optimum conditions: 20ºC – 50% RH.

Suggested starting formula

Here is a simple formula to get you started:

Touble Shooting Guide

Directly Compressible Chewing Gum – Common Problems and Potential Solutions Infographic

Introduction

For lipophilic drug substances that exhibit dissolution-rate limited absorption (BCS II and IV) self-emulsifying drug delivery systems (SEDDS), which are defined as “isotropic mixtures of oils, surfactants, solvents and co-solvents”, are a viable approach to enhance bioavailability.

SEDDS are relatively simple formulations to develop; the simplest systems comprise an oily vehicle (lipid), a surfactant, and a co-surfactant and optionally, and an antioxidant. Alternatively, a single excipient with self-emulsifying properties can be used.

Preparation of SEDDS simply involves adding all the hydrophobic ingredients together and heating to 50 ^oC. In a separate container the aqueous phase (solvents and surfactants) is also heated to 50 ^oC. The two phases are then blended to form SEDDS. This is illustrated below:

Figure 1: Preparation of a simple SEDDS Formulation

The system is designed to form a fine and stable oil-in-water (o/w) emulsion upon contact with digestive fluids and the agitation from the digestive processes. SEDDS can be dosed into either softgels or two-piece hard capsule shells.

A key aspect of SEDDS is the use of digestible lipids. These are required not only to carry the drug substance but also to provide the desired pharmacokinetics while minimizing food effects and variability.

The improvement in oral absorption for SEDDS, which depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability, is due to increased intestinal absorption via supersaturation, tight junction modulation, and reduced first-pass effect.

Advantages of SEDDS

1. SEDDS can be used with both hydrophobic and hydrophilic drug substances, as well as with liquids and solid dosage forms.
2. Lower levels of drug used in SEDDS compared with conventional formulations means less incidences of side-effects to consumers.
3. Finely divided oil droplets are more uniformly and consistently distributed within the GI tract which enhances absorption and bioavailability, while minimising localised pooling.
4. Ease of manufacture and scale- up compared with other drug delivery systems such as solid dispersions, liposome and nanoparticles.

Disadvantages of SEDDS

1. Generally, there is a lack of good predicative in vitro models for assessing SEDDS formulations. Traditional dissolution methods are not suitable since SEDDS require in-situ emulsification and digestion prior to releasing the drug.
2. The high surfactant concentrations in SEDDS formulations (approx. 30-70%) can instigate chemical instabilities of drug substance or even irritate the GI tract.
3. Volatile co-solvents in the SMEDDS formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs.
4. Formulations containing several components become more challenging to validate.

SEDDS Raw Material Selection

Note that there are only a select number of drug substances and excipients or excipient combinations that can efficiently form SEDDS systems.

Drug substance

SEDDS are ideally used to increase solubility of poorly soluble drugs; typically BCS class II and class IV drugs. The drug substance ought to possess enough lipophilicity and affinity to the oily vehicle (log P >2, ideally ³5, and solubility 50 mg/g) to enhance absorption and circulation into the lymphatic system.

Excipients

SEDDS places specific constraints on excipients. Furthermore, the self-emulsification process is specific to the levels and type of the oils – surfactants combination, surfactant – co-surfactant ratios and the temperature at which self-emulsification occurs.

Generally, the following are the materials for consideration:

• Oils: The first choice oils for SEDDS are medium chain triglycerides (MCT) and hydrolysed vegetable oils. These serve as the oily phase and to solubilise the drug substance. The presence of long- chain fatty acids such as oleate and linoleate can help boost the lymphatic absorption of highly lipophilic drug substances, especially if they have logP values of 5 or higher. This tactic can be used to avoid the first-pass
• Surfactants: Surfactant choice is limited to non-ionic surfactants with a high HLB and low oral toxicity. Examples of suitable surfactants include Polysorbate (e.g Span 80, Tween 80) and Hydrogenated castor oil derivatives (Kolliphor RH40).
• Co-surfactants: To lower potential GI tract effects associated with high levels of surfactants needed for SEDDS formulations co-surfactants are added. Co surfactants help lower the interfacial tension to a very low levels that facilitates ‘spontaneous’ emulsification. Examples of co-solvents include polyethylene glycol and ….
• Solvents and dispersants: Solvents and dispersants suitable for oral administration include ethanol, propylene glycol (PG), polyethylene glycol (PEG) and glycerin. Their purpose is to help solubilise the drug substance and surfactant or the drug into the lipids.

Optional excipients

Antioxidant Agents: Lipophilic antioxidants (e.g. α tocopherol, propyl gallate or ascorbic palmitate) to prevent oxidation of oils in SEDDS formulations.

• Viscosity Enhancers: Emulsion viscosity can be improved with the use of additional material such as gums and waxes (glyceryl monostearate, glyceryl tristearate, beeswax and stearic acid).
• Polymers: Polymer may be added at levels ranging from 5 to 10% w/w to form a matrix. Examples of suitable polymers include HPMC, HPC and Ethylcellulose.
• Mesoporous silica: Mesoporous silica can be used to added to convert liquid SEDDS into free-flowing powders that can be filled onto conventional capsule machines or compressed into tablets.

Starting Formula

Steps for Developing Successful SEDDS formulations

Successful formulation and development of SEDDS requires characterization and optimization of the formulation on the same basis as any other formulations, particularly in respect to drug solubility and loading, dispersibility and stability, and for scale-up studies, to achieve similar performance at larger manufacturing scale as was observed during development stages.

Figure 2: SEDDS Formulation Characterisation and Optimisation

Here below are a number of important ‘must dos’ for optimizing SEDDS formulations:

1. Determine equilibrium solubility at ambient conditions

The first step when developing a SEDDS formulation is to screen the solubility of the drug substance. Solubility is important since it gives the formulator an idea about the formulation’s expected maximum drug loading, stability and performance.

In this respect, equilibrium solubility should be determined at ambient conditions in a range of oily vehicles, surfactants and co-surfactants, as well as their combinations.

Equilibrium solubility in liquid vehicles is determined by equilibrating the drug substance at room temperature and assaying the amount dissolved using HPLC. In solid lipids, equilibration is best achieved at higher temperatures and allowing the mixture to solidify (e.g after 24 hrs) before it is examined by DSC or other suitable technique to establish the saturation concentration.

Frequently prevailing conditions, either from the substance or the dissolution medium, result into the formation of a supersaturated solution, where the amount of solute exceeds the equilibrium solubility. Such supersaturated solutions are thermodynamically unstable, and any such concentration values, represent kinetic solubility values rather than an equilibrium solubility values.

It is therefore important for formulators to make a distinction between equilibrium and kinetic solubility, and to know when a particular measurement represents an equilibrium solubility value, or if the determined value simply represents some type of metastable condition.

Solubility screening should be performed in a wide range of excipients, including solid and waxes. Depending on the type of drug substance, some solid excipients can adequately dissolve and enhance bioavailability. For solid vehicles that become molten at or above their melting points (40°-65°C) before adding the drug substance, the effect of the short heating and cooling rate on the API-formulation stability should be investigated.

When making decisions about the dose of the drug, it is important to limit the drug loading to below 80% of the saturation concentration to prevent nearing the drug’s saturation point in the system. This is because supersaturation can easily put at risk a formulation’s physical stability and potentially lead to crystallization during the product’s shelf life.

2. Perform Drug substance and Excipient Compatibility studies

Just like any other formulation project, drug substance – excipient compatibility studies constitute an important aspect of a SEDDS formulation programme. These studies serve to identify, quantify and predict any unwanted interactions (chemical and physical) as well as their significance on quality and performance of the product. The end game is to arrive at excipients that will be incorporated into the formulation. DSC and stress studies of binary and ternary blends can be performed by stressing blends and any degradants assayed using HPLC, IR or mass spectrometry.

3. Evaluate the Formulation’s Dispersibility

Dispersibility of a SEDDS formulation is undertaken to determine its capability to disperse into a fine and stable emulsion. The test relies on measuring the size of resulting emulsion dispersed phase and is undertaken using a standard USP Type 2 dissolution apparatus (Paddle Type).

One ml of each formulation is added to 500 ml of water at 37 + 0.5ºC and the paddle is rotated at 50 rpm. The SEDDS formulation should form a mixture or gel which is of different type depending upon which the in vitro performance of formulation. Nano or micro – emulsions, which are desired for SEDDS, form rapidly to yield a clear, bluish or slightly less clear emulsion, having a bluish-white appearance.

In addition to in-vitro dissolution tests, it is necessary to test the formulation under lipolysis conditions. This is because lipid digestion in the gut is the main physiological event that enhances the bioavailability of poorly soluble compounds. As the SEDDS formulation disperses and emulsifies in the GI tract, lipolytic enzymes and bile salts aid in the creation of colloidal structures such as unilamellar and multi- lamellar vesicles and mixed micelles, that further aid the solubilization of the drug substances.

It is for this reason that the vitro dispersion test should incorporate lipolytic components to render it more representative of in vivo conditions.

4. Determine the Optimal Filling Temperature

For SEDDS formulations to be effectively filled into capsules, the formulation filling temperature should be high enough to keep the formulation in a liquid state without affecting other aspects of the formulation. As part of the formulation development process, the optimal filling temperature should therefore be determined as well as the formulation’s viscosity at various temperatures and flow rates.

Useful Tips

Consider processing the formulations under vacuum

Manufacturing a SEDDS formulation can potentially introduce air into the formulation due to the necessity to mix different materials. Processing under vacuum can help prevent air from becoming incorporated into the product during mixing.

Use softgels in lieu of two-piece capsules for liquid SEDDS formulations

Softgels are more suitable for liquid formulations during large-scale manufacturing to remove the additional band-sealing step needed to prevent leakage observed with two-piece capsules.

Pay attention to small details

SEDDS formulations can be sensitive to variations in surfactant, aqueous phase and co-solvent levels. It is therefore important that lipid excipients are handled carefully in accordance with manufacturer-recommended instructions. A number of self-emulsifying excipients used in SEDDS are capable of absorbing moisture, therefore conditions of high humidity should be avoided.

Where semi-solid or solid excipients (such as Gelucire 44/14, Kollipho RH60, Dynasan 118 etc) are used it is advantageous to first gently melt them and homogenize the melt before sampling rather than scooping off material at the top.

Both the lipid and aqueous phases should be heated carefully to 50^oC before mixing.

References

1. Christopher Porter J H, et al: Enhancing intestinal drug solubilization using lipid-based delivery systems. Advanced Drug Delivery Reviews 2008; 60: 673–691.
2. Christiansen ML, Holm R, Kristensen J, et al. (2014). Cinnarizine food-effects in beagle dogs can be avoided by administration in a self nanoemulsifying drug delivery system (SNEDDS).Eur J Pharm Sci 57:164–72
3. Thomas N, Holm R, Müllertz A, Rades (2012). In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J Control Release 160:25–32

A product’s label is a window in its soul, that’s what the product stands for, its benefits to its consumers. Claims such as ‘Natural’, ‘Fresh’ or ‘Artificial’ have a particular resonance with consumers, playing a key role in shaping purchase decisions and other behaviours.

Within the personal care and food/nutrition sectors, ‘natural’ status carries a lot of acclaim, as evidenced from the ever increasing sales of natural products or those with ‘natural’ claims. Natural skincare and nutrition brands have been growing at twice the rate of conventional products, a trend product developers and marketers seem to know very well about.

In the pharmaceutical sector, natural claims, while not carrying similar implications, are still important. Not only are there many excipients and active ingredients, including carbohydrate polymers, gums, surfactants, oils, flavours, alkaloids and antibiotics that are natural in origins or are naturally derived but consumers everywhere are increasingly seeking natural products due to their perception as being sustainable and friendly to the planet.

However, despite the widespread use of the term natural, the definitions of the terminology around natural, natural origin or artificial remains, to this day, in the regulatory equivalent of ‘no man’s land’. Regulators are as yet to provide official definitions or guidance on what is natural or not. Maybe because of the legal ambiguity, consumer groups and lawyers have been pushing for restrictions and/or legal redress on the uses of ‘natural’ and claims around ‘no artificial’ ingredients.

Consider xanthan gum, a gum that is widely used in the food, personal care and pharmaceutical products. Xanthan gum is produced by the bacterium, Xanthomonas campestris, which converts glucose into the gum. The process is a ‘natural’ fermentation process that occurs at its own pace without human intervention. Yet controversy as to whether xanthan gum is a natural product or not persists. Manufacturers using xanthan gum and attaching ‘natural’ claims to it have been a target of lawsuits challenging the ‘natural’ status of this material.

So what do ‘natural’ and ‘naturally derived’ mean?

This is by no means a definitive, legal guide. The FDA has not provided a regulatory definition of what natural entails when it comes to regulated products. The EU has guidelines on the use of ‘natural’ for nutritional claims (Regulation (EC) 1925/2006 but when it comes to other product groups, there still remains ambiguity. Therefore the use of the term ‘natural’ in advertising or labelling requires good judgment and legal counsel to avoid legal jeopardy.

Nevertheless, a material is considered ‘natural’ when it is ordinarily identified in nature, obtained and used in its natural, raw state after being extracted from the source. For example, Virgin Almond Oil Ph. Eur is the oil obtained by cold expression of the ripe seeds of Prunus dulcis. No further treatment (refining) or additives have been added.

The types of ‘permitted’ treatments include physical, enzymatic or microbiological processes on the plant or animal source material.

A material is referred to as ‘naturally derived’ or ‘natural origin’ when the natural source is treated to access other properties of the natural raw material; for example, getting natural fatty acids and natural fatty alcohols from a coconut.

By way of an example, natural fatty acids may require further processing in order to unlock or create certain aspects of the material’s properties beneficial for its function. Equally, potassium benzoate and lecithin require extraction and purification before they are in a state suitable for performance as preservatives or emulsifiers. Provided they are from plants, these materials can be classified as naturally derived.

A less encountered term is ‘nature identical’ which is typically used in relation to flavours. Nature identical flavours (vs artificial flavours) are flavours obtained by synthesis or isolated through chemical processes. The components are chemically and organoleptically identical to flavouring components present naturally present in nature. From a regulatory perspective, nature identical and artificial flavours are undistinguishable.

Standards and Certifications

A number of international standards and certification schemes on naturalness have been developed in recent times. They aim to help raw material suppliers and product manufacturers harmonise definitions on ingredient definitions and guide consumers. Although initially aimed at the cosmetics sector, the technical definitions and qualification schemes are equally applicable to food and pharmaceutical ingredients.

Below are three of the most important standards and schemes:

The COSMOS-standard

The COSMOS-standard was introduced in 2010. It aims to define and implement a standard for organic and natural cosmetics. The COSMOS standard includes guidelines on origin and approved processing procedures of the ingredients if they are to qualify as natural or organic. In addition to ingredients, the COSMOS standard also defines naturalness of the total product.

NaTrue Standard

The NaTrue Standard was developed by the NaTrue Scientific Committee Criteria and Label, an international non-profit organization. Its main focus is on cosmetics for which it seeks to clarify and promote natural and organic cosmetics globally. For ingredients, the NaTrue Standard differentiates between natural substances, nature-identical substances and derived natural substances, with a list of approved treatment processes. Furthermore, there are positive lists available for nature-identical substances, comprising pigments, minerals and preservatives.

ISO 16128

The ISO 16128 is a standard from the Geneva-based International Standard Organization. It aims to provide “Guidelines on technical definitions and criteria for natural and organic cosmetic ingredients and products”. ISO 16128 consists of two parts. Part 1 provides definitions for different ingredient categories. Part 2 describes the procedure on how to calculate the naturality of ingredients and the natural origin content of a cosmetic formulation, based on the amount of natural components in each raw material.

Conclusions

Even with the availability of standards and certifications the distinction between natural and unnatural is not always clear. In the absence of regulatory guidance, it falls to the formulator and marketer to make their own decision about what is natural and what is not, as there is no absolute definition, only opinions. This technical note will hopefully assist you in navigating the maze of natural and artificial ingredients.

Changes in technology or a desire to achieve efficiencies may prompt pharmaceutical manufacturers to look at new suppliers. In this Technical Note we provide a defined approach for selecting and evaluating suppliers and their offerings. The process is split into three stages: Supplier Evaluation, Quality/Regulatory Compliance & Technical Evaluation, and Product Evaluation.

Supplier Evaluation

New supplier evaluation should involve verifying the ability to meet your requirements. This is an important step since supplier non-performance, even the most basic or for the simplest items, can have serious consequences for your company. Some of the important parameters to consider are:

• Capacity (equipment scale, batch size, minimum order quantity)
• Safety/Health/Environmental risk
• Financial solvency/business stability
• REACh compliance
• Delivery performance(distribution footprint & lead time)
• Supply chain management

For a long time, the film coatings supplier base was limited to two or three, mainly European and American companies. With the on-boarding of several small to medium suppliers, the situation is changing, bringing with it choice, innovation and flexibility for customers.

Regulatory Compliance and Technical Evaluation

The next consideration should be the supplier’s quality and regulatory track record. We suggest buyers evaluate suppliers on the basis of the following criteria:

• cGMP compliance & other quality management systems
• Recalls and complaints policies
• Change management policies
• Material management controls
• Quality agreement
• Production facilities
• Documentation standards
• Technical capabilities

Supplier technical capabilities assessment should look at their laboratory capabilities, technical skill/staff qualifications, new product development capabilities and process development/understanding capabilities. We suggest obtaining feedback from previous customers and asking about the supplier’s delivery performance, adherence to contract terms and ability to resolve issues.

Although film coatings are simple physical blends, their application is highly challenging and the availability of technical support is crucial to project success. Suppliers’ technical support is critical to timely and successful resolution of technical issues that may arise from time to time.

Product Evaluation

The final consideration is product assessment. The table below summarises some of the tests that can be performed on products to assess and compare their suitability.

Summary

Having undertaken the technical assessment, the final aspect of the product evaluation step is to look at the comparative price of the material, in particular, the full cost of use. For film coatings, it is especially useful to examine the material’s recommended weight gain as this single factor will influence the material needed for a comparable equipment load.