`
`
`
`REVIEW ARTICLE
`
`Parenteral Formulations of Small Molecules Therapeutics Marketed in
`the United States (lQQQl—Part l
`
`ROBERT G. STRlCKLEY
`
`Axys Pharmaceuticals, Inc, South San Francisco, Cali orm’a
`
`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 admins
`istration, company and the clinical indication (1—7).
`One purpose of this compilation is to assist the formula-
`lion scientist in being able to look at a drug's chemical
`structure and then be able to determine possible formulation
`approaches. This compilation will aISo be usefuLl‘or 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-eoncept 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 Alters, discuss the various formula-
`tion approaches with detailed tables of examples. In a
`compendium of excipients for parenteral formulations (10)
`Gcncntech 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 injectablc 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.
`
`Editor's Note: This review article on lnjcctuble Products is being pub»
`lished in several parts, The next installment(s) will appear in subsequent
`issues of tltchortrnai.
`Correspondence address:
`94080.
`
`l8!) Kimball Way, South San Francisco. CA
`
`324
`
`The word "parenteral" is Latin for “other than intestine.”
`thus by definition the parenteral sciences not only includes
`lnjcctable products but also transdermal, pulmonary, nasal,
`ophthalmic, and baccal 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
`vino ‘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 it liquid for reconstitw
`lion, and will
`likely soon see needle—free injectors and
`\
`pockct‘size infusion pumps.
`
`injectable Formulations
`
`Two key aspects of any successful injectoble fortitulatlon
`are: l) 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 "3% degradation. The ideal
`injectable
`formulation, from an in viva tolerability pointvof-view, is
`isotonic with physiological fluids and a neutral pH (i.e..
`PBS: phosphate buffered saline, 0.01M sodium phosphate
`with 0.]35M 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. lf stability is
`insufficient to provide a two~yeor 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. Solubllization Techniques
`
`1. pH Arfizrsmtenr‘wtd Soils
`
`if the drug molecule is ionizahlc, thcn 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 weal; acids are normally formulated at
`
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`Hydantoin
`
`Vol. 53, No.6 I November«0ecember1999
`
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`
`Functiona
`Grou I Name
`
`Sulfonic acid
`
`Phosphate ester
`
`Carboxylic acid
`
`4~Hydroxy
`coumnrin
`
`Sulfonamide
`
`Barbituric acid
`
`Guanine
`
`pH > 5 (Table l). weal: bases at pH < 7 (Table 11).
`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 cmboxylic acid and an amine. but are
`formulated as the cation at pH < 7. 0n 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.
`
`Neutral
`
`Bethamethasone
`Dexamethasone
`Fludara 3 inc
`Penicillin
`Ketorolac
`
`Flumuracil
`
`Acetamlamtde
`Clorothiazide
`Diazoxide
`
`Methohexital
`Pentobarbital
`Phenobarbital
`Seeobarbital
`
`Acyclovir
`Gancyclovir
`
`Phenytoin
`
`10.5
`emulsion
`organic
`oranic
`
`Liothyronine
`Propofil
`Etoposide
`Teni t aside
`
`The range in pH is quite broad and is between pH 2—12,
`and thus any molecule with a pKa between 3-ll can be
`potentially solubiiized by pH adjustment. However, when
`using extiemes in pH, care must be taken to minimize buffer
`capacity in order for the formulation to be in viva 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,
`325
`
`

`

`
`
`
`
`g
`i
`;
`’
`
`
`
`
`
`Table II. Examples 0 Weak Base Chemtca Functional Groups, Thetr - ppmximate pKa s
`and Formulation H's.
`
`Functional
`Grou Name
`
`Functional Group
`Structure
`
`Functional
`Grou Ka
`
`Formulation
`H
`
`Selected
`Examles
`
`lH-Imidazole
`
`Miconazole
`
`Ottdansetron
`
`
`
`
`
`
`Pyridine
`
`/
`
`Amrononc
`F\
`Milrinone
`2-4
`0 ~5
`
`
`Papaverine
`
`Pyridoxine
`Metoclopramidc
`Minocycline
`(Procaine
`Procainamide
`also have a
`tertiary amine)
`
`
`
`/
`
`~ 5
`
`2-6
`
`
`
` 4,5-Imidazoline
`Tolazoline
`
`
`
`Amine
`
`R2
`
`/
`
`7—10
`
`3~7
`
`
`Ateno 01
`Codeine
`
`
`
`Daunontbicin
`Morphine
`\
`
`'1
`
`9 o
`R3
`
`RHN
`
`
`
`
`7.4
`
`< S
`
`Doxaptam
`
`
`
`N—Alky
`morpholine
`
`
`
`
`Cimetidine
`\
`K
`3-6.5
`~ 7
`/
`Daearbazine
`\
`
`Phentoiamine
`
`
`
`
`Pcntamidine
`
`Amidine
`
`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, ehlordiazepoxide
`is administered intravenously or intramttscuittrly and forum
`lated at pH 3 with 20% propyienc glycol and 4% TWEEN
`20. Phenytoin sodium is administered either intravenously
`or intramuscularly and formulated at pH 10—32 with 40%
`propylene glycol and [0% ethanol. Subcutaneous fonnula-
`
`tions are slightly acidic such as methadone at pH 3~6, and
`lcvorphanol at pH 4.3.
`Watetosolublc 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 dmg (Table W). 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
`
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`

`Selected
`Example
`
`Chemical Structure
`
`Ciptofloxacln
`
`O
`
`Sufentanil
`
`H,c\/1LN
`
`J9COOH
`
`Audie
`Functional
`Group Name
`
`Basic
`Functional
`
`Group Name
`'
`
`Formulation
`
`pH
`(ionic state)
`
`Carboxylic
`acid
`~4
`
`Aniline ~ 4
`Amine ~ 9
`
`3-4
`(Cationic)
`
`Carboxylic
`acid
`~ 4
`
`Amine ~ 8
`
`3.5—6
`(Cationic)
`
`Ampicillin
`
`°
`
`0%":
`
`H
`
`N
`
`Carboxylic
`acid
`~4-
`
`Amine ~ 8
`
`8-10
`(Anionic)
`
`6-8
`(Anionic)
`
`Carboxylic
`
`Cephapirin
`
`0’5
`
`‘9“!
`053:3:
`
`OTC".
`
`acid
`~3
`
`Pyridine ~ 5
`
`
`
`the cations potassium. tromethumine and calE‘mm. There are
`many more anionic counterions and the most common is the
`hydrochloride salt followed by sulfate. mesylatc, maleate
`and tartmto. 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 pKaz = 9.4 and
`dissolving its sodium salt in water results in pll ~ ll.
`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
`
`‘ ist of outer Ion in Salt Forms of Parenteral Dru
`liner 0 instances
`
` Hydrochloride
`~__~__~_nmmmumcxquooag
`
`Moglumine
`Potassium l
`Calcium ‘:
`Tromcthamine‘r
`
`Sulfate
`Mesylate
`Chloride
`Maleate
`Tomato
`Citrate
`Bromide
`Lactate
`Acetate
`Phosphate
`Besylate
`Hydrobromide
`Fumarate
`Gluceptate
`Gluconate
`Glucuronate
`Lactoblonate
`Salicylate
`Tos late
`
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`
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`

`t
`
`
`
`i i
`
`Concentration in
`Formulation,
`Molarit
`
`Concentration
`Administered,
`Moiari
`
`Route of
`Administration
`
`IV infusion
`
`IV
`IV infusion,
`SC
`
`M, IV, IV
`infusion,
`
`IV, IV
`infusion
`
`W mfusmn,
`SC
`
`IV infusion
`IM
`
`Buffer ( Ka’s)
`
`Maieic acid
`(1.9, 6.2)
`Glycine
`
`Sodium lactate!
`Lactic acid
`3.8)
`Ascorbic acid
`4.2,
`l 1.6)
`Sodium citrates/
`Citric acid
`(3.1, 4.8, 6.4)
`0 turn acetate!
`Acetic acid
`
`Sodium
`bicarbonate!
`Carbonic acid
`
`succinatcl
`Succinic acid
`(4.2, 5.6) \~
`Histidine
`(1.8, 6.0, 9.2)
`
`benzoate/
`Benzoic acid
`(4.2)
`0mm
`
`IV, ' V m sion
`1M
`
`1M, 1V infusion
`Intra-arteriaily.
`Intrathcca]
`
`(Fomivcrscn)
`
`
`
`phosphates
`(2.2. 7.2. 12.4)
`ris(hydroxy-
`methyl)amino-
`methane
`\ (8-3)
`Soium
`bicarbonate]
`Sodium
`carbonate
`(6.3, 10.3
`
`
`= intramuscu ar
`IV = intravenous
`SC = subcutaneous
`
`include Citralcs. acetates, histidinc. phosphate. tris(hydroxy—
`methylmminomethanc. and carbonates. The buffer concen-
`tration must be high enough to maintain the desired pH, but
`must be balanced by in viva toierahiiity considerations, and
`thus it is good practice to minimize buffer capacity of the
`administered formulation.
`
`328
`
`2. Mixed Organic/Aqueous Fomzulmions
`
`If pH adjustment atone is insufficient in achieving the
`desired solution concentration. than a combination of pH
`and organic sotvent(s)
`is often employed. If the drug
`molecule is not ionimblc then pH has no effect on solubility,
`
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`

`but solubility enhancement can often be accomplished by a
`combination of aqueous and organic solvents (in. a cosol—
`vent). The currently used organic solvents used in mixed
`organic/aqueous formulations are propylene glycol, ethanol,
`polyethylene glycol 300 or 400. cromophor EL, TWEEN 80,
`sorbitol, glycerin and dimethylucetamide (DMA) (Table Vi).
`As with any formulation additive, the concentration that is
`administered should be minimized to avoid any in viva
`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 <l% for IV infusion.
`However. propylene glycol is ~70% of the oxytetmcycline
`marketed formulation and is injected intramusculariy with-
`out dilution.
`Similar to formulations using pl! 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% (dihydroergotarnine), glyc-
`erin 32% (epinephrine). and propylene glycol 10% {hydrolo-
`zine). Whereas, the intravenous bolus route can use ethanol
`up to 20% (paricnlcitrol), PEG 300 up to 50% (methocarba—
`mil), and propylene glycol up to 68% (phwabarbitol). The
`intramuscular route has similar in viva constraints to the
`intravenous route, but can tolerate even more organic
`solvent (see section 1.3, Totally Organic Solution Formula-
`lions).
`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, crcmophor BL is 11% of the
`miconuzole marketed fonnulatlon, 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, cremopltor EL at l0
`or TWEEN 80 at 25% can
`be administered by IV infusion \(sec section 1.3).
`3. Totally Organic Solution Fori‘mtlations
`
`Molecules that are nondonizable (have pKa < 2, or
`pKa > ll) and non~polar are water insoluble with no effect
`of pH on solubility, and thus are the most challenging for the
`formulation scientist. These watcninsoluble molecules can
`be formulated in 100% organic solvent, which is then
`usually but not always diluted prior to administration (Table
`Vll). For example, httsulfan 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. Paelltaxcl is marketed with 5l%
`cremophor EL and 49% ethanol. but is diluted 5— to 20-fold
`for IV infusion. Docctnxel is marketed in 100% TWEEN 80,
`but is diluted to 25% 1’0er infusion.
`
`Vol. 53. No.6 1' November~December1999
`
`4. Cyclnrlextrirts
`
`Some molecules can be solubilized by forming an inclu-
`sion complex with a cyclodextrin. Cyclodcxtrins have a
`hydrophilic exterior and a hydrophobic interior core of
`specific dimensions, and thus molecules with a non~polur,
`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 M complex between cyclo-
`dcxtrin and drug will not precipitate, but a drug dissolved in
`a cosolvcnt often precipitates upon dilution. Tuvo cyclodex—
`trins have been accepted for human injccmble use with the
`approval of alprostidol nlfndex and itmcouazolc. Alprostidol
`alfadex is marketed as a lyophilized powder with ct~cyclodcx-
`trio and is administered intracavernosally. ltraconazole was
`approved in April 1999 as a solution with 40% hydroxyproc
`pyl-B-cyclodextrin and is administered by intravenous info.
`sion after a 2-fold dilution with saline (6). The next
`cycloclextrin likely to be approved is sulfobutylethcr—p-
`cyclodextrin, which is in the clinical formulation of ziprasi-
`done for intramuscular injection (ll).
`
`5. Emulsions
`
`Oil-soluble molecules are generally neutral uncharged
`and nompolur molecules, but can be formulated for intrave-
`nous administration by the use an oil~in—waler emulsion.
`Emulsions can solubilizc oil~soluble drugs since the dmg
`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. Pradntg:
`
`Molecules which contain an alcohol. phenol, carboxylic
`acid, amine, hydantoin functional group can potentially be
`dcrivatized as n prodrug. Once the prodrug is administered
`in viva. the promoicty is hydrolyzed by either esterases or
`phosphatases releasing the parent drug. Although prodrugs
`are normally associated with orally administered products
`for better oral bioavailnhllity, 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 ,dcrivatized to be a neutral molecule (see section
`11.7b). 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 ctoposidc (etoposide
`phosphate) is dcrivatizcd as a water‘soluble phosphate ester.
`Water~soluble phosphate esters are also prodrugs for alcohol—
`containing betamcthasone, clindamycin, dexamethasone,
`lludarabinc, hydrocortisone, and prcdnlsolone. The hydan-
`
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`

`Solvent
`
`Crcmophor EL
`
`osolvents Used in Parenteral Formulations.
`Table VI. List 0
`%in Marketed
`‘
`Route of
`olntion dministered Anistration
`I
`V infusth
`1 I
`0.02-0.08
`IV infusion
`20
`0.1-!
`IV infusion
`50
`18
`50
`Intravesical
`S I
`25-10
`IV infusion
`65
`(165-33
`IV infusion
`IV infusron
`0. l 2-0.12
`3
`IV infusion
`
`Exem w
`Mtconazoie
`Tacrolimus
`Tenoposide
`Valrubicin
`Paciitaxel
`C 0103 - orin
`Tenoposrde
`Busulfan
`
`l
`
`2
`
`‘
`
`IV infusion
`
`1M, SC, IV
`1M, IV
`IV
`1M, IV
`IM, IV
`IM, IV
`IM, IV
`IV infusion
`IV
`IV infusion
`1V
`IV infusion
`IV infusion
`IV infusion
`Intravesical
`IV infusion
`IV infusion
`
`Medroxy-
`progesterone
`Dihydroergotamine
`Diazepam
`Digoxin
`Ketorolac
`Pentobarhital
`Phenobarbital
`Phenytoin
`Dooetaxel
`Paricalcitol
`Bsmolol
`
`Etoposide
`Cyclosporin
`Teniposide
`Pacl itaer
`Valrubicin
`Tacrolimus
`Carmustine
`
`1M, SC, IV
`IV infusion
`SC
`
`811 ogingtva
`
`Dihydroergotamine
`Idarubicin
`E u inc I hrine
`
`D xycyc me
`
`Oxytetracycline
`
`Etoposide
`Lorazepam
`Lorazeparn
`Busuifan
`
`IV infusion
`
`0.5
`
`61
`
`0
`2.5— 10
`10
`IO
`10
`i0
`
`10 (diluent)
`20
`l
`0.3-0.6
`035-1.?
`0.0844184
`25-10
`18
`0.08-0.32
`10
`
`l .
`25
`32
`
`100
`
`
`
`tmethy —
`acetamide
`(DMA)
`
`5
`g
`
`
`
`i
`‘
`
`it
`
`5 (diluent for
`LP)
`
`61
`
`0
`to
`10
`10
`10
`
`10
`13 (diluent)
`20
`25
`30
`35
`42
`49
`50 \a
`80
`100 (diluent for
`LP)
`15
`25
`32
`
`100 (diluent for
`LP)
`
`G ycerin
`
`—met yl—Z-
`pyrrolidone
`(Pharmasolve)
`Monothio-
`I care]
`
`toimcontaining phenytoin prodrug (fosphenytoin) is deriva-
`tized in a unique fashion as a water-soluble hydroxymethyl
`‘ phosphate ester, which after in viva enzymatic phosphate
`ester cleavage, the resulting hydroxymethyl
`intermediate
`quickly dissociates to phenytoin and formaldehyde ([2).
`Other water solubilizing prodrug approaches are a succinate
`ester of the alcohol methylprednisolone. and a piperidine
`carbamate in irinotccan a prodrng for a phenol drug.
`Prodrugs can also be used for stability reasons. For
`example, alatrolioxacin is
`the nlnninemlaninc dipcptitle
`prodrug for the primary amine trovafioxnein which is
`
`unstable in solution. The prodrug alatrofloxacin is marketed
`as a solution at pH 3.4-4.3.
`
`ll. Sustainedsfielease Techniques
`
`The research in control led release during the 1970s has in
`the 19905 become a commercial realization with the up
`proval of [iposomnh polymeric microsphcrc and polymeric
`gel formulations. However, traditional approaches are still in
`use such as suspensions, prodmgs and oil depots.
`
`330
`
`PDAJoumal of Pharmaceutical Science & Teehnotogy
`
`
`Suppiied by The British Library - "The worid‘s knowiedge"
`
`W
`
`AstraZeneca Exhibit 2112 p. 7
`
`

`

`
`
`Tab 6 VI (cont). List of Cosolvents Used in Parenteral Formulations.
`% in Marketed
`%
`Route of
`
`lvent
`Propylene glycol
`(PG)
`
`Formulation Admin Administraon
`1M,
`10
`1M
`20 (diluent for
`
`
`
`Exam 0 has
`
`Hydralnzine
`Chlordiazepoxide
`
`Esmolol
`Pariealcitol
`Etomidate
`
`Diazepam
`Digoxin
`Pentobarbital
`
`Phenytoin
`Dimenhydrinate
`Dimenhydrinate
`Fcnoidopam
`Medroxy—
`progesterone
`Oxytetracycline
`Phenobarbital
`Lorazepam
`Lot-nae . am
`
`hiet ylperazine
`Irinotecan
`
`Nicardipine
`Diltiazem
`Triamcinolone
`
`Dexamethasone
`Acetate '
`Calcitn'ol
`
`Chlordiazepoxide
`
`Etoposide
`Amiodarone
`Docetnxel
`
`IV infusion
`IV
`IV
`IM, IV
`IV
`1M, IV
`1M, IV
`1M
`TV infusion
`IV infusion
`IV infusion
`
`IM
`1M, IV
`
`IV infusion
`IV infusion
`IV
`Intro-articular,
`Intralesional
`1M
`
`IV bolus
`
`M N
`
`IV infusion
`IV infusion
`
`0.075
`
`0.4
`4
`
`0.08-0.16
`0.4
`25
`
`60 (diluent for
`LP)
`67-75
`68
`80
`80
`
`TWEEN 80
`
`0.075
`
`(Polysorbate 80)
`
`0.4
`4 (diluent for
`LP)
`
`8 1
`
`0
`100
`
`= intramuscu or
`IV = intravenous
`LP = lyophilized powder
`PEG = polyethylencglycol
`SC 2 subcutaneous\
`
`i
`70. Suspension Fonmdmions ;
`
`Suspension fomtulations provide a Sttslnined~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 1X)
`Almost all suspensions are administered intramuscularly.
`intmlesionelly or intrncarticulntly. 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 (dmg in
`solution) and sustained activity (crystalline drug in suspen.
`sion). The only sesame oil suspension is the anti-rheumatic
`
`aurotltioglucose, which is administered intromuscularly ev—
`ery 1—4 weeks.
`
`7!). Prodmgs in Suspension Fonmtlmialts
`
`Most of the other suspension formulations are aqueous-
`based and contain water-insoluble prodmgs which are
`lipophilie esters of alcohols. For example. hydrocortisone
`acetate and dexametltasone acetate are acetate esters of their
`alcohol~containing parent drug, and are administered intra-
`musculariy, intralesionally or intra-anicularly once every
`l—3 weeks. The contraceptive ntedroxyprogesterone acetate
`is administered intramuscularly once every 13 weeks. Aque-
`ous~bnsed suspensions typically contain TWEEN 80 at
`~0.75—4 ntg/mL (0.4%) along with a suspending agent such
`
`Vol. 53. No. 6 I November—December 3999
`
`331
`
`
`'
`
`il
`
`Supplied by The British Library ~ "The world‘s knowledge”
`
`
`lW
`
`AstraZeneca Exhibit 2112 p. 8
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`Vol. 53, No.6 I November—Decemberisss
`
`Supplied by The British Library - "The world's knowledge"
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`AstraZeneca Exhibit 2112 p. 16
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`340
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`PDAJournal of Phasmaceuzical Science & Technofogy
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`Supplied by The British Library - "The worid’s knowledge”
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`WM
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`AstraZeneca Exhibit 2112 p. 17
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`A polymeric PLGA microspltere formulation of human
`growth hormone (Nutropin Depot) finished Phase ill clinical
`trials in 1999 (13).
`In this Formulation, human growth
`hormone is made into an insoluble complex with zinc, and
`encapsulated into PLGA microsphcrcs in a non—aqueous
`cryogenic process (14).Thc resulting free-flowing powder is
`reconstituted to u suspension prior to subcutaneous or
`intramuscular administration.
`
`11. Polymeric Gels
`
`Polymeric gels provide rt depot of drug that is released
`over 1-4 weeks. The era of controlled release using poly-
`meric gels began with the approval of doxycyclino hydate
`which is available as a 7-day controlled-release system that
`is a solution upon subgingival administration, but solidifies
`upon contact with the crevicular lluid. This product
`is
`marketed as Atridox‘8i in nAtrigel Delivery System which is
`a two-syringe set-up where syringe A contains the polymer
`poly(DL-lactide) dissolved in N»mcihyl-2vpyrrolidone, and
`syringe B contains solid doxycyclinc. 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