CONTEMPORARY PHARMACEUTICAL COMPOUNDING Loyd V. Allen, Jr., Ph.D., R.Ph. Editor-in-Chief...

CONTEMPORARY PHARMACEUTICAL

COMPOUNDING

Loyd V. Allen, Jr., Ph.D., R.Ph.

Editor-in-Chief

International Journal of Pharmaceutical Compounding

Role of the Compounding Pharmacist

• “Individualizing Drug Therapy”

IJPC First Issue Cover

OUTLINE

• Introduction

• Compounded Pharmaceuticals

• U.S. Pharmacopeia

• FDA and Contemporary Compounding

• Current USP Compounding Activities

• New Drug Delivery Systems

• Summary

INTRODUCTION

• History of Pharmacy Compounding in the United States

• Reasons for the Growth of Compounding

• Special Patient Populations

• Examples of Pharmaceutical Compounding

History of Pharmacy Compounding in the U.S.• In the past, Compounding Was Pharmacy• 1900s gave way to commercially

prepared pharmaceuticals• Many strengths/dosage forms available• Economics changed all that• Limited strengths/dosage forms• “One Size Fits All” approach

Reasons for the Growth of Pharmacy Compounding

• Limited dosage forms• Limited strengths• Home health care• Hospice• Nonavailable drug products/combinations

– Discontinued Drugs– Drug Shortages

• Orphan drugs• Veterinary compounding• New therapeutic approaches• Special Patient Populations

SPECIAL PATIENT POPULATIONS

• Pediatrics• Geriatrics• Bioidentical Hormone Replacement Therapy• Pain Management• Dental Patients• Environmentally & Cosmetic Sensitive• Sports Injuries• Veterinary Compounding

– Small, Large, Herd, Exotic, Companion

..

MEETING PATIENTS NEEDS

• Traditional Dosage Forms

• New Dosage Forms

COMPOUNDED DOSAGE FORMS

Oral Solids (Capsules, Tablets)

Oral Liquids (Solutions, Susp, Emulsions)

Topicals (Creams, Ointments, Gels)

Suppositories, Inserts

Injectables

Many, many others….

NEWER COMPOUNDED DOSAGE FORMS

• Oral

• Topical

• Parenteral

• Specialty

RAPID-DISSOLVING TABLETS

• Active Drug qs

• Lactose 70 mg

• PEG 3350 30 mg

• Actual size depends upon mold.

• ‘Bridging’ mechanism

Compounded Gummy Bears

GUMMY GELS

• Fentanyl citrate 1.884 mg• Chewable gummy gel base 23.35 g• Bentonite 500 mg• Aspartame 500 mg• Acacia powder 500 mg• Citric acid monohydrate 650 mg• Flavor concentrate 10-12 drops

VETERINARY ORAL PASTE

• Ingredient #1 #2 #3 #4

• PEG 300 65 25 - -

• PEG 3350 35 25 25 -

• Prop Glycol - 50 25 -

• Molasses - - 50 -

• Peanut Butter - - - 65

• Hydrog Veg Oil - - 35

ORAL PASTES

• VANCOMYCIN PASTE

• (VANC PASTE) •

• Vancomycin 500 mg

• Aspartame 200 mg

• Flavor qs

• Sodium benzoate 200 mg

• Methylcellulose 2% Gel qs100 mL

Compounded Lollipops

LOLLIPOPS

• Sodium chloride 46.56 g• Potassium chloride 3 g• Calcium lactate 6.12 g• Magnesium citrate 2.04 g• Sodium bicarbonate 22.44 g• Sodium phosphate monobasic 3.84 g• Silica gel 3.6 g• Flavor qs• PEG 1450 qs

Compounded Popsicles

POPSICLES

• NYSTATIN POPSICLES•

• -------------------------------------------

• Nystatin powder2,500,000 u

• Sorbitol 70% solution 20 mL

• Syrup 50 mL

• Flavoring (banana, etc.) 5 mL

• Purified water qs 300 mL

TROCHES/LOZENGES

• TESTOSTERONE 2 MG TROCHES •• Testosterone 24 mg• Citric acid 300 mg• Stevia powder 250 mg• Saccharin sodium 30 mg• Polyethylene glycol 145020 g• Citrus flavor qs

SUBLINGUAL DROPS

• TESTOSTERONE 10 mg/0.1 mL SL •

• Testosterone 1 g

• Saccharin 100 mg

• Silica gel 200 mg

• Tangerine oil qs

• Almond oil qs 10 mL

Compounded PLO Gels

TOPICAL PLO GELS

• PROMETHAZINE HCL 50 mg/mL PLO GEL •

• -------------------------------------------------

Promethazine HCl 5 g

• Purified water 4 mL

• Lecithin:Isopropyl palmitate 22 mL

• Pluronic F127 30% Gel qs 100 mL

TOPICAL PLO GELS

• Capsaicin 75 mg

• Ketamine HCl 2 g

• Ketoprofen 10 g

• Ethoxy diglycol 10 mL

• Lecithin:Isopropyl palmitate 22 mL

• Pluronic F127 30% gel qs 100 mL

RAPID-PENETRATING TOPICALS

• PROGESTERONE 50 mg/mL CLEAR SOLUTION •

• Progesterone 5 g

• Benzyl alcohol 20 mL

• Alcohol, absolute 20 mL

• DMSO 20 mL

• Propylene glycol qs 100 mL

LIPID CRYSTALS CREAM

• ANTHRALIN 1% IN LIPID CRYTALS •• Anthralin 1 g• Glyceryl laurate 7 g• Glyceryl myristate 21 g• Citric acid 1 g• Sodium hydroxide 140 mg• Purified water qs 100 g

...

Compounding Parenterals

AMBULATORY PUMP INFUSION SOLUTION• CEFTAZIDIME 20 mg/mL •

• -------------------------------------------

• Ceftazidime 2.5 g

• Sterile water for injection qs

• 0.9% Sodium chloride inj qs125 mL

Ambulatory Pumps

INTRATHECAL INJECTION

• Fentanyl citrate 314 μg

• Bupivacaine HCl 100 mg

• Baclofen 500 μg

• 0.9% Sodium chloride inj. qs 20 mL

SPONGE DISKS

• VANCOMYCIN SPONGE DISKS •

• --------------------------------------------

• Vancomycin HCl 5 mg

• Sponge (collagen or gelatin) qs

IMPLANTABLE BEADS

• TOBRAMYCIN IMPREGNATED POLYMETHYLMETHACYLRATE BEADS •

• --------------------------------------------

• Tobramycin sulfate 1.2 g

• Palacos Bone cement 40 g

IONTOPHORETIC SOLUTION

• Dexamethasone sodium phosphate 400 mg

• Sterile water for injection qs 100 mL

Iontophoresis Unit

Iontophoresis Unit

Iontophoresis Unit

Inside Iontophoresis Unit

Size of a Dupel Iontophoresis Unit

PHONOPHORESIS PREPARATIONS

• HYDROCORTISONE 10% PHONOPHORESIS GEL •

• Hydrocortisone 10 g• Carbopol 940 1.25 g• Propylene glycol 15 mL• Methylparaben 200 mg• Propyleparaben 100 mg• Purified water qs 100 mL• Sodium hydroxide 10% Sol qs

Compounding Oral Inhalation Solutions

Compounded Oral Inhalation Solutions

U.S. PHARMACOPEIA

Setting Standards for Drugs in the U.S. since 1906

Pharmacopeia Development

Pharmacopeia

• Pharmakon drug• poiein to make• Used together in Pharmacopeia means

any recipe or formula or other standards required to make or prepare a drug.

• 1580 Bergamo, Italy…..first used in connection with a local book of drug standards.

Pharmacopeias

• Local, City and National Pharmacopeias in Europe

• The London, Edinburgh and Dublin Pharmacopeias were official until 1864

• Replaced by the British Pharmacopoeia

• How about in the U.S.?

Pharmacopoeias of the U.S.

• 1778 Lititz Pharmacopeia– First Pharmacopeia in the U.S.– Published in Lititz, Pennsylvania for use by

the Military Hospital of the U.S. Army

• 1808 Massachusetts Medical Society– published a 272 page pharmacopeia with

information on 536 drugs and preparations

Pharmacopoeias of the U.S.

• Jan 1817 Dr. Lyman Spalding• Submitted a plan• Medical Society of the County of New York• Creation of a national pharmacopeia• ----• Divided U.S. into 4 geographical districts• Medical schools and societies were to develop a• pharmacopeia and appoint delegates to a

general convention to be held in Washington, DC

Pharmacopoeias of the U.S.

• Jan 1820 First U.S. Pharmacopeial Convention

– Only 2 districts submitted plans

– These were reviewed, consolidated and adopted.

• Dec 1820 First U.S. Pharmacopeia was published

– 272 pages containing 217 drugs/preparations

USP I

• Preface:(in part)• It is the object of the Pharmacopeia to select

from among substances which possess medicinal power, those, the utility of which is most fully established and best understood; and to form from them preparations and compositions, in which their powers may be exerted to the greatest advantage……..

USP AND CONTEMPORARY COMPOUNDING

U.S. PHARMACOPEIA AND FDAMA

• 1985 USP Convention– Resolution 4

• Compounding Information in the USP

– Resolution 5• Standards for Repackaged and Compounded

Parenterals

• 1990 USP Convention– Established the Expert Advisory Panel on

Pharmacy Compounding

Resolution #4

• Be it resolved that the COR examine the desirability and feasibility of developing, with a view to inclusion in the USP, the following types of information:

• 1. The short-term stability of drugs when dissolved in common diluents and stored in common standardized containers and/or delivery systems at room, refrigerator and freezer temperatures;

Resolution #4 (cont’d)

• 2. pKa and minimum solubility of drugs in common diluents; and

• 3. pH, osmolality and osmolarity of reconstituted injectables and liquid dosage forms.

Resolution #5

• Be it resolved that the COR be charged with the responsibility for providing standards and test methods; specifications for packaging, labeling, and storage; guidelines for appropriate documentation; and, where necessary, procedures for compounding parenteral preparations.

PSD Subcommittee

• Expert Advisory Panel on Pharmacy Compounding was formed to advise the PSD Subcommittee

• Also, the Review Panel on Pharmacy Compounding Practices was formed to assist the Expert Advisory Panel by providing immediate expert review on materials produced by the Panel

Expert Advisory Panel

• Oct 1993 First meeting

• Organized into 2 groups– General Chapter Group

• to prepare a general informational chapter on compounding

– Monograph Group• develop monographs for specific preparations

– those widely compounded but not available commercially

U.S. PHARMACOPEIA AND FDAMA

• 1993-2000 Expert Advisory Panel Activities

• I. General Chapter Group– <795> Pharmacy Compounding

• II. Monograph Group– develop monographs for specific

preparations

FDA AND CONTEMPORARY COMPOUNDING

FDA ACTIVITIES

• Mid 1990s FDA began investigating a number of pharmacies that were compounding large quantities of selected drug products.

• Manufacturing under the guise of compounding

• “New Drugs”

Food and Drug Administration Activities

• FDA considered compounded preparations as “New Drugs” and subject to the New Drug Provisions– IND– NDA– Safety– Efficacy

• Enforcement Activities

FDAMA 97 Passage

• Pharmacy professional organizations

• U.S. Congress

• FDAMA 97

• Compounding provisions

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT

• New Drug Requirements– shall not apply to a drug product if the drug

product is compounded for an individual patient based on the unsolicited receipt of a valid prescription order…..if the compounding is by:

– a licensed pharmacist– a licensed physician

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT

• Anticipatory Compounding

• Physician-Patient-Pharmacist “Triad”

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT

• Compounding must be done using the following sources of ingredients:

• USP/NF monographs

• Commercial products

• Bulk Drug Substances List (being developed)

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT

• Compounding cannot be done from:

• Drugs on the “Negative List”– drugs that have been withdrawn due to

safety or efficacy reasons– List was developed

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT• Cannot compound regularly or in

inordinate amounts any drug products that are essentially copies of commercially available products

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT• Cannot compound a drug product that

“presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety and effectiveness of that drug product”. (list)

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT• Memorandum of Understanding

– Distribution of inordinate amounts interstate

– Handling of complaints

FOOD AND DRUG ADMINISTRATION

MODERNIZATION ACT

• Advertising– The pharmacy, pharmacist or physician

cannot advertise or promote the compounding of any particular drug, class of drug, or type of drug.

FDA Modernization Act of 1997

• FDA Advisory Committee on Compounding

• Function: to advise the FDA in the areas of bulk drug substances, safety and efficacy and difficult-to-compound products.

• FDA Pharmacy Compounding Steering Committee (Internal to FDA)

FDA Modernization Act of 1997Three Lists

• Products not to be compounded because they were withdrawn from the market based on safety and efficacy concerns

• Bulk drug substances of proven quality accepted for use in pharmacy compounding

• Difficult-to-compound products

IMPLEMENTATION OF FDAMA

• Ongoing since 1997

• FDA Steering Committee (Internal)

• FDA Compounding Advisory Committee (External)

• Work with USP

USP I

• Preface:(in part)• It is the object of the Pharmacopeia to select

from among substances which possess medicinal power, those, the utility of which is most fully established and best understood; and to form from them preparations and compositions, in which their powers may be exerted to the greatest advantage……..

FDAMA IMPLEMENTATION AND THE USP

• <1161>Pharmacy Compounding Practices became

<795 Pharmacy Compounding• Monographs of accepted bulk drug substances

are being developed• <1206> Sterile Preparations-Pharmacy

Practices has been recommended as guidelines for sterile preparations compounding…being renumbered as <797>

• New chapters being written

Current USP Compounding Activities

USP 2000-2005

• New structure from Committee of Revision to Expert Committees

• Compounding Pharmacy Expert Committee– General Chapters, incl <795>– Nonsterile preparation monographs

• Parenteral Products--Compounding and Preparation Expert Committee– General Chapters, incl <1206>– Sterile preparation monographs

USP Convention 2000

• Resolution• Continue to develop and institute, in

collaboration with other organizations as appropriate, specific initiatives focused on the development of appropriate compounding guidelines and monographs for non-commercially available, but commonly prescribed, medicines and dosage forms for use in special populations, notably neonatal, pediatric, geriatric, and terminally ill patients.

U.S. PHARMACOPEIA AND FDAMA

• Activities to date:• 15 official compounding monographs• 8 more stability studies underway• 6 formulas being processed through PF• 2 official chapters and 2 additional

chapters in process:– Pharmacy Calculations– Good Compounding Practices

CURRENT ACTIVITIES OF PHARMACY COMPOUNDING

EXPERT COMMITTEE

• Survey of compounding pharmacists in hospitals, community pharmacies and long-term care facilities (August 2000)

• List of over 150 preparations, mostly pediatric, that need to be considered.

• 2000 Resolution:

U.S. PHARMACOPEIA

• 2001

• Recent survey listed over 1000 other preparations need monographs

• Well over 5,000 different formulations routinely compounded

FDAMA and the 9th District

• Early 2001– the Ninth Circuit ruled that the FDAMA

section dealing with compounding was invalid in the 9th Circuit District (NV, CA, WA, OR, MT, ID, AZ, AK, HI) but still in effect in the rest of the US.

FDAMA and the 9th District

• April 29, 2002

• U.S. Supreme Court ruled the advertising restrictions unconstitutional and the section not severable.

• Entire 503a now is thrown out and nonenforceable

SUMMARY

• Pharmacy compounding is now legally recognized by the FDA, the Supreme Court, Congress, etc. as a necessary component of quality health care

• Emphasis on quality of compounding is increasing with documentation of quality being recommended and required

• Clinical pharmacy becomes more of a reality with compounding pharmacy

A LOOK INTO THE NEAR FUTURE

New Compounded Drug Delivery Systems (DDS)

Future Trends

• Adhesive Site-Specific DDS

• Antibody-Based DDS

• Biocompatible Microsphere DDS

• Biodegradable Polymers DDS

• Biologic-Based DDS

• Electromagnetic/Radiation-Activated DDS

Future Trends

• Immunomodulator DDS

• Implant-Enhanced DDS

• Microorganism-Containing Microcapsule DDS

• Lipid Microcylinders

• Liposome Enhancements

• Living-Cell Therapies

Future Trends

• Magnetic System DDS

• Maze-Escape DDS

• Monoclonal Antibody DDS

• Novel Nasal DDS

• New Osmotic DDS

• Transmucosal DDS

• Polymer Drug Complex DDS

Future Trends

• Pulsatile DDS

• Resealed Erythrocyte DDS

• Respiratory DDS

• Self-Assembling Controlled-Release DDS

• Programmed Skin-Surface DDS

NANOTECHNOLOGY: The Ultimate Alchemy

NANOTECHNOLOGY

• The art and science of building molecular structures so they are sufficiently large and complex to function as machines or devices

• Atomically precise, functional machine systems developed on the scale of the nanometer

• Builds objects atom by atom, molecule by molecule

POTENTIAL PRODUCTS

• Activated Pharmaceuticals (Magic Bullets)

• Cell-herding machines to stimulate rapid wound healing

• Nanosurgeons to repair damaged cellular parts

• Nanocruisers to attack viruses and bacteria

FORECASTS: 2-5 YEARS

• Inexpensive handheld biosensors built on the basis of nanoscale ion channel switches

• Simple detection of diseases, within minutes, from a small sample of saliva or blood

FORECASTS

• DNA vaccines will begin to be available in the next 5-10 years

• Superior and safer than traditional vaccines• Ability to directly mimic body components

and can “rebuild” worn, defective, damaged, diseased cells/tissues/organs

• Blood products, artificial skin products, bioartificial organs, blood vessels

FORECASTS

• IF a breakthrough to a universal assembler occurs during the next 10-15 years, an entirely new field of “nanomedicine” and “nanopharmacy” will emerge by 2020.

NANOMEDICINE

• Monitoring, repair, construction and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures.

NANOPHARMACY

Preparation and delivery of ultra-small pharmaceuticals, therapeutic substances and delivery systems.

NANOPHARMACY AND NANOPHARMACEUTICALS• Motors consisting of, for example,

ATPase molecules with a metallic substrate and a chemical “propeller” on the other. As the ATP breaks down, the biomotor moves.

• This motor may be able to compound tiny quantities of drugs and pump them directly to the target tissues.

NANOPHARMACY AND NANOPHARMACEUTICALS

• The uses of biomolecular motors could be used for sensing or placing in living cells as a pharmacy to deliver medicine when required.

NANOPHARMACY AND NANOPHARMACEUTICALS

• New formulations and routes for drug delivery

• Pharmaceuticals based on an individuals genome

CONCLUSIONS

• We must live in today and prepare for tomorrow

• Compounding pharmacists roles in “individualizing drug therapy” is preparing the foundation for the “NANOPHARMACY” of tomorrow.