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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

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Contemporary pharmaceutical compounding
CONTEMPORARY PHARMACEUTICAL COMPOUNDING

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

Editor-in-Chief

International Journal of Pharmaceutical Compounding


Role of the compounding pharmacist
Role of the Compounding Pharmacist

  • “Individualizing Drug Therapy”



Outline
OUTLINE

  • Introduction

  • Compounded Pharmaceuticals

  • U.S. Pharmacopeia

  • FDA and Contemporary Compounding

  • Current USP Compounding Activities

  • New Drug Delivery Systems

  • Summary


Introduction
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
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
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
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
MEETING PATIENTS NEEDS

  • Traditional Dosage Forms

  • New Dosage Forms


Compounded 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
NEWER COMPOUNDED DOSAGE FORMS

  • Oral

  • Topical

  • Parenteral

  • Specialty


Rapid dissolving tablets
RAPID-DISSOLVING TABLETS

  • Active Drugqs

  • Lactose70 mg

  • PEG 335030 mg

  • Actual size depends upon mold.

  • ‘Bridging’ mechanism



Gummy gels
GUMMY GELS

  • Fentanyl citrate1.884 mg

  • Chewable gummy gel base23.35 g

  • Bentonite500 mg

  • Aspartame500 mg

  • Acacia powder500 mg

  • Citric acid monohydrate650 mg

  • Flavor concentrate10-12 drops


Veterinary oral paste
VETERINARY ORAL PASTE

  • Ingredient#1#2#3#4

  • PEG 3006525--

  • PEG 3350352525-

  • Prop Glycol-5025-

  • Molasses--50-

  • Peanut Butter---65

  • Hydrog Veg Oil--35


Oral pastes
ORAL PASTES

  • VANCOMYCIN PASTE

  • (VANC PASTE)•

  • Vancomycin500 mg

  • Aspartame200 mg

  • Flavorqs

  • Sodium benzoate200 mg

  • Methylcellulose 2% Gelqs100 mL



Lollipops
LOLLIPOPS

  • Sodium chloride46.56 g

  • Potassium chloride3 g

  • Calcium lactate6.12 g

  • Magnesium citrate2.04 g

  • Sodium bicarbonate22.44 g

  • Sodium phosphate monobasic3.84 g

  • Silica gel3.6 g

  • Flavorqs

  • PEG 1450qs



Popsicles
POPSICLES

  • NYSTATIN POPSICLES•

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

  • Nystatin powder2,500,000 u

  • Sorbitol 70% solution20 mL

  • Syrup50 mL

  • Flavoring (banana, etc.)5 mL

  • Purified waterqs300 mL


Troches lozenges
TROCHES/LOZENGES

  • TESTOSTERONE 2 MG TROCHES•

  • Testosterone24 mg

  • Citric acid300 mg

  • Stevia powder250 mg

  • Saccharin sodium30 mg

  • Polyethylene glycol 145020 g

  • Citrus flavorqs


Sublingual drops
SUBLINGUAL DROPS

  • TESTOSTERONE 10 mg/0.1 mL SL •

  • Testosterone1 g

  • Saccharin100 mg

  • Silica gel200 mg

  • Tangerine oilqs

  • Almond oilqs10mL



Topical plo gels
TOPICAL PLO GELS

  • PROMETHAZINE HCL 50 mg/mL PLO GEL •

  • -------------------------------------------------Promethazine HCl5 g

  • Purified water4 mL

  • Lecithin:Isopropyl palmitate 22 mL

  • Pluronic F127 30% Gelqs 100 mL


Topical plo gels1
TOPICAL PLO GELS

  • Capsaicin75 mg

  • Ketamine HCl2 g

  • Ketoprofen10 g

  • Ethoxy diglycol10 mL

  • Lecithin:Isopropyl palmitate 22 mL

  • Pluronic F127 30% gelqs 100 mL


Rapid penetrating topicals
RAPID-PENETRATING TOPICALS

  • PROGESTERONE 50 mg/mL CLEAR SOLUTION•

  • Progesterone5 g

  • Benzyl alcohol20 mL

  • Alcohol, absolute20 mL

  • DMSO20 mL

  • Propylene glycolqs100 mL


Lipid crystals cream
LIPID CRYSTALS CREAM

  • ANTHRALIN 1% IN LIPID CRYTALS•

  • Anthralin1 g

  • Glyceryl laurate7 g

  • Glyceryl myristate21 g

  • Citric acid1 g

  • Sodium hydroxide140 mg

  • Purified waterqs100 g




Ambulatory pump infusion solution
AMBULATORY PUMP INFUSION SOLUTION

  • CEFTAZIDIME 20 mg/mL •

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

  • Ceftazidime2.5 g

  • Sterile water for injectionqs

  • 0.9% Sodium chloride injqs125 mL



Intrathecal injection
INTRATHECAL INJECTION

  • Fentanyl citrate314 μg

  • Bupivacaine HCl100 mg

  • Baclofen500 μg

  • 0.9% Sodium chloride inj. qs 20 mL


Sponge disks
SPONGE DISKS

  • VANCOMYCIN SPONGE DISKS•

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

  • Vancomycin HCl5 mg

  • Sponge (collagen or gelatin)qs


Implantable beads
IMPLANTABLE BEADS

  • TOBRAMYCIN IMPREGNATED POLYMETHYLMETHACYLRATE BEADS•

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

  • Tobramycin sulfate1.2 g

  • Palacos Bone cement40 g


Iontophoretic solution
IONTOPHORETIC SOLUTION

  • Dexamethasone sodium phosphate400 mg

  • Sterile water for injectionqs 100 mL







Phonophoresis preparations
PHONOPHORESIS PREPARATIONS

  • HYDROCORTISONE 10% PHONOPHORESIS GEL•

  • Hydrocortisone10 g

  • Carbopol 9401.25 g

  • Propylene glycol15 mL

  • Methylparaben200 mg

  • Propyleparaben100 mg

  • Purified waterqs100 mL

  • Sodium hydroxide 10% Solqs




U s pharmacopeia
U.S. PHARMACOPEIA

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



Pharmacopeia
Pharmacopeia

  • Pharmakondrug

  • poieinto 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
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
Pharmacopoeias of the U.S.

  • 1778Lititz Pharmacopeia

    • First Pharmacopeia in the U.S.

    • Published in Lititz, Pennsylvania for use by the Military Hospital of the U.S. Army

  • 1808Massachusetts Medical Society

    • published a 272 page pharmacopeia with information on 536 drugs and preparations


Pharmacopoeias of the u s1
Pharmacopoeias of the U.S.

  • Jan 1817Dr. 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 s2
Pharmacopoeias of the U.S.

  • Jan 1820First U.S. Pharmacopeial Convention

    • Only 2 districts submitted plans

    • These were reviewed, consolidated and adopted.

  • Dec 1820First U.S. Pharmacopeia was published

    • 272 pages containing 217 drugs/preparations


Usp i
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……..



U s pharmacopeia and fdama
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
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
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
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
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
Expert Advisory Panel

  • Oct 1993First 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 fdama1
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 activities
FDA ACTIVITIES

  • Mid 1990sFDA 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
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
FDAMA 97 Passage

  • Pharmacy professional organizations

  • U.S. Congress

  • FDAMA 97

  • Compounding provisions


Food and drug administration modernization act
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 act1
FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT

  • Anticipatory Compounding

  • Physician-Patient-Pharmacist “Triad”


Food and drug administration modernization act2
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 act3
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 act4
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 act5
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 act6
FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT

  • Memorandum of Understanding

    • Distribution of inordinate amounts interstate

    • Handling of complaints


Food and drug administration modernization act7
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 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 1997 three lists
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
IMPLEMENTATION OF FDAMA

  • Ongoing since 1997

  • FDA Steering Committee (Internal)

  • FDA Compounding Advisory Committee (External)

  • Work with USP


Usp i1
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
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



Usp 2000 2005
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
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 fdama2
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
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 pharmacopeia1
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
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 district1
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
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
A LOOK INTO THE NEAR FUTURE

New Compounded Drug Delivery Systems (DDS)


Future trends
Future Trends

  • Adhesive Site-Specific DDS

  • Antibody-Based DDS

  • Biocompatible Microsphere DDS

  • Biodegradable Polymers DDS

  • Biologic-Based DDS

  • Electromagnetic/Radiation-Activated DDS


Future trends1
Future Trends

  • Immunomodulator DDS

  • Implant-Enhanced DDS

  • Microorganism-Containing Microcapsule DDS

  • Lipid Microcylinders

  • Liposome Enhancements

  • Living-Cell Therapies


Future trends2
Future Trends

  • Magnetic System DDS

  • Maze-Escape DDS

  • Monoclonal Antibody DDS

  • Novel Nasal DDS

  • New Osmotic DDS

  • Transmucosal DDS

  • Polymer Drug Complex DDS


Future trends3
Future Trends

  • Pulsatile DDS

  • Resealed Erythrocyte DDS

  • Respiratory DDS

  • Self-Assembling Controlled-Release DDS

  • Programmed Skin-Surface DDS



Nanotechnology
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
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
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
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


Forecasts1
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
NANOMEDICINE

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


Nanopharmacy
NANOPHARMACY

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


Nanopharmacy and nanopharmaceuticals
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 nanopharmaceuticals1
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 nanopharmaceuticals2
NANOPHARMACY AND NANOPHARMACEUTICALS

  • New formulations and routes for drug delivery

  • Pharmaceuticals based on an individuals genome


Conclusions
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.


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