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Majella Lane, PhD Senior Lecturer in Pharmaceutics, School of Pharmacy University of London Vinod Shah, PhD Chair of the Special Interest Group, Regulatory Science International Pharmaceutical Federation (FIP) and Distinguished Pharmaceutical Scientist and Consultant US Pharmacopeia Michael Lowenborg R&D Manager, Formulation and Process Development DPT Laboratories

Majella E. Lane School of Pharmacy, University of London, U.K


• • •

Largest organ in body
Total surface area 2 m2 Protection from external environment

Maintain stable condition within body
• • • ingress and egress of materials
• water

temperature regulation communication with external stimuli
• heat, pain, touch etc.

Stratum corneum (15mm) viable epidermis (150 mm)

stratum germinativum
blood vessels dermis (2-5 mm) subcutaneous fat (variable)

Sweat glands (2-5 million but only small fraction of area) hair follicles & sebaceous glands (widespread but only 0.1% total area)

}
28 days

14 days

Major barrier is in stratum corneum (15 μm thick)

transcellular intercellular

follicular eccrine
Role of lipids Corneodesmosomes

3 layers above, in reality at least 10, therefore larger effect observed
Rate inversely proportional to length

Tortuosity & permeability : water loss
Forehead Mean area: 822 TEWL: 24.53

Forearm 1 Mean area: 1268 TEWL: 9.05

Lane, Hadgraft 2009

60:25:15 Prevalence of Atopic Eczema
1950 1970 1980 1990 – – – – 5% of children 12% 18% 25%
Prevalence of atopic eczem a 30 25
% of children

20 15 10 5 0 1940

1950

1960

1970 year

1980

1990

2000

Stratum Corneum Epidermis

Keratolytics Antifungals
Antipsoriatics Antiviral Superficial itch and pain Anti-inflammatory - Eczema - Dermatitis - Muscle Pain

Dermis

Anti-Acne

NSAID Diclofenac Ketorolac Ketoprofen Indomethacin Tenoxicam

Flux, J ug/cm2/hr 1.4 13 16 0.7 0.7

IC 50 (COX2), uM 0.03 0.38 0.74 0.16 55.26

EI (COX-2)* 46.7 34.2 21.6 4.4 0.01

Piroxicam

0.08

34.9

0.002

In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs. Cordero JA et al. European Journal of Pharmaceutics and Biopharmaceutics. 2001: 51(2): 135-142.

Summary of formulation types
Alcohol, IPA, Volatile liquids

surfactants

tincture
Lotion o/w Cream o/w Spray solution
glycols polyols water

Cream w/o

fatty acids & esters fatty alcohols

ointment

suspending agents

lotion powder

paste
vegetable, animal, mineral oils, waxes

0.25% hydrocortisone alcohol applied to forearm, corresponds to 1.7% absorbed
(Feldmann and Maibach, J. Invest Derm. 1967 48 181-183)

Where does the active go? What is the role of the excipient(s) How long do excipients remain in the skin?

500 amount permeated (nmol/cm2) 450 400 350 300 250 200 150 100 50 0 OSAL

PG

0

4

8

12

16

20

24

time (hours) 80% active left on or in the skin from PG

Tape stripping cannot discriminate between crystallised drug and drug in solution in skin
1.8 1.6

Artofen
Ibu concentration in SC (M)

1.8 1.6

Brufen

Ibu concentration in SC (M)

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0

1.4 1.2 1.0 0.8 0.6 0.4 0.2

Subject A Subject B Subject C Subject D

Subject A Subject B Subject C Subject D

x/L

0.0 0.0 0.2 0.4 0.6 0.8 1.0

x/L
1.8 1.6

Iprogel
Ibu concentration in SC (M)

1.8 1.6

Optifen

Ibu concentration in SC (M)

1.4 1.2 1.0 0.8 0.6 0.4 0.2

1.4 1.2 1.0 0.8 0.6 0.4 0.2

Subject A Subject B Subject C Subject D

Subject A Subject B Subject C Subject D

0.0 0.0 0.2 0.4 0.6 0.8 1.0

0.0 0.0 0.2 0.4 0.6 0.8 1.0

x/L

x/L

C. Herkenne et al., J. Invest. Derm. 127 (2007) 135-142

Role of excipients - propylene glycol content determines ibuprofen permeation

Hadgraft, et al. Skin Pharmacol. Appl. Skin Physiol. 16 (2003) 137-142.

30

*

25
Protease activity (nU/ug of protein)

20 15 10

5
0 TC IPM Mix PG PGL Control

Human stratum corneum chymotryptic enzyme (KLK7) after24 hr application of IPM to forearm n=6.
Hirata et al. 2010

Computer-aided formulation design Based on Hansen solubility parameters 3D plot of API in Hansen space Distance in Hansen space determines how well API dissolves in solvent

A formulation with the same HSP as stratum corneum will have maximal skin flux

Dermatological Product Design Map
Consumers

Pharmaceutical Quality

Product Design
Formulation Design / Pack Competitors

Pharmacology: potency, specificity Drug and its Delivery

Formulation design Aesthetic Quality

Prototypes & models

Drug design
Drug PK: skin penetration, clearance

Vinod P. Shah, Ph. D. Distinguished Pharmaceutical Scientist and Consultant USP

Two categories of topical drug products

For local effects after topical application – e.g., creams, gels, ointments, lotions, sprays etc. For systemic effects after absorption through the skin into the blood circulation, commonly referred as transdermal delivery systems.

USP General chapters (GC) provide an important backbone in the quality control and performance testing of manufactured drug products.
 

GC below <1000> Mandatory GC above <1000> Informational

Tier 1 – Route of Administration
Delineated by region of the body to which the drug substance is first delivered by the dosage form.

1. 2. 3. 4. 5.

Injectables Gastro-Intestinal (oral) Topical – dermal and transdermal Mucosal Inhalation – Lungs

25

A USP drug product monograph contains tests, analytical procedures and acceptance criteria. Drug products tests are divided into two categories:

(1) those that assess general quality attributes such as identity, strength, purity, content uniformity, viscosity, sterility (for ophthalmic products)
(2) those that assess product performance, i.e., in vitro release of the drug substance from the drug product.

Quality tests assess the integrity of the dosage form,

whereas performance tests assess drug release and
other attributes that relate to in vivo drug performance. Taken together, quality and performance tests assure the identity, strength, quality, and purity of the pharmaceutical dosage form.

27

Pharmaceutical Dosage Forms

<1> Injectables

<2> Oral

<3> Topical

<4> Mucosal

<5> Inhalation

28

 

Topical and Transdermal Drug Products <3>Product Quality Test
◦ ◦ ◦ ◦ Pharmacopeial Forum 35(3) May-June, 2009 USP Workshop: September 14-15, 2009 Revised <3> in 36(6) November-December, 2010 General Chapter <3> in USP 35 – NF 30, Official May 2012 Pharmacopeial Forum 35(3) May – June 2009 USP Workshop: September 14-15, 2009 Deleted based on the comments received. Replaced by <1724>

<725>Product Performance Test
◦ ◦ ◦ ◦

<1724> Semisolid Drug Products – Performance Tests PF 37(5) (Sept – Oct 2011)

◦ Published in USP 35 – NF 30 Official as of May 1, 2012. ◦ Contents
 Introduction  Product Quality Tests for Topically Applied Drug Products  Universal Tests  Specific Tests – Apparent Viscosity, Uniformity in Containers  Specific Tests for Transdermal Delivery Systems
30


  

Specifications: Test procedures and acceptance criteria for New Drug Substances and New Drug Products – as in ICH Guidance Q6A Description Identification Assay Impurities

   


  

Uniformity of dosage units Water content Microbial limits Antimicrobial preservative content Antioxidant content Sterility (ophthalmic drug products) pH Particle size

Apparent Viscosity
◦ Semisolid pharmaceutical dosage forms which are non-Newtonian products exhibit an apparent viscosity ◦ Specifications are based on data obtained during product development and shelf life testing

Essential to evaluate the uniformity of the finished product at the time of batch release and shelf life

◦ Evaluation of physical attributes – visually and/or under microscope ◦ Analytical tube uniformity testing – top, middle, bottom ◦ Within-tube content uniformity ◦ Single dose application container ◦ Multiple dose application container (tube or jar)

Uniformity reflects the quality and integrity of the product

Performance Test – In vitro drug release (VDC) ◦ Identified in FDA’s SUPAC-SS Guidance for post approval changes; to assure product sameness (1977).
 “IVR testing, alone, is not a surrogate test for in vivo BA or BE

Topical (semisolid) drug products
◦ In vitro drug release using the vertical diffusion cell (VDC)
 Why vertical diffusion cell?
 Experience, described in FDA Guidance

 What about other test systems?  <1724> provides information on VDC, Immersion cell Apparatus and Flow-through cell.  USP plans to transfer drug release methodology for semisolid dosage forms using the vertical diffusion cell into chapter <724>.

Vertical Diffusion Cell (VDC) testing To support batch release during product development or in evaluation of SUPAC related changes (not for release testing of all batches). Product performance Tests are not intended as the basis for establishing Bioequivalence between Generic product and Brand name product. Same standards for all products – Brand name as well as Generic

If Q1 and Q2 equivalent ◦ in vitro testing ◦ in vivo testing waived based on in vitro results  If Q1 equivalent but Q2 difference ◦ in vitro testing ◦ in vivo tests if Q2 difference is potentially significant  If Q1 and Q2 differ ◦ in vitro testing ◦ in vivo tests required to demonstrate no formulation effect on absorption

Ref: Advisory Committee meeting for Pharmaceutical Sciences, April 14, 2004. http://www.fda.gov/ohrms/dockets/AC/04/slides/4034S2_12_Lionberger.ppt

Product Quality Tests

  

Peel Adhesion Test Release Liner Peel Test Tack Test Leak Test

Product Performance Test – <724> Drug Release
◦ Apparatus 5 (Paddle over Disk) ◦ Apparatus 6 (Cylinder) ◦ Apparatus 7 (Reciprocating Holder)

Michael Lowenborg
Manager, R&D Formulation and Process Development

DPT Laboratories, LTD

What product dosage forms are developed to deliver drugs topically? What are the Critical Process Parameters (CPP’s) that must be controlled to execute an optimized process for topical drug products? How do we study and test these CPP’s? Examples of manufacturing issues and solutions

 

   


Emulsions* Gels* Ointments* Solutions* Suspensions* Foams

*Definitions in CDER Data Standards Manual.

   


 

Temperature and rates of heating and cooling Mixing methods and speeds Mixing times Flow rates Phase and ingredient order of addition Protection from degradation (UV light and O ) Equipment constraints
2

Temperature is critical:
Too much heat or too much cooling Vs. Not enough heating or not enough cooling

Heating and Cooling rates:
Heating or cooling too quickly Vs. Heating or cooling too slowly

High shear or low shear
 Emulsification typically requires high shear  Mixing of a Gel may require low shear

Obtaining proper mixing speeds for each phase at every batch scale
◦ Development/Feasibility batches

Setting time parameters
◦ Mixing times
 What is the minimum time required to obtain optimal effectiveness  What is the maximum time allowed before product failure

◦ Dissolution times for ingredients
 Preformulation studies

Finding the optimal flow rate for required processing steps
◦ Emulsification – Rate of Oil to Water or Water to Oil ◦ Recirculation through a high shear mixer compared to use of internal high shear mixer ◦ Transfer of product at completion of process and during packaging

Formulations are primarily composed of one or more phases
◦ Emulsions

Most ingredients have an optimal method for incorporation into a formulation
◦ Preservative interactions with some surfactants ◦ Polymers such as micro-crystalline cellulose/sodium carboxymethylcellulose have certain processing requirements

Active Pharmaceutical Ingredients may have physical degradation pathways The manufacturing process must be properly designed to protect from degradation.
◦ Use of Yellow/Amber light ◦ Use of Nitrogen, Argon, or any other inert gas to purge the product of oxygen and protect.
 Retinoic acid compounds are very sensitive to both UV light and oxygen.

Must be able to manufacture using current equipment capabilities
◦ Scale-up path for 1:10 batch size from pilot/clinical supplies to commercial must exist with similar equipment

SUPAC-SS Equipment Addendum provides basis of comparison for design and operating principles of equipment

Batch #

Emulsification Time of Temperature of RPM Emulsification Emulsification

High Shear on cool down

Temperature switch to CMM

CMM Speed

Initial Viscosity (cps)

1 week Viscosity (cps)

1 2 3 4 5 6 7 8 9

High High High High High High High High High

"x" minutes "x" minutes "x" minutes "x" minutes "x" minutes "x" minutes "x" minutes "x" minutes "x" minutes

75 - 80°C 75 - 80°C 75 - 80°C 75 - 80°C 75 - 80°C 75 - 80°C 75 - 80°C 75 - 80°C 75 - 80°C

Low Low Low Medium Medium Medium High High High

Low Medium High Low Medium High Low Medium High

"x" rpm "x" rpm "x" rpm "x" rpm "x" rpm "x" rpm "x" rpm "x" rpm "x" rpm

110,000 100,000 100,000 120,000 70,000 60,000 120,000 100,000 90,000

70,000 80,000 70,000 110,000 60,000 50,000 120,000 70,000 70,000

First time manufacturing at commercial scale 15% discrepancy among uniformity sampling Addition of a recirculation loop during mixing.

Addition of polymers (Carbomer) and gums (Xanthan) must be performed in a very controlled manner if adding directly to batch Several alternate methods of polymer and gum incorporation are:
◦ Eductors such as Tri-Blender® and Quadro Ytron® dispersers ◦ Preparing a slurry of polymer or gum in a medium of low or no solubility

Fatty acid based emulsion, neutralized using a amine With the amine in the water phase upon emulsification, the product immediately gained viscosity As the product cooled, the formulation hit a critical temperature in which it rapidly thinned out and began mixing out of the tank The product was re-sequenced to add the amine post-emulsification

There are many different physical forms that can effectively deliver a drug topically. The methods of processing which we choose to prepare these drug formulations are many and must be controlled as tightly as possible Rigorous experimentation and feasibility batch studies are critical in developing a commercializable manufacturing process.

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