Drug Delivery Via The Oral Route Biology Essay

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Drug delivery via the oral route is currently the most accepted method of drug administration in the UK.1 With advantages such as patient convenience and low manufacturing costs,2 pharmaceutical companies have prioritised peroral formulations over any other route of administration.1 Peroral formulations however are flawed in that prior to systemic absorption, active pharmaceutical ingredients (APIs) incorporated within the formulation are highly susceptible to hepatic metabolism and degradation via enzymes within the gastrointestinal tract (GIT).3 Furthermore dosage forms, such as tablets and capsule, are inconvenient to patients who have difficulty in swallowing3 or suffer from nausea.4

The medical term for 'difficulty in swallowing' is dysphagia and this condition often affects children and elderly.3 For paediatric patients there are alternatives such as liquid dosage forms available, however these present several disadvantages including instability of the drug, transport problems due to bulkiness of the product and inaccurate dosing.5

An alternative formulation, oral disintegrating tablets (ODTs), has been developed keeping ease of swallowing in mind.6 ODTs allow rapid absorption through the oral cavity and thus eliminate premature hepatic metabolism of API, GI degradation and cause lesser systemic side effects than those associated with peroral dosage forms.7 ODTs make it easy for the patient to swallow and they require no water during administration consequently making them more acceptable for dyphagic patients.6

ODTs, however, are fragile in nature and present high vulnerability towards moisture thus lacking in strength and stability.7 Furthermore re-educating patients on the correct method of administration of ODTs has proved difficult since patients often do not read key information on labels such as "do not swallow" or "do not chew".1

The issues related to oral dosage forms are widely acknowledged by the pharmaceutical industry and thus pharmaceutical companies are always focusing on the development of novel oral formulations which allow even quicker systemic absorption (than 30seconds - recorded time for ODTs8) through the oral cavity, one of which is Oral Disintegrating Films (ODFs).

CHAPTER 2

Oral Disintegrating Films

ODFs are stamp sized films1 with a thickness of approximately 70µm9 (figure 2-111). When placed in the mouth, ODF adheres to the tongue or any other mucosal surface stimulating saliva11. Within seconds the film disintegrates and releases APIs from the film. APIs are rapidly absorbed into the bloodstream11 for systemic or local action.12 The quick absorption of ODFs means the therapeutic response is obtained quicker compared to peroral dosage forms.Fast Dissolving Film

Figure 2: A representation of an ODF (Courtesy of Hughes medical corp11) Background

The production of transdermal patches incepted the concept of ODFs11. By 2001 ODFs were produced by pharmaceutical companies such as Pfizer and marketed as oral care products.13 Over the last decade over 50 pharmaceutical companies within the US market, such as Lavipharm, have incorporated APIs into these formulations14 (table 2-1) with the aim of producing a more comfortable way of delivering the formulations. I WANNA FORGET THE COMPLIANCE IN INTRO TOTALLY - I THINK YOU SHOULD MENTION THIS IN YOU DISCUSSION AS LITERALLY ONE POINT? novel technique for drug delivery, which presented the potential in improving issues related to compliance.14

Distributor

Brand

API

Strength (mg)

Novartis

Gas - X

Simethicone

6.25

Pfizer

Benadryl

Sudafed

Diphenyhdramine HCl

Phenylephrine HCl

12.5

10

Prestige

Chloraseptic

Benzocaine/Menthol

3/3

Hughes

Medical Corp

Folic Acid

Loratidine

Caffine

1-5

10-20

2.5

Table 2: Some of the ODFs available within the US market, the concentration of API present within each strip and the Pharmaceutical Manufacturer. 3,14 Abbreviations; API: Active Pharmaceutical Ingredient, HCl: Hydrochloric Acid mg: Miligrams

ODFs within the UK

In 2002 Wrigley's released an ODF marketed as a new 'non-chewing gum' into the confectionary market called 'Extra Thin Ice'.15 According to an article written in The Grocers magazine,16 Wrigley's ODFs made a profit of £14m in the first 12 months of introduction; however in 2007 their sales plunged and due to poor advertising their impact on the market was limited.16 Although there is no official evidence to explain why these are no longer available, many internet sources point towards low public acceptability towards the ODFs.17

The UK pharmaceutical market has only adopted the use of ODFs for limited conditions. Currently in the UK there are snoreeze oral strips available over-the-counter (OTC)1,18 (AND POSSIBLY NRT?) in pharmacies nationwide. This includes big giants such as Boots Pharmacy, Tesco Pharmacy, Sainsbury Pharmacy and Asda Pharmacy. Boots pharmacies have also manufactured their own brand alternative strip called "Boots Alternatives Snoring relief Strips". 18

Mechanism of API Absorption Though the Oral Cavity

Figure 2: A representation of the layout of the oral cavity19.The oral cavity allows greater permeability of drugs compared to the skin however not as high as the intestine.19 Figure 2-2 is a diagrammatic representation of the oral mucosa. As can be seen in order for an API administered to reach blood vessels it must cross: closely packed epithelial cells, the basement membrane, lamina propia and finally enter the highly vascularised sub - mucosa.19 Patel describes the oral cavity and its permeability in detail.19 Table 2-2 summarises the factors affecting drug absorption within the oral cavity. NOTE TO SELF COME BACK TO THIS

Tissue

Thickness

(µm)

Turnover Time (days)

Surface area (cm2)

Permeability

Residence Time

Blood Flow

Buccal

500-600

5-7

50.2

Intermediate

Intermediate

20.3

Sublingual

100-200

20

26.5

Very Good

Poor

12.2

Gingival

200

-

-

Poor

Intermediate

19.5

Palatal

250

24

20.1

Poor

Very Good

7.0

Table 2: Characteristics of the oral mucosa (Table taken from Patel19).

Classification of ODFs

ODFs may be classified into three subgroups: flash release, mucoadhesive melt-away wafers and mucoadhesive sustained-release wafers. 13

They are grouped according to how they react when placed in the mouth. 'Flash release' are designed to release the API within 60 seconds of placing inside the mouth whereas 'mucoadhesive melt away' and 'mucoadhesive sustained-release wafer' take minutes and hours respectively.13 The differences in disintegration times between the different types of ODFs, means that the rate of drug release from the formulation can be controlled by selecting the right ODF. However in doing so one must accept the other properties of that type of ODF (table 2-3).13,20

Property

Type of ODF

Flash Release

Mucoadhesive melt away

Mucoadhesive sustained release

Area (cm2)

2-8

2-7

2-4

Thickness (µm)

20-70

50-500

50-250

Application

Tongue

Gingival/buccal

Gingival or other areas

Excipients

Highly hydrophillic polymers

Hydrophillic polymers

Non soluble polymers

Table 2: Properties of the three subcategories of ODFs.13,20 Abbreviations; ODF: Oral disintegrating film, cm2: centimeters2, µm: micrometers

Advantages of ODFs

ODFs have a larger surface area than ODTs, therefore disintegration and dissolution of the films will occur at a fast rate.21

The films provide accurate dosing, as opposed to liquid oral dosage forms.14

They avoid drug degradation via the GIT and hepatic metabolism, therefore allows a wide range of drugs to be incorporated at lower doses consequently reducing side effects and improves cost-effectiveness.1,21, 22

Improves compliance within patients because it's easier to swallow and it doesn't require any water when taking the medication. It's also ideal for dysphagic patients or patients who are suffering from conditions such as nausea (a common problem associated with tablets and capsules).14,21

Some drugs degrade over time when exposed to water, ODF films can be packaged to avoid aqueous environment and exhibit greater stability compared to liquid forms.14

ODFs are flexible and stronger compared to dosage forms such as ODTs and therefore transport, storage and patient handling is significantly improved.21

Disadvantages of ODFs

The quantity of API incorpotated within the film cannot exceed 50mg,13 however one exception is the Gas-X strip which contains 62.5mg Simethicone per strip.1

Even though dosing is accurate compared to liquid oral dosage forms, it is difficult to gain uniformity in dose as seen with tablets and capsules24.

The thickness of the film increases with the concentration of incorporated API, this can sometimes compromise the properties of the film.13

Some drugs can degrade over time as they are extremely susceptible to hydrolytic and oxidative degradation, therefore the formulation and packaging of the film is required to be carefully considered to ensure stability.14

Formulation of ODFs

In order for an ODF to be accepted by patients many factors need to be considered during its formulation. These include its appearance, taste, disintegration time, mouth feel, and compatibility of excipients and API within the formulation.21

Table 2-4 shows the typical composition of an ODF.3

Execipient

Quantity (%W/W)

Drug

1 - 25

Polymer

60 - 65

Plasticiser

0 - 20

Fillers, Colours, Flavours etc

0 - 40

Table 2: Typical composition of an ODF.3 Abbreviations: %W/W: Percentage weight in weightBelow is an overview of all the excipients that may be incorporated during ODF formulation.

Strip forming polymers

An essential component of ODF formulation is the addition of a polymer as it dictates the strength and elongation properties of the film produced1 and consequently the ability of the film to withstand forces applied during manufacturing, packaging, storage and handling, 13 however the film is still required to retain an acceptable disintegration time when placed in the oral cavity.1

Referring back to table 2-4 it can be seen that the concentration of polymer incorporated within a film is typically between 60-65%, this is because the polymer will form the base of the ODF13.

An ideal polymer is required to be non-toxic, non-irritant, easily wetted, have good spreadability and cheap to manufacture.3

Commonly used polymers include pullulan, Hydroxy propyl methyl cellulose should it be capital C? (HPMC), Hydroxy Propyl Cellulose (HPC) and gelatin1.

Polymers that will be utilised in this project include; Methocel (HPMC) E5, Methocel (HPMC) E50, Klucel (HPC) and Starch. Table 2-5 below shows the properties of these polymers.23

Type of Polymer

Property of the Polymer

Description

Solubility

Stability and safety

Regulatory Status

Methocel E5 and Methocel E50

Odorless, tasteless,

White granular powder.

Soluble in cold water/ ethanol.

Insoluble in hot water.

Hygroscopic after drying.

Excessive oral consumption may cause a laxative effect.

GRAS listed and approved for use in UK.

No specified ADI*.

Klucel

Odorless, tasteless,

White granular powder.

1 in 2.5 parts ethanol.

1 in 2 parts water.

Insoluble in hot water.

Hygroscopic after drying.

GRAS listed and approved for use in UK.

ADI: 1500mg/kg body weight.

Starch

Odourless,

Slight Taste

Fine, off white powder.

Slightly soluble in cold water.

None, however consumption of large amounts may be harmful.

Approved for use in UK.

No specified ADI.

Table 2:Properties of Polymers,23 Abbreviations; ADI: Approved Daily Intake, UK: United Kingdom, GRAS: Generally recognised as safe

The use of a mixture of polymers improves ODF properties such as the hydrophobicity, flexibility, mouth feel and solubility.1 A study carried out by Kulkarni24 focused on the performance of various polymer mixes and demonstrated the ability of polymer bends to lower disintegration times of ODFs and improve their appearance.

Plasticisers

Incorporation of plasticisers allows production of flexible ODFs and reduction of brittleness caused by the addition of a polymer.21 Plasticiser molecules work by inserting themselves between polymer molecules, decreasing the attraction and consequently decreasing Glass Transition temperature (Tg).1 As seen in table 2-4 the concentration of plasticisers incorporated within the formulation is low, this is because a high concentration results in film cracking, peeling and splitting, thus affecting the API absorption rate.21 An ideal plasticiser is required to be compatible with the polymer and solvent included within the formulation.13 Furthermore some studies also show that APIs incorporated may also imitate the activity of a plasticiser, hence increasing the rate of dissolution.1 The major downfall associated with plasticiser use may affect the rate of absoprtion of the drug.13

Common plasticisers include Polyethylene Glycol (PEG) 400 and glycerol. Plasticiser utilised within this project is PEG 400, properties of PEG 400 can be seen in table 2-6 below.23

Plasticiser

Property

Description

Solubility

Stability and safety

Regulatory Status

PEG

Clear, viscous liquid,

Slight odour,

Slight bitter taste.

Soluble in water.

Excessive oral consumption can have a laxative effect

Approved for use in UK.

ADI: 10mg/kg body weight

Table 2: Properties of Plasticisers. 23 Abbreviations; PEG: Polyethylene glycol, UK: United Kingdom, ADI : Approved daily intake.

The active pharmaceutical ingredient

Prior to API incorporation the properties of the drug on the oral cavity, i.e. taste, mucosal irritancy and adverse effects such as staining of the teeth, need to be considered.3 Furthermore other factors that require thought include drug compatibility with other excipients and stability within pH of the mouth.1,3

Table 2-7 shows examples of some drugs and the dose that have successfully been incorporated into ODFs.1 As seen in table 2-7 there are a wide range of APIs that may be added to ODFs, the only limitation to API addition to ODFs is the concentration. As only a low concentration can be incorporated, the number of potential drug candidates limited.13

Molecule

Therapeutic Category

Dose

Nicotine

Nitroglycerin Dervivatives

Zolmitripan

Loratidine

Loperamide

Ketoprofen

Diclyclomine

Smoking Cessation

Vasodilator

Anti Migrane

Antihistamine

Antidiarroheal

Anti inflammatory

Muscle relaxant

1.0 - 15.0mg

0.3 - 0.6mg

2.5mg

5 - 10mg

2.0mg

12.5 - 25.0mg

25.0mg

Table 2: List of pharmaceutical drugs that maybe incorporated into ODFs9. Abbreviations; mg: miligram

This project involves the formulation of ODFs containing benzocaine as the API, its pharmacological activity and formulation considerations are discussed in detail in chapter 3.

Other excipients

Other excipients are included within the formulation to improve film properties such as appearance, taste and disintegration time. Sweeteners such as sorbitol1 and flavouring agents for instance peppermint oil14 are for enhancing flavour, saliva stimulating agents e.g. citric acid13 are incorporated to increase the production of saliva.13 Other excipients include stabilizing agents, thickening agents and colouring agents (Table 2-7).21,23

Excipient

Property

Description

Solubility

Stability and safety

Regulatory Status

Glucose

White solid

Odourless

Sweet tasting.

Soluble in water.

Partially soluble in ethanol.

None

GRAS listed.

Approved for use in UK.

Sorbitol

White solid.

Odourless.

Sweet taste.

1 in 25 parts ethanol.

1 in 0.5 parts water

None

GRAS listed.

Approved for use in UK.

Sodium Sachharin

White solid.

Odourless.

Sweet taste.

1 in 50 parts ethanol

1 in 1.2 parts water.

None

Approved for use in UK.

ADI set by WHO: 2.5mg/kg.

ADI set by COT: 5mg/kg

Citric Acid

White crystals.

Odourless

Strong acidic taste.

1 in 1.5 parts ethanol.

1 in <1 parts water.

None

GRAS listed.

Approved for use in UK.

Table 2: Properties of other excipients incorporated in to ODF23, Abbreviations; WHO: World Health Organisation, COT: Committee on Toxicity of Chemicals in Food, Consumer Products, and the Environment, GRAS: Genreally recognised as safe.

Manufacture

There are several methods that may be utilised for the casting of the formulation, which can be found in various sources of literature such as those discussed by Dixit1 and Arya11. The two common methods are Solvent casting and the hot melt extrusion method.1,11

Table 6 highlights the main differences between the solvent casting and the hot melt extrusion methods of manufacture.25

Solvent Casting Method

Hot Melt Extrustion Method

API may be thermoliable

Solvent incorporation is necessary

High possibility of containing air bubbles

Water is incorporated as a solvent

Rollers and coaters are required for large scale production

API incorporated must be thermostable

No solvent is required

Incorporation of air bubbles in low.

Water incorporation is not necessary

Hot melt extruder is required for large scale production

Table 2: Major differences in the solvent casting method and hot melt extrusion method of manufacture of ODFs.25 Abbreviations; API: Active pharmaceutical ingredient

The method of manufacture that will be used in this project is the solvent casting method. This method involves mixing all water soluble excipeints with water a homogeneous solution, remaining excipients are then added consecutively until a homogeneous mix is produced. The mixture is then degassed to remove air and cast for drying.13 The benefit of this method is that it does not necessarily require exposure to heat for the drying process hence can be used for thermoliable APIs.1

Testing

Once an ODF has been manufactured it is tested against Pharmacopoial and target standards to ensure the product is ready for the market. This includes checking the product has been manufactured as predicted and the film produced meets the quality criteria. There are a wide range of tests that can be carried out on the ODFs produced and these are well referenced.1,3,9,11,13,14,20,27

The tests that will be carried out in this project include:

Thickness

It is important to test the thickness of a particular strip as it indicates the uniformity of the drug content and thus shows how successful the process of manufacturing was.1 The thickness can be measured using a micrometer (μm) screw gauge at approximately 5 different locations on the film strips manufactured and the mean thickness is then calculated.21

Folding endurance

The strip is folded repeatedly in the same place until it breaks.1 The number of times the film can be folded before a tear appears is the endurance value. The rationale of this test is to examine the films capacity when repeatedly folded, hence determining its physical strength.27

Disintegration time

The disintegration time looks at how fast the strip will dissolve when placed in a small volume of water, thus enabling analysis of the time the ODF will take to disintegrate when placed in the mouth.1 The limit for ODTs according to pharmacopoeial specifications is usually 30s or less,26 however since ODF specification are not yet established tablet standards will be used.

Content uniformity tests

This method involves the use of UV analysis to determine the API content within each strip and hence evaluate on film uniformity. 13 To do this a standard analysis will be done for the API and compared to the analysis CHECK PHARMACOPOIEA. Pharmacopeial specifications estimate the uniformity of the drug within any formulation to be usually within 85-115%.1,26

Uniformity of weight

3 strips from each batch will be individually weighed and an average calculated. These weights should not deviate too much from each others as high deviation indicates poor mix. Together with the content uniformity test it enables analysis of homogeneity of the film.27

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