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CONTEMPORARY PHARMACEUTICAL COMPOUNDING
Loyd V. Allen, Jr., Ph.D., R.Ph. Editor-in-Chief International Journal of Pharmaceutical Compounding
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Role of the Compounding Pharmacist
“Individualizing Drug Therapy”
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IJPC First Issue Cover
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OUTLINE Introduction Compounded Pharmaceuticals U.S. Pharmacopeia
FDA and Contemporary Compounding Current USP Compounding Activities New Drug Delivery Systems Summary
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INTRODUCTION History of Pharmacy Compounding in the United States
Reasons for the Growth of Compounding Special Patient Populations Examples of Pharmaceutical Compounding
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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
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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
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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
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..
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MEETING PATIENTS NEEDS
Traditional Dosage Forms New Dosage Forms
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COMPOUNDED DOSAGE FORMS
Oral Solids (Capsules, Tablets) Oral Liquids (Solutions, Susp, Emulsions) Topicals (Creams, Ointments, Gels) Suppositories, Inserts Injectables Many, many others….
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NEWER COMPOUNDED DOSAGE FORMS
Oral Topical Parenteral Specialty
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RAPID-DISSOLVING TABLETS
Active Drug qs Lactose 70 mg PEG mg Actual size depends upon mold. ‘Bridging’ mechanism
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Compounded Gummy Bears
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GUMMY GELS Fentanyl citrate 1.884 mg Chewable gummy gel base 23.35 g
Bentonite mg Aspartame mg Acacia powder mg Citric acid monohydrate 650 mg Flavor concentrate drops
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VETERINARY ORAL PASTE Ingredient #1 #2 #3 #4 PEG 300 65 25 - -
Prop Glycol Molasses Peanut Butter Hydrog Veg Oil
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ORAL PASTES Vancomycin 500 mg Aspartame 200 mg Flavor qs
VANCOMYCIN PASTE (VANC PASTE) • Vancomycin mg Aspartame mg Flavor qs Sodium benzoate 200 mg Methylcellulose 2% Gel qs100 mL
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Compounded Lollipops
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LOLLIPOPS Sodium chloride 46.56 g Potassium chloride 3 g
Calcium lactate g Magnesium citrate g Sodium bicarbonate g Sodium phosphate monobasic 3.84 g Silica gel g Flavor qs PEG qs
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Compounded Popsicles
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POPSICLES NYSTATIN POPSICLES•
Nystatin powder 2,500,000 u Sorbitol 70% solution 20 mL Syrup mL Flavoring (banana, etc.) 5 mL Purified water qs 300 mL
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TROCHES/LOZENGES TESTOSTERONE 2 MG TROCHES • Testosterone 24 mg
Citric acid mg Stevia powder mg Saccharin sodium 30 mg Polyethylene glycol g Citrus flavor qs
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SUBLINGUAL DROPS Testosterone 1 g Saccharin 100 mg Silica gel 200 mg
TESTOSTERONE 10 mg/0.1 mL SL • Testosterone 1 g Saccharin mg Silica gel mg Tangerine oil qs Almond oil qs 10 mL
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Compounded PLO Gels
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TOPICAL PLO GELS Purified water 4 mL
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
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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
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RAPID-PENETRATING TOPICALS
PROGESTERONE 50 mg/mL CLEAR SOLUTION • Progesterone 5 g Benzyl alcohol 20 mL Alcohol, absolute 20 mL DMSO mL Propylene glycol qs 100 mL
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LIPID CRYSTALS CREAM Anthralin 1 g Glyceryl laurate 7 g
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
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Compounding Parenterals
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AMBULATORY PUMP INFUSION SOLUTION
CEFTAZIDIME 20 mg/mL • Ceftazidime g Sterile water for injection qs 0.9% Sodium chloride inj qs125 mL
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Ambulatory Pumps
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INTRATHECAL INJECTION
Fentanyl citrate 314 μg Bupivacaine HCl 100 mg Baclofen μg 0.9% Sodium chloride inj. qs 20 mL
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SPONGE DISKS --------------------------------------------
VANCOMYCIN SPONGE DISKS • Vancomycin HCl 5 mg Sponge (collagen or gelatin) qs
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IMPLANTABLE BEADS --------------------------------------------
TOBRAMYCIN IMPREGNATED POLYMETHYLMETHACYLRATE BEADS • Tobramycin sulfate g Palacos Bone cement 40 g
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IONTOPHORETIC SOLUTION
Dexamethasone sodium phosphate 400 mg Sterile water for injection qs 100 mL
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Iontophoresis Unit
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Iontophoresis Unit
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Iontophoresis Unit
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Inside Iontophoresis Unit
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Size of a Dupel Iontophoresis Unit
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PHONOPHORESIS PREPARATIONS
HYDROCORTISONE 10% PHONOPHORESIS GEL • Hydrocortisone 10 g Carbopol g Propylene glycol 15 mL Methylparaben mg Propyleparaben mg Purified water qs 100 mL Sodium hydroxide 10% Sol qs
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Compounding Oral Inhalation Solutions
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Compounded Oral Inhalation Solutions
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Setting Standards for Drugs in the U.S. since 1906
U.S. PHARMACOPEIA Setting Standards for Drugs in the U.S. since 1906
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Pharmacopeia Development
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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.
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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.?
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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
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Pharmacopoeias of the U.S.
Jan 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
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Pharmacopoeias of the U.S.
Jan 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
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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……..
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USP AND CONTEMPORARY COMPOUNDING
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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
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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;
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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.
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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.
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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
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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
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U.S. PHARMACOPEIA AND FDAMA
Expert Advisory Panel Activities I. General Chapter Group <795> Pharmacy Compounding II. Monograph Group develop monographs for specific preparations
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FDA AND CONTEMPORARY COMPOUNDING
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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”
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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
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FDAMA 97 Passage Pharmacy professional organizations U.S. Congress
Compounding provisions
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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
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FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT
Anticipatory Compounding Physician-Patient-Pharmacist “Triad”
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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)
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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
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FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT
Cannot compound regularly or in inordinate amounts any drug products that are essentially copies of commercially available products
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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)
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FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT
Memorandum of Understanding Distribution of inordinate amounts interstate Handling of complaints
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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.
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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)
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FDA Modernization Act of 1997 Three 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
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IMPLEMENTATION OF FDAMA
Ongoing since 1997 FDA Steering Committee (Internal) FDA Compounding Advisory Committee (External) Work with USP
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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……..
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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
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Current USP Compounding Activities
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USP 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
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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.
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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
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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:
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U.S. PHARMACOPEIA 2001 Recent survey listed over 1000 other preparations need monographs Well over 5,000 different formulations routinely compounded
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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.
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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
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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
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A LOOK INTO THE NEAR FUTURE
New Compounded Drug Delivery Systems (DDS)
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Future Trends Adhesive Site-Specific DDS Antibody-Based DDS
Biocompatible Microsphere DDS Biodegradable Polymers DDS Biologic-Based DDS Electromagnetic/Radiation- Activated DDS
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Future Trends Immunomodulator DDS Implant-Enhanced DDS
Microorganism-Containing Microcapsule DDS Lipid Microcylinders Liposome Enhancements Living-Cell Therapies
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Future Trends Magnetic System DDS Maze-Escape DDS
Monoclonal Antibody DDS Novel Nasal DDS New Osmotic DDS Transmucosal DDS Polymer Drug Complex DDS
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Future Trends Pulsatile DDS Resealed Erythrocyte DDS Respiratory DDS
Self-Assembling Controlled-Release DDS Programmed Skin-Surface DDS
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NANOTECHNOLOGY: The Ultimate Alchemy
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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
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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
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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
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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
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FORECASTS IF a breakthrough to a universal assembler occurs during the next years, an entirely new field of “nanomedicine” and “nanopharmacy” will emerge by 2020.
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NANOMEDICINE Monitoring, repair, construction and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures.
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NANOPHARMACY Preparation and delivery of ultra-small pharmaceuticals, therapeutic substances and delivery systems.
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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.
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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.
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NANOPHARMACY AND NANOPHARMACEUTICALS
New formulations and routes for drug delivery Pharmaceuticals based on an individuals genome
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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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