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Dosage Form Design for the Elderly

Prof. Dr. Pornsak Sriamornsak

Faculty of Pharmacy, Silpakorn University Pharmaceutical Biopolymer Group, Silpakorn University Academy of Science, The Royal Society of Thailand Thai Industrial Pharmacist Association Elderly population 1 Elderly population in South East Asia 2

Main reasons for elderly population growth 1. The success in public health policy and medical advancement cause of reduction in death rate 2. Economic development and national development Problems and challenges for medicine in elderly 3

10 Common Chronic Condition for Elderly

Have at least 1 80% chronic condition

Have 2 or more 68% chronic conditions

Source : Centers for Medicare & Medicaid Services, Chronic conditions Prevalence Stage/County table: All-for-Service Beneficiaries. 2015

Polypharmacy Compliance Effect of Aging on The concurrent use of Adherence Body Physiology multiple Efficacy by a patient Safety Problems and challenges for medicine in elderly 4

Physiological changes on aging Decreasing of Efficacy and Safety

Absorption and distribution in the older adults and elimination in the older adults

Source : John Wahlich, Sven Stegemann, Mine Orlu-Gul. Meeting commentary—“Medicines for older adults: Learning from practice to develop patient centric products”. International Journal of Pharmaceutics. 2013;456:251-57.

Polypharmacy Compliance Effect of Aging on The concurrent use of Adherence Body Physiology multiple medications Efficacy by a patient Safety Problems and challenges for medicine in elderly 5

Polypharmacy Decreasing of Compliance, Adherence and Safety

• Polypharmacy, the use of more than 5 different simultaneously, is very common in older adults.

• Most elderly patients have poor memories and get confused.

• They may live alone, or with a partner who is no better. They find it difficult to follow even simple instructions, and the complicated schedules sometimes offered, with many drugs to be taken at different times.

Polypharmacy Compliance Effect of Aging on The concurrent use of Adherence Body Physiology multiple medications Efficacy by a patient Safety Problems and challenges for medicine in elderly 6

Global maker by administration mode

32 % Inhation

8 %

3 % Injectable/Implant 53 % Oral 2 % Ocular 2 % Nasal

The selection and design of patient-centered oral pharmaceutical dosage forms continues to be one of the most significant challenges in the development of medicinal products for elderly populations due to the diverse needs and characteristics of these patient groups Problems and challenges in oral drug delivery technologies 7

• While the oral route is the most convenient method of drug administration, advances in oral A drug delivery technologies have been limited

• One of the reasons for this is the limitations imposed by the unique GI physiology

B • Even small improvements in drug delivery technology can make significant differences in enhancing patient compliance and drug D C bioavailability

(A) Mouth; (B) Stomach; (C) Small intestine; (D) Colon Problems and challenges in oral drug delivery technologies 8

Swallowing considerations (Oral delivery)

• It is estimated that approximately one-third of the population has pill-swallowing difficulties, primarily the elderly populations

• Modification of the dosage form in terms of opening and crushing is considered as a common practice in nursing homes. This has the following consequences:

 Uncoated or large tablets can be difficult to swallow

 Older adults may often resort to crushing, chewing or splitting tablets with the risk of not receiving the full

 The contents of a capsule or a crushed tablet may be mixed with to facilitate swallowing and this may lead to poor or inappropriate dosing or compatibility issues Formulations for ease of administration 9

The factors to consider for elderly oral dosage form design in relation to these 3 criteria

o o Acceptable tolerability Dosage consideration o and safety Patient Safety Risk of mis-dosing Acceptability o Dosage preparation o Ease of 1 2 o Stability o Manufacturing and 3 development complexity Access o Supply chain o Relative cost Formulations for ease of administration 10

Oral disintegrating tablets (ODT)

Orally Disintegrating Tablet (ODT) is a solid dosage form containing drugs that disintegrates rapidly and dissolves in the mouth without taking water within 60 seconds or less. Formulations for ease of administration 11

Oral disintegrating tablets (ODT)

Orally Disintegrating Tablet (ODT) is also called as oro-disperse, mouth dissolving, rapidly disintegrating, fast melt, quick dissolve and freeze dried wafers

ODT Formulations for ease of administration (ODT) 12

Some ODTs in the market and name of patented ODTs technologies, their basis and advantages

Source : Abay FB, Ugurlu T. Patient acceptability, safety and access: Orally Disintegrating Tablets: A Short Review. Journal of Pharmaceutics & Drug Development. 2015;3. Formulations for ease of administration (ODT) 13

Advantages of ODTs Disadvantages of ODTs

• Administration to the patients who cannot • Hygroscopic in nature swallow, such as the elderly, stroke victims, patients who refuse to swallow • Low amount of drug can be incorporated in each dose • Rapid drug therapy intervention • Some time it possesses mouth feeling • Achieve increased bioavailability/rapid absorption through pre-gastric absorption • Highly fragile sometimes of drugs • ODT requires special packaging for • Convenient for administration and patient properly stabilization & safety of stable compliant for disabled, bedridden patients product and for travelers and busy people, who do • Eating and drinking may become restricted not always have access to water Formulations for ease of administration (ODT) 14

Formulation Development of ODTs

Active pharmaceutical ingredient selection

• It should be dissolved in the • It is important for disintegrating oral cavity and absorbed the tablet immediately and also important for masking bitter taste • It shouldn’t have bitter taste • Main excipient groups are • It is in low dose, small to o Diluents moderate molecular weight, o Disintegrants good solubility in water and/or o Flavors and taste masking agents saliva o Sweeteners o Binders • Non-ionized property in pH o Lyoprotectants 5.5-7.4 o Glidants and lubricants Formulations for ease of administration (ODT) 15

• WOWTAB® • ZYDIS® • ORASOLV® • LYOC® • DURASOLV® • QUICKSOLV® ® • ADVATAB ODT • FLASHTAB® Technologies

Floss formation (Cotton Candy Process)

• FLASHDOSE® Formulations for ease of administration (ODT) 16

Source: http://pharmtech.findpharma.com/pharmtech/article/articleDetail.jsp?id=185957 Formulations for ease of administration (ODT) 17

• WOWTAB® • ZYDIS® • ORASOLV® • LYOC® • DURASOLV® • QUICKSOLV® ® • ADVATAB ODT • FLASHTAB® Technologies

Floss formation (Cotton Candy Process)

ZipDose® Technology • FLASHDOSE® (3D printing technique) Formulations for ease of administration (ODT) 18

First, a powdered medicine is spread into a thin layer

Then, a is dropped onto the

This selectively binds the particles together in a thin, porous layer • In 2015, FDA Approves as the First 3D Printed Drug Product by Aprecia Pharmaceuticals This process is repeated a • Pill can be made more porous than typical pills, specific number of times to add more layers based on the rapidly disintegrate dosage, building the product from bottom to top • Support dose loading up to 1,000 mg Formulations for ease of administration (ODT) 19

Challenges in ODTs

Disintegration time and mechanical strength

Taste masking

Sensitivity to environmental conditions

Mouth feel

Cost 20 Other dosage forms and innovations

Swallowing Aid Jelly 21 Other dosage forms and innovations

Swallowing Aid Jelly • Stress on the throat, when swallowing

The above shows that the throat experiences stress When medicines are taken with “jelly”, the throat when medicines are taken with “water”. does not experience any stress.

• Time to reach the stomach.

“Water” takes as much as approx. 18 seconds to “Jelly” takes only approx. 8 seconds to reach the reach the stomach. stomach. Source : https://www.ryukakusan.co.jp/company/en#company_03 Other dosage forms and innovations 22

Swallowing Flavored Spray

A flavored spray product requires the patient to apply the spray to the back of the mouth and tongue before taking tablets or capsules. The spray creates a lubricated surface in the mouth and thus facilitates swallowing. It has been found to be helpful in adolescents with difficulties in swallowing tablets.

Spray Pill Glide in mouth Place tablet or capsule in Swallow with a few sips of (2-4 sprays is sufficient for your mouth. water. most people to coat their tongue and throat). Other dosage forms and innovations 23

Pill Coating

• Easier to swallow: The coating is slippery and saliva stimulating which make tablets easier to swallow.

• Taste good: The coating masks the taste of tablets and replaces it with a pleasant and refreshing taste of citrus. Other dosage forms and innovations 24

Pill Coating Other dosage forms and innovations 25

Polypill Technology

• A polypill is a that is a drug product in pill form (i.e., tablet or capsule) that combines multiple active pharmaceutical ingredients.

• It is commonly manufactured as a fixed-dose combination (FDC) drug product targeting treatment or prevention of chronic disease.

• Polypills can reduce the number of tablets or capsules (generally orally administered) that need to be taken, which in turn may facilitate handling and administration of pharmaceuticals as well as alleviate patient pill- burden.

ADHERANCE ↑ Other dosage forms and innovations 26

Polypill Technology

A list of selected examples of commercially available FDCs in these therapeutic areas

Diabetes HIV/AIDs Cardiovascular diseases Others

Actoplus Met Atripla Simcor Treximet (pioglitazone/metformin: 15/500 mg, (efavirenz/emtricitabine/tenofovir: (niacin ext/simvastatin: 500/20 mg, (sumatriptan/naproxen: 85/500 mg) 15/850 mg) 600/200/300 mg) 750/20 mg, 1000/20 mg) Tylenol with codeine Avandamet Combivir Advicor (/codeine: 300/30 mg, (rosiglitazone/metformin: 2/500 mg, (lamivudine/zidovudine: 150/300 mg) (niacin/lovastatin: 500/20 mg, 750/20 300/60 mg) 4/500 mg, 2/1000 mg) mg, 1000/20 mg, 1000/40 mg) Eqzicom Avandaryl (abacavir/lamivudine: 600/300 mg) Caduet (rosiglitazone/glimepiride: 4/1 mg, (amlodipine/atorvastatin: 2.5/10 mg, 4/2 mg, 4/4 mg, 8/2 mg, 8/4 mg) Kaletra 2.5/40 mg, 5/10 mg, 10/40 mg, 10/80 (lopinavir/ ritonavir: 200/50 mg, mg) Duetact 100/25 mg) Accuretic (pioglitazone/glimepiride: 30/2 Trizivir mg, 30/4 mg) (quinapril/HCTZ: 10/12.5 mg, 20/12.5 (abacavir/lamivudine,zidovudine: mg, 20/25 mg) Glucovance 300/150/300 mg) (glyburide/metformin: 12.5/250 mg, Diovan HCT 2.5/500 mg, 5/500 mg) (valsartan, HCTZ:80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, 320/25 mg)

Source : https://www.americanpharmaceuticalreview.com/Featured-Articles/117118-Manufacturing-Process-Considerations-for-Fixed-Dose-Combination- Drug-Products/ Other dosage forms and innovations 27

Polypill Technology

Disadvantages of the FDC products

1. FDC products reduce dosing flexibility.

2. The adverse drug reactions of the FDC products as more than one drug is administered in a single dosing unit.

3. Pharmacists and physicians can easily overlook the limit of certain drugs in FDCs, because some patients cannot use drug dosing that contained in a tablet for their treatment.

4. The FDC contains multiple drugs in one tablet, sometimes, the tablet size may be too big to swallow for elderly patients. Other dosage forms and innovations 28

Polypill Technology

Formulation development challenges and strategies for FDC oral solid dosage forms

• Physicochemical compatibility among all drugs as well as in FDCs

• Disproportionate drug dose combinations can be very challenging in achieving good content uniformity, especially in weight control of low dose layer of multilayer tablets that contains low dose in the second layer

• The tablet size of the FDC product can become critical in achieving patient acceptance Legal and professional implications 29

• Off-label drug use (opening a capsule or crushing a tablet before administration)

• Lack of consent for administration (patient may be unaware of medication provided in food)

• Cross contamination (one crushing device being used for multiple patients’ medicines, placing patients at risk of adverse effects such as allergic reactions) Conclusions 30

Age-related changes in Pharmacokinetic physiological functionality changes of tissues and organs

Chronic diseases Polypharmacy Compliance Adherence Efficacy Safety The factors to consider for elderly dosage forms design and development Oral dosage forms

Swallowing ODTs, Access difficulty swallowing devices Acceptability 1. Stability 2. Manufacturing and 1. Acceptable tolerability Safety Polypharmacy Polypill technology Development complexity and safety 1. Dosage consideration 3. Supply chain 2. Dosage preparation 2. Risk of mis-dosing 4. Relative cost 3. Ease of ingestion Compliance Adherence Efficacy Safety Thank you

Thanks also go to K. Thanawuth for graphic design and slide preparation