`
` Parenteral Formulations of Small Molecules Therapeutics
`Part I
`Marketed in the United States (1999)
`Robert G. Strickley
`
`
`
` PDA J Pharm Sci and Tech
`
`1999
`
`53,
`
` 324-349
`
`MYLAN INST. EXHIBIT 1088 PAGE 1
`
`--
`

`

`REVIEW ARTICLE
`
`Parenteral Formulations of Small Molecules Therapeutics Marketed in
`the United States (1999)—Part I
`
`ROBERT G. STRICKLEY
`
`Axys Pharmaceuticals, Inc., South San Francisco, California
`
`Overview
`
`Introduction
`
`The chemical structure of a molecule determines the
`potential successful formulation approaches available to the
`parenteral scientist. However, there is no comprehensive
`listing of parenteral products with the chemical structure and
`formulation. A review of domestically marketed injectable
`product formulations of small molecule therapeutics is
`presented herein with the intent of compiling a comprehen-
`sive source of public information for the formulation
`scientist. The compilation lists the drug name, marketed
`name, chemical structure of the drug, marketed injectable
`formulation, preadministration preparation, route of admin-
`istration, company and the clinical indication (1–7).
`One purpose of this compilation is to assist the formula-
`tion scientist in being able to look at a drug’s chemical
`structure and then be able to determine possible formulation
`approaches. This compilation will also be useful for those
`interested in knowing what additives are currently used in
`injectable products and at what concentrations they are
`administered in practice. This compilation only focuses on
`marketed formulations and does not delve into the subject of
`preclinical or drug discovery formulations associated with
`early-stages pharmacokinetics or proof-of-concept pharma-
`codynamics, where the formulation scientist is not bound by
`regulatory constraints.
`There are a few published reviews on parenteral formula-
`tions (8) and in an excellent review article (9) Lilly
`scientists, Sweetana and Akers, discuss the various formula-
`tion approaches with detailed tables of examples. In a
`compendium of excipients for parenteral formulations (10)
`Genentech scientists, Powell, Nguyen and Baloian, list the
`acceptable excipients as well as their percent’s within the
`formulations, route of administration and pH. The compila-
`tion herein is an additional resource to the parenteral
`scientist by presenting the chemical structure and the
`formulation in a side-by-side fashion. An examination of
`this compilation reveals many examples of injectable formu-
`lation techniques to improve solubility or provide a sus-
`tained release. The next few sections highlight various
`formulation approaches with specific examples and tables,
`as well as general discussions of parenteral formulations.
`
`The word ‘‘parenteral’’ is Latin for ‘‘other than intestine,’’
`thus by definition the parenteral sciences not only includes
`injectable products but also transdermal, pulmonary, nasal,
`ophthalmic, and buccal routes of administration. However,
`in practice, parenteral usually refers to injectable products.
`Recently we have seen the commercialization of previously
`academic pursuits such as controlled-release formulations
`using microspheres, liposomes and polymeric gels, longer in
`vivo circulating times using PEGylated liposomes (also
`known as stealth liposomes) and PEGylated proteins, and
`new excipients such as cyclodextrin derivatives used as
`complexing agents for increasing water solubility of poorly
`soluble drugs. We have also seen the commercialization of
`injection devices such as prefilled syringes, dual chamber
`syringes containing solid drug and a liquid for reconstitu-
`tion, and will likely soon see needle-free injectors and
`pocket-size infusion pumps.
`
`Injectable Formulations
`
`Two key aspects of any successful injectable formulation
`are: 1) to achieve the required drug concentration, and 2) the
`drug must be chemically and physically stable in order to
`have a sufficient shelf-life, which is generally considered to
`be the time for 10% degradation. The ideal
`injectable
`formulation, from an in vivo tolerability point-of-view, is
`isotonic with physiological fluids and a neutral pH (i.e.,
`PBS: phosphate buffered saline, 0.01M sodium phosphate
`with 0.135M NaCl and 0.003M KCl, pH 7.4). However, in
`many instances the drug does not have sufficient water
`solubility at pH 7.4, and thus the formulation scientist must
`use a wide variety of solubilization techniques. If stability is
`insufficient to provide a two-year shelf-life, then the formu-
`lation scientist must either change the solution conditions to
`achieve both the solubility and stability requirements or
`develop a lyophilized product. This manuscript focuses on
`solubilization techniques for small molecules, and will not
`focus on stability or stabilization techniques.
`
`I. Solubilization Techniques
`
`1. pH Adjustment and Salts
`
`Editor’s Note: This review article on Injectable Products is being pub-
`lished in several parts. The next installment(s) will appear in subsequent
`issues of the Journal.
`Correspondence address: 180 Kimball Way, South San Francisco, CA
`94080.
`
`If the drug molecule is ionizable, then pH adjustment can
`be utilized to increase water solubility since the ionized
`molecular species has higher water solubility than its neutral
`species. Indeed, the most common solubilization technique
`is pH adjustment and weak acids are normally formulated at
`
`324
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 2
`
`

`

`pH . 5 (Table I), weak bases at pH , 7 (Table II).
`Zwitterionic molecules have multiple ionizable groups and
`can be either cationic, anionic or neutral (positive and
`negative charges cancel each other, for an overall net neutral
`molecule) and are usually formulated at a pH in which the
`drug is ionic (Table III). For example, both ciprofloxacin and
`sufentanil have a carboxylic acid and an amine, but are
`formulated as the cation at pH , 7. On the other hand, both
`ampicillin and cephapirin have a carboxylic acid and an
`amine or pyridine, but are formulated as the anion at pH . 5.
`
`The range in pH is quite broad and is between pH 2–12,
`and thus any molecule with a pKa between 3–11 can be
`potentially solubilized by pH adjustment. However, when
`using extremes in pH, care must be taken to minimize buffer
`capacity in order for the formulation to be in vivo compat-
`ible. When given intravenously, the formulation components
`are quickly diluted by the flow of blood and neutralized by
`the buffer capacity of blood. When given via intramuscular
`injection, the rate of dilution is reduced but rapid enough to
`still be able to inject in the range pH , 3–11. However,
`
`Vol. 53, No. 6 / November–December 1999
`
`325
`
`MYLAN INST. EXHIBIT 1088 PAGE 3
`
`

`

`when given subcutaneously the rate of dilution is reduced
`further with more potential for irritation at the injection site
`and thus the range is pH 3–6. For example, chlordiazepoxide
`is administered intravenously or intramuscularly and formu-
`lated at pH 3 with 20% propylene glycol and 4% TWEEN
`20. Phenytoin sodium is administered either intravenously
`or intramuscularly and formulated at pH 10–12 with 40%
`propylene glycol and 10% ethanol. Subcutaneous formula-
`
`tions are slightly acidic such as methadone at pH 3–6, and
`levorphanol at pH 4.3.
`Water-soluble salt forms (i.e., sodium salts of weak acids,
`or hydrochloride salts of weak bases) utilize the same
`principle of ionization, and are often the marketed form of
`the drug (Table IV). The most common cationic counterion
`is sodium which accounts for . 90% of the cations, and
`there are three meglumine salts, while only one salt each of
`
`326
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 4
`
`

`

`the cations potassium, tromethamine and calcium. There are
`many more anionic counterions and the most common is the
`hydrochloride salt followed by sulfate, mesylate, maleate
`and tartrate. When a salt is dissolved in non-buffered water,
`the resulting pH is generally ,2 pKa units away from the
`pKa, because protons are either added to (salt of a weak
`
`base) or taken away from water (salt of a weak acid). For
`example, gancyclovir is a weak acid with pKa2 5 9.4 and
`dissolving its sodium salt in water results in pH , 11.
`In order to maintain a desirable pH range, many formula-
`tions that utilize pH adjustment also use buffers to control
`pH (Table V). Buffers span the range of pH 2.5–11 and
`
`Vol. 53, No. 6 / November–December 1999
`
`327
`
`MYLAN INST. EXHIBIT 1088 PAGE 5
`
`

`

`include citrates, acetates, histidine, phosphate, tris(hydroxy-
`methyl)aminomethane, and carbonates. The buffer concen-
`tration must be high enough to maintain the desired pH, but
`must be balanced by in vivo tolerability considerations, and
`thus it is good practice to minimize buffer capacity of the
`administered formulation.
`
`2. Mixed Organic/Aqueous Formulations
`
`If pH adjustment alone is insufficient in achieving the
`desired solution concentration, then a combination of pH
`and organic solvent(s) is often employed. If the drug
`molecule is not ionizable then pH has no effect on solubility,
`
`328
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 6
`
`

`

`but solubility enhancement can often be accomplished by a
`combination of aqueous and organic solvents (i.e., a cosol-
`vent). The currently used organic solvents used in mixed
`organic/aqueous formulations are propylene glycol, ethanol,
`polyethylene glycol 300 or 400, cremophor EL, TWEEN 80,
`sorbitol, glycerin and dimethylacetamide (DMA) (Table VI).
`As with any formulation additive, the concentration that is
`administered should be minimized to avoid any in vivo
`complications such as local irritation or precipitation at the
`injection site. Many cosolvent formulations are marketed
`using rather high concentrations of organic solvent, and are
`usually but not always diluted prior to injection. For
`example, propylene glycol
`is 50% of the fenoldopam
`marketed formulation, but is diluted to ,1% for IV infusion.
`However, propylene glycol is ,70% of the oxytetracycline
`marketed formulation and is injected intramuscularly with-
`out dilution.
`Similar to formulations using pH adjustment, of the three
`main routes of administration (i.e., intravenous, intramuscu-
`lar and subcutaneous), the subcutaneous route has the most
`constraints when using cosolvent due to the reduced volume
`flow away from the injection site compared to intravenous
`and intramuscular. As a result, only three cosolvent products
`are administered subcutaneously and the amount of organic
`solvent is limited to ethanol 6% (dihydroergotamine), glyc-
`erin 32% (epinephrine), and propylene glycol 10% (hydrala-
`zine). Whereas, the intravenous bolus route can use ethanol
`up to 20% (paricalcitrol), PEG 300 up to 50% (methocarba-
`mil), and propylene glycol up to 68% (phenobarbitol). The
`intramuscular route has similar in vivo constraints to the
`intravenous route, but can tolerate even more organic
`solvent (see section I.3, Totally Organic Solution Formula-
`tions).
`Surfactant formulations seem to be on the increase with
`excipients Cremophor EL and TWEEN 80 leading the way.
`These formulations, in general, are supersaturated upon
`dilution and must be used soon after dilution into IV
`compatible fluids. For example, cremophor EL is 11% of the
`miconazole marketed formulation, but is diluted to 1% for
`IV infusion. Also, TWEEN 80 is 10% of the amiodarone
`marketed formulation, but is diluted to 0.4% for IV infusion.
`However, cremophor EL at 10% or TWEEN 80 at 25% can
`be administered by IV infusion (see section I.3).
`
`3. Totally Organic Solution Formulations
`
`Molecules that are non-ionizable (have pKa , 2, or
`pKa . 11) and non-polar are water insoluble with no effect
`of pH on solubility, and thus are the most challenging for the
`formulation scientist. These water-insoluble molecules can
`be formulated in 100% organic solvent, which is then
`usually but not always diluted prior to administration (Table
`VII). For example, busulfan is marketed in 33% dimethyl-
`acetamide and 67% PEG 400, but is diluted 10-fold prior to
`IV infusion. The lorazepam marketed formulation is 80%
`propylene glycol, 18% ethanol and 2% benzyl alcohol, but is
`diluted 2-fold for IV bolus injection, but not diluted for
`intramuscular injection. Paclitaxel is marketed with 51%
`cremophor EL and 49% ethanol, but is diluted 5- to 20-fold
`for IV infusion. Docetaxel is marketed in 100% TWEEN 80,
`but is diluted to 25% for IV infusion.
`
`4. Cyclodextrins
`
`Some molecules can be solubilized by forming an inclu-
`sion complex with a cyclodextrin. Cyclodextrins have a
`hydrophilic exterior and a hydrophobic interior core of
`specific dimensions, and thus molecules with a non-polar,
`aromatic or heterocyclic ring can potentially fit inside the
`core. Increased water solubility through molecular complex-
`ation with cyclodextrins has advantages over the cosolvent
`approach since upon dilution a 1:1 complex between cyclo-
`dextrin and drug will not precipitate, but a drug dissolved in
`a cosolvent often precipitates upon dilution. Two cyclodex-
`trins have been accepted for human injectable use with the
`approval of alprostidol alfadex and itraconazole. Alprostidol
`alfadex is marketed as a lyophilized powder with a-cyclodex-
`trin and is administered intracavernosally. Itraconazole was
`approved in April 1999 as a solution with 40% hydroxypro-
`pyl-b-cyclodextrin and is administered by intravenous infu-
`sion after a 2-fold dilution with saline (6). The next
`cyclodextrin likely to be approved is sulfobutylether-b-
`cyclodextrin, which is in the clinical formulation of ziprasi-
`done for intramuscular injection (11).
`
`5. Emulsions
`
`Oil-soluble molecules are generally neutral uncharged
`and non-polar molecules, but can be formulated for intrave-
`nous administration by the use an oil-in-water emulsion.
`Emulsions can solubilize oil-soluble drugs since the drug
`partitions into the oil phase. A typical emulsion is composed
`of water with 10–20% soybean and/or safflower oil, 2%
`glycerol, 1% egg lecithin and pH 7–8, and is injected by
`either IV bolus or IV infusion. The only marketed emulsion
`formulation is propofol, which is in a typical emulsion
`composed of 10% soybean oil containing 10 mg/mL drug.
`The total parenteral nutrition (TPN) formulations are the
`lipid emulsions Intralipid and Liposyn, which are adminis-
`tered by intravenous infusion as nutritional supplements.
`
`6. Prodrugs
`
`Molecules which contain an alcohol, phenol, carboxylic
`acid, amine, hydantoin functional group can potentially be
`derivatized as a prodrug. Once the prodrug is administered
`in vivo, the promoiety is hydrolyzed by either esterases or
`phosphatases releasing the parent drug. Although prodrugs
`are normally associated with orally administered products
`for better oral bioavailability, many parenteral products are
`prodrugs (Table VIII).
`The versatility of the prodrug approach is demonstrated
`with prodrugs that in design either increase or decrease
`water solubility. A water-soluble prodrug has an electroni-
`cally charged promoiety, while a water insoluble prodrug
`has been derivatized to be a neutral molecule (see section
`II.7b). Recently, a few water-soluble phosphate ester pro-
`drugs have been developed and marketed in order to replace
`the original formulations that contain high concentrations of
`organic solvent. The phenol-containing etoposide (etoposide
`phosphate) is derivatized as a water-soluble phosphate ester.
`Water-soluble phosphate esters are also prodrugs for alcohol-
`containing betamethasone, clindamycin, dexamethasone,
`fludarabine, hydrocortisone, and prednisolone. The hydan-
`
`Vol. 53, No. 6 / November–December 1999
`
`329
`
`MYLAN INST. EXHIBIT 1088 PAGE 7
`
`

`

`toin-containing phenytoin prodrug (fosphenytoin) is deriva-
`tized in a unique fashion as a water-soluble hydroxymethyl
`phosphate ester, which after in vivo enzymatic phosphate
`ester cleavage, the resulting hydroxymethyl intermediate
`quickly dissociates to phenytoin and formaldehyde (12).
`Other water solubilizing prodrug approaches are a succinate
`ester of the alcohol methylprednisolone, and a piperidine
`carbamate in irinotecan a prodrug for a phenol drug.
`Prodrugs can also be used for stability reasons. For
`example, alatrofloxacin is the alanine-alanine dipeptide
`prodrug for the primary amine trovafloxacin which is
`
`unstable in solution. The prodrug alatrofloxacin is marketed
`as a solution at pH 3.4–4.3.
`
`II. Sustained-Release Techniques
`
`The research in controlled release during the 1970s has in
`the 1990s become a commercial realization with the ap-
`proval of liposomal, polymeric microsphere and polymeric
`gel formulations. However, traditional approaches are still in
`use such as suspensions, prodrugs and oil depots.
`
`330
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 8
`
`

`

`7a. Suspension Formulations
`
`Suspension formulations provide a sustained-release de-
`pot at the injection site that releases prodrug by dissolution.
`Suspensions used for sustained delivery are composed of a
`drug dispersion in either an aqueous or oil-based suspension
`(Table IX).
`Almost all suspensions are administered intramuscularly,
`intralesionally or intra-articularly. The only subcutaneously
`administered suspension of a small molecule (many proteins
`are administered subcutaneous, e.g., human insulin) is
`epinephrine, which is administered every 6 hours and is
`formulated in 32% glycerin providing both rapid (drug in
`solution) and sustained activity (crystalline drug in suspen-
`sion). The only sesame oil suspension is the anti-rheumatic
`
`aurothioglucose, which is administered intramuscularly ev-
`ery 1–4 weeks.
`
`7b. Prodrugs in Suspension Formulations
`
`Most of the other suspension formulations are aqueous-
`based and contain water-insoluble prodrugs which are
`lipophilic esters of alcohols. For example, hydrocortisone
`acetate and dexamethasone acetate are acetate esters of their
`alcohol-containing parent drug, and are administered intra-
`muscularly, intralesionally or intra-articularly once every
`1–3 weeks. The contraceptive medroxyprogesterone acetate
`is administered intramuscularly once every 13 weeks. Aque-
`ous-based suspensions typically contain TWEEN 80 at
`,0.75–4 mg/mL (0.4%) along with a suspending agent such
`
`Vol. 53, No. 6 / November–December 1999
`
`331
`
`MYLAN INST. EXHIBIT 1088 PAGE 9
`
`

`

`332
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 10
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`333
`
`MYLAN INST. EXHIBIT 1088 PAGE 11
`
`

`

`334
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 12
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`335
`
`MYLAN INST. EXHIBIT 1088 PAGE 13
`
`

`

`336
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 14
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`337
`
`MYLAN INST. EXHIBIT 1088 PAGE 15
`
`

`

`338
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 16
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`339
`
`MYLAN INST. EXHIBIT 1088 PAGE 17
`
`

`

`340
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 18
`
`

`

`as sodium carboxymethylcellulose at ,5 mg/mL (i.e.,
`dexamethasone acetate), PEG 3350 at 30 mg/mL (i.e.,
`methylprednisolone acetate) or sorbitol at 50% (i.e., triam-
`cinolone hexacetonide).
`
`8. Depots
`
`Sesame oil formulations of oil-soluble drugs provide a
`sustained-release depot at the injection site that releases drug
`by diffusion-like uptake of oil. For example, the prodrugs
`haloperidol deconate and testosterone enanthate are formu-
`lated in 100% sesame oil and administered intramuscularly
`once a month.
`
`9. Liposomes
`
`An exciting new era of the parenteral sciences began with
`the approval of liposomal products. A liposome is a lipid
`bilayer and an aqueous-based multilayered spherical drug
`delivery system where the drug is encapsulated inside the
`liposome, and is released as the liposome is eroded in vivo. A
`typical liposome formulation contains water with lipid at ,5
`mg/mL, an isotonicifier, a pH 5–8 buffer, and with or without
`cholesterol. These liposomes are injected either by IV
`infusion or intrathecally. Table X lists the six currently
`available liposomal products of the four drugs amphotericin
`B (3 liposome formulations), cytarabine, daunorubicin and
`doxorubicin. The amphotericin B liposomal products are
`administered by IV infusion and have an in vivo elimination
`half-life of 40–150 hours. The daunorubicin liposomal
`formulation has an in vivo half-life of 4.4 hours compared to
`0.8 hours for the conventional formulation (1, pg. 1970). The
`cytarabine liposomal formulation, Depocyt, is administered
`intrathecally once every 2 weeks, while the conventional
`formulation is given twice per week.
`To further increase the in vivo circulating times, lipo-
`somes can be covalently derivatized with polyethylenegly-
`col to produce PEGylated or stealth liposomes. The only
`commercially available PEGylated liposome is doxorubicin
`in Doxil and is administered by IV infusion and has a
`half-life of 50–55 hours (1, pg. 2985). The proteins adeno-
`sine deaminase (Adagen) and asparginase (Oncaspar) are
`also available as a PEGylated derivative.
`
`10. Polymeric Microspheres
`
`The era of controlled release using polymeric micro-
`spheres began with the approval of the peptide leuprolide as
`lupron depot. The drug is incorporated into a biocompatible
`polymer and transformed into lyophilized microspheres
`during the manufacturing process. The reconstituted micro-
`spheres are injected intramuscularly and slowly erode in
`vivo, releasing the drug. In the marketed formulation, leupro-
`lide is in lyophilized microspheres with DL-lactic/glycolic
`acid copolymer (PLGA), gelatin and mannitol, which is then
`reconstituted prior to administration to a suspension using an
`aqueous solution of sodium carboxymethylcellulose, TWEEN
`80 and mannitol. The microspheres provide a depot of drug
`and are administered once every 1–4 months, depending on
`the dose (3.75 mg/l month, 30 mg/4 months). One of the
`leuprolide formulations uses a dual chamber syringe for ease
`of reconstitution and administration.
`
`A polymeric PLGA microsphere formulation of human
`growth hormone (Nutropin Depot) finished Phase III clinical
`trials in 1999 (13). In this formulation, human growth
`hormone is made into an insoluble complex with zinc, and
`encapsulated into PLGA microspheres in a non-aqueous
`cryogenic process (14). The resulting free-flowing powder is
`reconstituted to a suspension prior to subcutaneous or
`intramuscular administration.
`
`11. Polymeric Gels
`
`Polymeric gels provide a depot of drug that is released
`over 1–4 weeks. The era of controlled release using poly-
`meric gels began with the approval of doxycycline hyclate
`which is available as a 7-day controlled-release system that
`is a solution upon subgingival administration, but solidifies
`upon contact with the crevicular fluid. This product
`is
`marketed as Atridoxt in a Atrigel Delivery System which is
`a two-syringe set-up where syringe A contains the polymer
`poly(DL-lactide) dissolved in N-methyl-2-pyrrolidone, and
`syringe B contains solid doxycycline. Upon coupling the
`two syringes, the liquid in syringe A is injected into syringe
`B and repeatedly mixed to complete dissolution, and then
`the yellow viscous liquid is administered subgingivally.
`Local delivery directly into tumors of the anti-tumor
`cancer drugs fluorouracil and cisplatin, as well a subcutane-
`ous injection of leuprolide are in clinical trials using a
`polymeric gel formulation.
`
`III. Containers/Vials
`
`Most injectable products are still marketed in traditional
`vials, ampules and infusion bags. However, there is in-
`creased use of more convenient containers such as prefilled
`syringes, dual chamber syringes and pen-type injectors.
`Prefilled syringes are especially useful in emergency situa-
`tions such as in the use of the antithrombotics dalteparin,
`danaparoid and enoxaparin; the analgesics morphine, hydro-
`morphone, fentanyl, lidocaine and sumatripan; the sedatives
`lorazepam and propofol; and the antihypertensive labetalol.
`Dual chamber syringes are used to avoid the usual manipula-
`tions involved in reconstitution of a lyophilized powder, and
`one syringe contains the solid drug while the second syringe
`contains the liquid diluent, which are mixed prior to
`administration. Products that use a dual chamber set-up
`include diltiazem, doxycycline and leuprolide. Pen-type
`injectors such as NovoPent with insulin involve a 1–3 mL
`cartridge that goes into the pen-like delivery device, and the
`epinephrine autoinjector for intramuscular self-administra-
`tion.
`
`IV. Future
`
`The future is promising for the formulation sciences, in
`general, and also for the parenteral formulation sciences.
`New parenteral achievements will likely include targeted
`delivery, more sophisticated controlled delivery, novel for-
`mulations and new excipients, which may utilize new
`technologies and be marketed in new devices. Biotechnol-
`ogy proteins and antibodies will likely continue to be at the
`forefronts of the parenteral sciences. The new and exciting
`field of gene therapy will likely rely on injectable and
`
`Vol. 53, No. 6 / November–December 1999
`
`341
`
`MYLAN INST. EXHIBIT 1088 PAGE 19
`
`

`

`342
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 20
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`343
`
`MYLAN INST. EXHIBIT 1088 PAGE 21
`
`

`

`344
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 22
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`345
`
`MYLAN INST. EXHIBIT 1088 PAGE 23
`
`

`

`346
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 24
`
`

`

`Vol. 53, No. 6 / November–December 1999
`
`347
`
`MYLAN INST. EXHIBIT 1088 PAGE 25
`
`

`

`solution formulations for delivery of antisense oligonucleo-
`tides (15, 16), such as with the anti-sense ophthalmic
`product fomiversen (Vitravene). In general, formulation
`approaches along with drug design will be the means to
`achieve optimal drug delivery based upon therapeutic needs.
`New approaches could include nanoparticles (17), submi-
`cron solid particles coated with either natural or semisyn-
`thetic phospholipids (18), mixed-micelles, microemulsions
`for injection (19), and soluble self-assembled block copoly-
`mers to either solubilize drug in a micelle-like structure
`[PEO-b-PAA-DOX, poly(ethylene oxide)-block-poly(aspar-
`tic acid)-doxorubicin] or covalently bind drug (20). ‘‘Smart’’
`controlled-release systems that deliver drug when needed
`could be the next generation in controlled release, including
`pulsatile delivery to mimic human circadian rhythms or
`normal hormone production. The release of drug could be
`triggered by timed events or more sophisticated means, such
`as a chemical stimulus, photosensors, blood pressure sen-
`sors, or some type of biofeedback mechanism. New excipi-
`ents will
`likely be approved, such as sulfobutyl ether
`b-cyclodextrin, tetraglycol, triglyme, transcutol, 2-pyrrol-
`idone (Soluphort P), glycerol formal, Solutol HS-15, and
`poloxamers which will expand the number of formulation
`additives available to the formulation scientist.
`Devices such as needle-free injectors (already in use with
`vaccines) for both solutions and solids (21) could revolution-
`ize the manner in which injectable drugs are administered.
`The increased emphasis on home health care will likely
`result in home infusion devices and set-ups such as battery
`operated and/or pocket-sized infusion pumps. We are likely
`to continue to see more applications of convenient injection
`devices, prefilled syringes, dual chamber devices and ready-
`to-use solutions.
`
`Advanced technologies will likely be used in commercial
`production of future parenteral products; for example, the
`use of nanoparticles for injection of water-insoluble drugs.
`Supercritical fluid processing to form spherical micropar-
`ticles (22) and perhaps a designed distribution of particle
`size has tremendous potential in future formulations and
`pharmaceutical manufacturing.
`Combinations of novel formulations and novel delivery
`systems that are in active research (23) will certainly be
`developed. One can imagine the many combinations of
`needle-free injection of solutions or solids, controlled-
`release systems, ‘‘stealth’’ carriers, targeted delivery, vac-
`cines, gene therapy, antibodies and specially designed small
`molecules. Yes, as the parenteral sciences continue to
`mature, future products will be science fiction come true!
`
`Notes on the Compilation
`
`A few comments on the compilation are in order to help
`the reader understand the table format, chemical structures,
`some occasional additional information, highlighted por-
`tions, and abbreviations.
`
`1) The order of lines within the formulation box is:
`a) Solution or lyophilized powder
`b) Drug concentration or amount (i.e., mg/mL, mg,
`units/mL, etc.)
`c) Excipients and concentration or amount (i.e.,
`mg/mL, %, mg, etc.)
`—organic solvent(s)
`—suspending agent(s)
`—bulking agent(s)
`—isotonicifier(s)
`
`348
`
`PDA Journal of Pharmaceutical Science & Technology
`
`MYLAN INST. EXHIBIT 1088 PAGE 26
`
`

`

`—preservative(s)
`—buffer
`d) pH
`2) Some drugs have the pKa listed, but this is not compre-
`hensive and is added for informative purposes.
`3) The chemical structures are drawn in most instances as
`the neutral species even though the market product
`may be a salt form.
`4) In the drug name, the counter ion is in lower case, but a
`covalently bound prodrug moiety is capitalized.
`5) Some entries were not found in the 1999 PDR at all or
`not as injectables, but were found in other references.
`In these cases ‘‘(Not in 1999 PDR)’’ is added under the
`marketed name.
`6) Various portions of some entries are highlighted in
`bold typeface, in order to help the reader clearly notice
`key formulation aspect(s).
`7) Some drugs are marketed in multiple formulations,
`and in these cases the formulations are numbered.
`8) There are some peptide entries to highlight new formu-
`lation approaches.
`9) Abbreviations used herein (Table XI).
`
`References
`
`1. Physician’s Desk Reference, 53rd ed., Medical Economics Company,
`Inc., Montvale, NJ, 1999.
`2. Lawrence A. Trissel, Handbook on Injectable Drugs, 10th ed., Ameri-
`can Society of Health-System Pharmacists, Inc., Bethesda, MD, 1998.
`3. Lynn D. Phillips and Merrily A. Huhn. Manual of IV Medications, 2nd
`ed., Lippincott-Raven Publishers, Philadelphia, PA, 1999.
`4. D. A. Hussar, ‘‘New drugs of 1998,’’ Journal of the American Pharma-
`ceutical Association, 39, 151 (1999).
`5. D. A. Hussar, ‘‘New drugs of 1997,’’ Journal of the American Pharma-
`ceutical Association, 38, 155 (1998).
`6. Food and Drug Administration internet website, http://www.fda.gov/,
`See human drugs, then what’s new, then new and generics approvals.
`7. A. Depalma, Managing editor, http://pharmaceuticalonline.com/, Weekly
`update on applications and approvals.
`
`8. Y-C J. Wang and R. R. Kowal, ‘‘Review of excipients and pHs for
`parenteral products used in the United States,’’ J. Parent. Sci. Technol.,
`34, 452 (1980).
`9. S. Sweetana and M. J. Akers, ‘‘Solubility principles and practices for
`parenteral dosage form development,’’ PDA J. Parent. Sci. Technol.,
`50, 330 (1996).
`10. M. F. Powell, T. Nguyen, and L. Baloian, ‘‘Compendium of excipients
`for parenteral formulations,’’ PDA J. Parent. Sci. Technol., 52, 238
`(1998).
`11. Y. Kim, D. A. Oksanen, W. Massrfski, J. F. Blake, E. M. Duffy, and B.
`Chrunyx, ‘‘Inclusion complexation of ziprasidone mesylate with b-cy-
`clodextrin sulfobutyl ether,’’ Journal of Pharmaceutical Sciences, 87,
`1560 (1998).
`12. V. J. Stella, ‘‘A case for prodrugs: Fosphenytoin,’’ Adv. Drug Del. Rev.,
`19, 331 (1996).
`13. A. Depalma, ‘‘Alkermers and genentech expand collaboration for
`nutropin depot,’’ feature article, April 19, 1999, http://pharmaceuticalon-
`line.com
`14. O. L. Johnson, W. Jaworowicz, J. L. Cleland, L. Bailey, M. Charnis, E.
`Duenas, C. Wu, D. Shepard, S. Magil, T. Last, A. J. S. Jones, and S. D.
`Putney, ‘‘The stabilization and encapsulation of human growth hor-
`mone into biodegradable microspheres,’’ Pharmaceutical Research,
`14, 730 (1997).
`15. David A. Putnam, ‘‘Antisense strategies and therapeutic applications.’’
`Am. J. Health-Syst. Pharm., 53, 151 (1996).
`16. R. L. Juliano, S. Alahari, R. Kole, and M. Cho, ‘‘Antisense pharmaco-
`dynamics: Critical issues in the transport and delivery of antisense
`oligonucleotides,’’ Pharmaceutical Research, 16, 494 (1999).
`17. G. Caponetti, J. S. Hrkach, B. Kriwet, M. Poh, N. Lotan, P. Colombo,
`and R. Langer, ‘‘Microparticles of novel branched copolymers of lactic
`acid and amino acids: Preparation and characterization,’’ Journal of
`Pharmaceutical Sciences, 88, 136 (1999).
`18. S. N. Pace, G. W. Pace, I. Parikh, and A. K. Mishra, ‘‘Novel