EP1189599A2 - Pharmaceutical materials and methods for their preparation and use - Google Patents

Pharmaceutical materials and methods for their preparation and use

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Publication number
EP1189599A2
EP1189599A2 EP00939811A EP00939811A EP1189599A2 EP 1189599 A2 EP1189599 A2 EP 1189599A2 EP 00939811 A EP00939811 A EP 00939811A EP 00939811 A EP00939811 A EP 00939811A EP 1189599 A2 EP1189599 A2 EP 1189599A2
Authority
EP
European Patent Office
Prior art keywords
crystals
phase
active pharmaceutical
pharmaceutical ingredient
crystal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00939811A
Other languages
German (de)
French (fr)
Inventor
Jean A. Chmielewski
Bart E. Kahr
Jerry Lewis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1189599A2 publication Critical patent/EP1189599A2/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to pharmaceutical formulations involving the inclusion of an active pharmaceutical ingredient ("API") in a pharmaceuticaUy- acceptable single crystal matrix. More particularly, the crystals contain growth- sector specific, oriented inclusions of active pharmaceutical ingredients which are isolated. The active pharmaceutical ingredients have higher stability and shelf-life, and can be delivered in conventional dosage forms.
  • This invention has general application to active pharmaceutical ingredients, and in one aspect has particular application to biopharmaceuticals.
  • biopharmaceuticals is used to refer to a subset of API's which are polymeric in nature, including for example, proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids. Description of the Prior Art:
  • compositions which are capable of maintaining the quality and efficacy of the API during storage and delivery.
  • the loss of potency of an API is a critical concern in assuring that viable, effective drugs are delivered to patients. It is similarly desirable to have formulations which do not require special packaging or handling. FuVther, it remains a constant goal to provide active pharmaceutical ingredients in a form which facilitates their use by the consumer, such as through convenient dosage forms.
  • the present invention addresses these and other issues concerning pharmaceutical compositions and formulations.
  • biopharmaceuticals Although not limited to biopharmaceuticals, the usefulness of the present invention is well exemplified with respect to biopharmaceuticals, many of which demonstrate the problems encountered in prior-art approaches. Ensuring long-term stability and maintaining activity of biopharmaceuticals is a prevalent concern.
  • the chemical complexity and conformational fragility of protein drugs make them highly susceptible to both physical and chemical instabilities and threaten their emergence into the marketplace. Denaturation, adsorption with container walls, aggregation, and precipitation can result from non-covalent interactions between a drug and its environment. Insulin, for instance, has been shown to adsorb onto the surfaces of glass and plastic containers, and to have interactions at air-water interfaces, leading to denaturation, aggregation and precipitation.
  • HGH human growth hormone
  • glucagon in solution has been shown to readily gel or aggregate when subjected to mechanical stress.
  • researchers have distinguished nine major reaction mechanisms by which proteins degrade, including hydrolysis, imide formation, deamidation, isomerization, racemization, diketopiperazine formation, oxidation, disulfide exchange, and photodecomposition. The rates of these deleterious processes depend in large measure on the protein and its environment.
  • the primary chemical degradation products of glucagon include oxidation of Met (27), deamidation of Gin (24), and acid-catalyzed hydrolysis at Asp (9), Asp (15) and Asp (21). HGH undergoes chemical decomposition via oxidation at Met (14) and deamidation at Asn (149).
  • biopharmaceuticals One technique used in formulating biopharmaceuticals has been lyophilization of the biopharmaceutical solution in the presence of excipients, buffers and/or bulking agents.
  • lyophilized preparations must typically be stored under refrigeration, a requirement which is neither technically nor economically feasible in many markets and inhibits flexibility of patient use.
  • formulations of many biopharmaceuticals which would permit their storage at ambient temperatures. This would permit more rapid development of products, increasing flexibility in shipping, storing and carrying the drug products, and allowing introduction and use of such products in markets where refrigeration is too costly.
  • the increased stabilization of biopharmaceuticals would naturally improve the general use of the biopharmaceuticals where shelf life is an important consideration, whether or not refrigeration or other concerns are at issue.
  • aqueous solution containing a biopharmaceutical with a limited amount of excipient(s) is frozen and then dried under vacuum to produce solids of sufficient stability for storage and distribution.
  • Excipients are added to prevent blow out of the product, to provide stability during lyophilization and/or dissolution, and to enhance compatibility for parenteral use.
  • Various excipients used with lyophilization have included salts, metal ions, polyalcohols, surfactants, reducing agents, chelating agents, other proteins, amino acids, fatty acids, and phospholipids.
  • excipients include mannitol, alanine, glycine, sorbitol, lactose, arginine, and maltose.
  • the results obtained with such excipients have usually been inconsistent.
  • Most lyophilized biopharmaceuticals are amorphous powders that have no specific structure, and as a result, the amount and location of the incorporated biopharmaceutical varies widely for the product particles. Also, they are typically readily dissolved, rendering them unsuitable for use as a sustained-release material. Further, there is no isolation of the pharmaceutical molecules from the environment or one another, leaving them susceptible to degradation by various mechanisms. Studies have shown that lyophilization of excipients can typically damage proteins rather than protect them.
  • Crystallized pharmaceuticals have been used in some instances, but there have been inherent limitations. Some API's , e.g. insulin, can be crystallized themselves, and are useful in that form for administration to patients. However, the majority of biopharmaceuticals either do not crystallize or the crystallization is very difficult, particularly on a commercial scale. Further, crystallization procedures are limited to the use of pharmaceuticaUy-acceptable ingredients and process conditions that do not adversely affect the active pharmaceutical ingredient, thus further constraining the ability to obtain desired microcrystalline suspensions.
  • United States Patent No. 5,075,291 describes a process for preparing a uniformly-dispersed, pharmaceutically-active material in a crystalline sugar alcohol matrix.
  • this process requires the addition of the API into a molten sugar alcohol with considerable mechanical agitation.
  • Many API's and virtually all biopharmaceuticals would not be stable in the extreme temperature of 110°C and the physical stresses of a high-shear vortex mixer used for agitation.
  • the present invention does not require these extremes of temperature and physical agitation.
  • the process of the present invention slowly includes the API into the growing crystal lattice in specific growth sectors, instead of homogeneous mixing and entrapping of the active pharmaceutical ingredient in a viscous melt.
  • the present invention relates to pharmaceutical compositions comprising single crystals of a pharmaceuticaUy-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation.
  • the crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the API's to a patient.
  • the crystals may be coated or combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing dosage amounts of the API's.
  • the crystals are prepared as depot formulations which may be administered, as by subcutaneous injection or implantation, to provide a long-term payout or sustained release of the active pharmaceutical ingredient.
  • the present invention further provides methods for preparing the crystals and for storing and administering the active pharmaceutical ingredient either in crystal form or upon reconstitution to a solution.
  • Another object of the present invention is to provide compositions comprising API's included in single crystals to provide improved stability and shelf-life.
  • the active pharmaceutical ingredients may therefore be stored for extended periods of time prior to use either as crystals or as reconstituted solutions. It is a further object of the present invention to provide single crystals with included API's to provide quick, delayed-release or sustained-release formulations for flexibility in pharmacokinetic profiles in delivery of the API's to patients.
  • Another object of the present invention is to provide pharmaceutical delivery units including an amount of single crystals sufficient to provide a dosage amount of the included active pharmaceutical ingredient.
  • the pharmaceutical delivery units include a quantity of crystals sufficient to provide a prolonged payout of the active pharmaceutical ingredient.
  • the crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants including excipients, diluents and carriers.
  • a further object of the present invention is to provide methods for preparing compositions comprising single crystals with growth-sector specific inclusions of API's.
  • Figure 1 is a photomicrograph illustrating fluorescence of a single crystal of green fluorescent protein in ⁇ -lactose monohydrate (1.8 (h) x 0.8 (w) x 0.5 (d) mm 3 ) with an idealized representation of habit.
  • the sides of the crystal in the photomicrograph are bright due to internal reflection.
  • Figure 2 is a graph of the fluorescence decay of the green fluorescent protein at 333°K in several environments: mixed crystal in ⁇ -lactose monohydrate (triangle), saturated lactose solution (square), and lyophilized ⁇ -lactose monohydrate (diamond).
  • the present invention utilizes single-crystal matrix inclusion of active pharmaceutical ingredients ("API's”) to achieve advantageous storage and delivery of the API's.
  • API's active pharmaceutical ingredients
  • This invention has application to a wide range of API's to provide enhanced stability and/or delivery of the active pharmaceutical ingredients.
  • the invention is particularly advantageous in providing greater stability over time and in providing alternative delivery and sustained release formulations to patients .
  • the small molecule host crystals comprise a crystal lattice component which includes the API's in an oriented, growth-sector specific manner.
  • the crystals and included API's are prepared to be pharmaceutically acceptable and pure, thereby being useful for administration to patients to be treated with the API's.
  • the term "pharmaceuticaUy-acceptable" refers to sufficient quality to meet regulatory and compendial requirements for administration to humans and/or animals.
  • the crystals provide a regular, predictable inclusion of the guest active pharmaceutical ingredient, and the crystals can consequently be used for obtaining a predetermined amount of the active pharmaceutical ingredient for delivery to a patient.
  • the host crystal gradually dissolves upon contact with body tissue or fluids, and is therefore useful as a system for delivery of the active pharmaceutical ingredient into the body.
  • the crystals and included active pharmaceutical ingredient may be reconstituted into a solution for administration to a patient.
  • the active pharmaceutical ingredient molecules are generally isolated from one another and are insulated from the environment by the host crystal. This leads to reduced susceptibility of the API to degradation, and therefore enhanced stability and shelf-life. Also, the use of appropriate host crystal compounds, or selected dosage forms, permits the design of quick, delayed, or sustained-release formulations for delivery of the active pharmaceutical ingredient. Sustained- release formulations are particularly advantageous for treatment of chronic conditions as they provide a consistent amount of drug delivery over a long period of time to improve ease of use and patient compliance in administering the API.
  • the crystals preferentially incorporate the active pharmaceutical ingredient on certain faces, thereby providing a growth-sector specific inclusion and orientation to the API's.
  • growth-sector specific inclusion and orientation refers to the fact that the API molecules are included primarily at certain faces of the crystal matrix.
  • the growth-sector specific inclusion and orientation can be determined by one skilled in the art, as demonstrated in the examples herein, by fluorescence microscopy and anisotropy measurements, single crystal desorption mass spectrometry, and autoradiography of 14 C-labeled material. In one embodiment, at least about
  • 0.001% (on weight/weight (w/w) basis) of the pharmaceutical is included within specific faces of the crystal matrix, and in another embodiment at least about 0.1% (w/w) and up to about 10%.
  • the crystal parameters including the particular crystal lattice component for a given API, the concentration of API, the use of crystal adjuvants, and the crystallization conditions, are selected to achieve the growth-sector specific inclusion and orientation of the API within the crystals.
  • the method of the present invention broadly involves the including of the active pharmaceutical ingredient into the single crystal matrix formed from a pharmaceutically-acceptable crystal lattice component.
  • the term "included” in the crystals refers to the active pharmaceutical ingredient being chemically adsorbed within the crystal lattice as the crystal is formed.
  • This inclusion of the active pharmaceutical ingredient molecules is distinguished from crystallization of the API molecules with one another, and from simple and random entrapment of the API molecules by the formed crystal.
  • the crystal product of the present invention is ordered, in contrast to the amorphous material produced by other approaches.
  • the API is incorporated in the crystal in relation to its degree of affinity for the crystal lattice molecules.
  • the crystal lattice component is therefore selected to be both chemically and physically compatible with the API such that the API is received by the crystal during formation, and remains stable and efficacious while within the crystal and upon release therefrom.
  • the including of the active pharmaceutical ingredient involves combining the crystal lattice component, the active pharmaceutical ingredient and a pharmaceutically-acceptable adjuvant in a liquid state.
  • the crystal lattice component is then crystallized under pharmaceutically-acceptable conditions to form the inventive crystals.
  • one method uses spiking of the API into a saturated or supersaturated solution of the crystal lattice component in a suitable organic and/or aqueous solvent system.
  • the saturated or supersaturated solution of the crystal lattice component may be spiked into the API solution.
  • Other components may also be added to the solution, including compounds which facilitate or modify crystal growth or which are desired for incorporation in the final formulation.
  • the solution may be seeded using any of a variety of conventional techniques.
  • the solution is allowed to evaporate and/or equilibrate to cooler conditions for growth of the crystals.
  • the crystals are then grown as the solvent is slowly evaporated away and/or the solution is cooled, with the evaporation and temperature gradient conditions being selected dependent on such factors as the solvent system and the desired crystal size.
  • the crystals containing the active pharmaceutical ingredient are harvested from the remaining solution and are preferably washed to remove surface contamination. This procedure yields crystals which include the active pharmaceutical ingredient at a predictable concentration and facial orientation.
  • crystals are grown under pharmaceutically-acceptable conditions.
  • pharmaceutically-acceptable conditions refers to the use of crystal and API compounds which are pharmaceutically-pure, and for which such pharmaceutical purity is maintained in the final crystals.
  • the crystal and API compounds are pharmaceutically pure, or have pharmaceutical purity, if they are of sufficient purity to be suitable for administration under applicable FDA or other administrative regulations regarding purity.
  • pharmaceutically-acceptable conditions further refers to the use of crystallization conditions through which the API compounds retain pharmaceutical efficacy in the final crystals and upon subsequent administration to patients.
  • the present invention readily allows the inclusion of API's by affinity with the small host molecules in the growing crystal lattice. This overcomes many of the limitations associated with previous approaches.
  • the processing involved with preparing the present crystals does not expose the API's to harsh conditions, thereby substantially reducing or avoiding the possible degradation or disruption of the structural aspects of the API which could occur with prior art techniques.
  • the inventive crystals have an added advantage in that they do not interfere with normal analytical methodologies used for characterizing the pharmaceutical product.
  • the small host molecules can be easily separated on the basis of molecular size, which is not the case for prior art techniques which use polymers that interfere with analytical methodologies.
  • the API molecules are incorporated into the host crystals typically at rates of at least about 0.001% (w/w), preferably at least about 0.1%, and more preferably about 1% to about 10% (w/w). Alternatively, the API molecules are included at rates of at least about 0.01 %, and as much as at least about 1 % (w/w).
  • the limited molar concentration of the active pharmaceutical ingredient in the host crystals means that the active pharmaceutical ingredient molecules are generally isolated from one another in the crystals. Isolation of the API molecules is particularly advantageous for those molecules, such as certain biopharmaceuticals, which could otherwise react with one another (e.g., by polymerization) or the surrounding environment. The degree of isolation can be verified by those skilled in the art using atomic force microscopy or reaction fluorescence energy techniques.
  • the present invention has a particular application to guest-host systems in which the guest API molecules are reactive with one another, but in which these molecules are sufficiently isolated from one another in the crystals as to substantially prevent such interaction. Consequently, the invention provides containment of the API molecules in the solid state crystals and provides for the API to be comformationally stable.
  • the method preferably involves preparing a mixture of crystals of substantially uniform size. This may include processing of the harvested crystals, such as by grinding or milling, to reduce the crystals to a substantially uniform size. Greater uniformity can be achieved by sorting the processed crystals, such as by sieving.
  • a preferred method further includes obtaining crystals which have a substantially uniform concentration of pharmaceuticals, for example, about 1% (w/w) of pharmaceuticals, that do not vary between crystals by more than 10 percent.
  • the method of the present invention may further include formulating the crystals into pharmaceutical preparations.
  • the collected crystals may optionally be coated with a suitable composition.
  • Coated or uncoated crystals may be blended with one or more pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof.
  • the blended crystals and adjuvant(s) are then formulated into pharmaceutical delivery units.
  • each unit includes a predetermined amount of the pharmaceutical.
  • the crystals are combined in a delivery unit intended to deliver multiple or sustained dosing of the API over a period of time, such as by subcutaneous implantation of the delivery unit.
  • a further aspect of the method of the present invention involves reconstituting the crystals to liquid form.
  • the harvested crystals are dissolved in a suitable diluent for the crystal lattice component.
  • the dissolution of the crystals releases the API from the crystals.
  • the resulting solution may include other adjuvants, such as excipients, diluents or carriers, and the mixture is formulated under conventional procedures to desired delivery forms.
  • the crystals are used to store the pharmaceutical for a period of time, such as at least one month, or at least one year, and the crystals are subsequently dissolved to use the active pharmaceutical ingredient.
  • the present invention involves the use of any of a wide variety of pharmaceutically-acceptable host crystal systems that can incorporate API's in a growing crystal lattice.
  • the crystal lattice component is selected to be compatible with the guest API, and to be suited to the use of the resulting formulation for storage and administration. Selection of the crystal lattice component will involve consideration of such factors as affinity for the API, crystal size distribution and morphology, and desired pharmaceutical concentration and delivery rate, as well as other factors well known in the art of pharmaceutical delivery systems.
  • the crystal systems must consistently incorporate the guest active pharmaceutical ingredient in terms of concentration and placement within the crystal lattice.
  • the crystals also must grow under conditions which will not degrade or otherwise adversely affect the viability of the active pharmaceutical ingredient.
  • Preferred host crystal materials are those that have a high affinity for the included API. It appears that the oriented inclusion of the API's is related to the affinity between the crystal lattice component and the API. The affinity between these materials is therefore important in obtaining the desired inclusion of the API's, and also permits control of the inclusion based upon this affinity. For example, the concentration of the pharmaceutical in a crystal can be controlled by selecting the host component to have an affinity for the API which yields the desired inclusion rate. Also, mixtures of host materials, or of host materials and other excipients, can be used to provide an affinity yielding the desired inclusion level. In one aspect of the present invention, the API's are incorporated at levels of at least about 0.001% (w/w of guest ⁇ ost), more preferably at least about 0.1% (w/w).
  • the preferred host crystal materials will also be very stable and readily crystallizable, and will maintain their "order" or crystal morphology when including a guest molecule, particularly large biomolecules.
  • the use of particular host crystal components will also depend on such factors as how small or large the crystals can be produced and how readily they dissolve.
  • it is desirable to have very small crystals e.g., pulmonary
  • moderately sized crystals e.g., injectable
  • very large crystals e.g., implantation and long term payout.
  • the useful crystal sizes will therefore vary accordingly, ranging from submicron to millimeter sizes.
  • the preferred crystals are in the order of 5-100 microns in size.
  • the useful host crystal systems are therefore diverse, and include various small molecule crystal systems which meet the desired criteria.
  • pharmaceutically-acceptable crystal lattice components include sugars, polyhydroxy alcohols, single and polyamino acids, vitamins, salts, metals, preservatives, aromatic compounds especially aromatic acids, purified natural products, and polymers.
  • Preferred crystal lattice components include, for example, sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, and potassium citrate. Also, compatible mixtures of these materials are also useful, and can be selected to obtain the desired rate of inclusion of the pharmaceutical, or to achieve desired characteristics, such as dissolution rate and pharmacokinetic profile, for the product crystals.
  • the crystal lattice components are selected to achieve the desired pharmacokinetics for the final crystals.
  • the term "pharmacokinetics" is used to refer to the profile of the delivery of active pharmaceutical ingredient from the crystals into the circulatory system. This will depend primarily on the concentration of the active pharmaceutical ingredient in the crystals, as well as parameters of the active pharmaceutical ingredient itself. While given crystal lattice components will have associated inclusion and dissolution characteristics, these can be modified by including other crystal lattice components, other API's, or a variety of excipients. Thus, single crystals having two different, co-crystallized lattice components will typically be characterized by pharmacokinetic profiles different from crystals prepared with either of the crystal lattice components alone.
  • the present invention involves the use of mixtures of crystals having different pharmacokinetics in order to achieve desired payout profiles.
  • a pharmaceutical product can be obtained by combining two different types of crystals, one type of crystal using a first crystal lattice component characterized by a first pharmacokinetic profile, and the second type of crystal using a second crystal lattice component characterized by a second pharmacokinetic profile.
  • the mixture of crystals will give a payout of API that is different from either of the individual payouts for the two crystal types.
  • the included API's are similarly diverse, limited simply by the requirements of compatibility with the host crystal and the crystal growth conditions.
  • the active pharmaceutical ingredient cannot be unacceptably degraded or otherwise adversely affected by the conditions under which the crystals are formed. Also, the active pharmaceutical ingredient should remain stable for an extended period of time while included within the host crystal, and pharmaceutically efficacious upon release from the crystal.
  • API's useful in accordance with the present include: antibiotics (such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin), fluoxetine, raloxifene, olanzapine, and nizatidine.
  • antibiotics such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin
  • fluoxetine raloxifene
  • olanzapine olanzapine
  • nizatidine nizatidine
  • Tissue Piasminogen Activator T-PA
  • Intravenous injection- Lyophilized powder which is reconstituted with sterile water (supplied) to 1 mg/mL and results in a final pK of 7.3. Can not be reconstituted with preserved water due to precipitation.
  • the 1 mg mL solution can be diluted 1 : 1 with 0.9% NaCl or D5W and help for 8 hou ⁇ at room temperature. TPA is incapable with preservatives.
  • Expression System Natural source - human leukocytes which arc exposed to an avian vims in order to produce interferon.
  • Glyc ⁇ protein single N-linked complex carbohydrate
  • 166 amino acids with a predicted molecular weight of 22,500 daltons, human sequence, has a specific activity of 200 million units per mg protein.
  • ⁇ Formulation Lyophilized product (stored refrigerated) which is reconstituted with 0-54% NaCl (supplied] to 0.25 mg/mL i__te.fa.on beta-lb, 12.5 mg mL human albumin, 12.5 mg/ml dextrose, and has a pH of approximately 7.3 (recon solution is stable for 3 hours). Injected subcutaneously every other day (chronic use).
  • Cost of therapy is $13,140 (based on 025 mg/injection, dose every other day for 1 year; equals 46 mg protein).
  • Formulation Comes in a lyophilized and a solution formulation.
  • the lyophilized formulations when reconstituted with 0.9% benzyl alcohol (supplied) contains either 0.015, 0.025, 0.05, 0.90, or 0.125 mg/ml.
  • Interferon alfa-2b 20 mg/ml glycine, 2.3 mg/ml sodium phosphate dibasic, 0-55 mg/ml sodium phosphate monobasic, and 1 mg/ml human albumin
  • the solution formulations contain either 0.05, 0.114, or 0.1 5 mg/mL Interferon alfa-2b, 20 mg/ml glycine, 2.3 mg ml sodium phosphate dibasic, 0.55 mg/ml sodium phosphate monobasic, 1 mg/ml human albumin, 1.2 mg/mL methylparaben, and 0.12 mg/ml propyparaben.
  • These formulations be injected intramusc ⁇ lar, subcutaneous, or intralesi ⁇ nal. All formulations and reconstituted products are stored at reftigerated temperatures.
  • Multi-use and lyophilized formulation indented for intramuscular or subcutaneous administration contains either 0.015, 0.045, 0.090, 0.18 mg/mL Interferon alfa-2a, 9 mg/ml NaCl. 5 g/ l human albumin, and 3 mg/ml phenol.
  • the lyophilized formulation reconstituted with 3 mL of supplied diluent (6 mg ml NaCl, .3 mg/ml phenol) consists of 0.03 mg/ml Interferon alfa-2*, 9 rag/ml NaCl, 1.67 mg/ml human albumin, and 3.3 mg/ml phenol.
  • Cost of therapy is $59,200 (28mg protein over 1 year). Specific activity is 200 million international units per mg protein.
  • Lyophilized product which is reconstituted with sterile water containing 0.3% m-cresoL 1.7% glycerin (supplied) to 2 mg/inL hGH and has a final pH of approximately 7.5, subcutaneous or intramuscular _uin_Jnistratio ⁇ .
  • Each 5 mg lyophilized vial contains 5 mg hGH, 25 mg mannitol, 1.13 mg dibasic sodium phosphate, and 5 mg glycine.
  • Strncture 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary- derived material.
  • Lyophilized product which is reconstituted with bacteriostatic water (0.9% benzyl alcohol, supplied) to 5 mg/mL hGH and has a final pH of approximately 7.4, subcutaneous or ulcerramuscular administration.
  • Each 5 mg lyophilized vial contains 5 g hGH, 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg monobasic and 1.3 mg dibasic), and 1.7 mg glycine.
  • Expression System E. coli, expressed with a leading secretion signal precursor which directs the protein to the plasma membrane of the cell where the sequence is removed and the native protein is secreted into the periplas so that the protein if folded appropriately as it is synthesized
  • Lyophilized product 212 units ghicocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysotbate-80; stored refrigerated
  • Lyophilized product 212 units ghicocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysotbate-80; stored refrigerated
  • 5.1 mL of sterile water final pH is approximately 6.1.
  • the reconstituted material is combined with 100 to 200 mL of 0.9% NaCl and administered intravenously.
  • Recombinant protein differs from human placental ghicocerebrosidase by a arginine substituted for histidine at position 495 and the glycosylation sites have been modified to terminate in mannose sugars (which are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease).
  • Orphan Drug sales > S100 million- Cost of therapy is $351,130 (1 year).
  • Formulation Suspension (20 ⁇ g/mL hepatitis B surface antigen adsorbed onto 0.5 mg aluminum, 1:20,000 thimerosal, 9 mg/ml NaCl, 1.7 mg/ml sodium phosphates). IJcrO ⁇ uscular administration.
  • Formulation contains no more than 5% yeast proteins.
  • Formulation Suspension (lO ⁇ g/ml hepatitis B surface antigen adsorbed onto 0.5 mg aliiminuirj, 1:20, 00G thimerosal). Intramuscular administration.
  • Formulation contains no more than 1% yeast proteins.
  • Produet name Epogen or Epoetin alfa (Also sold under the name Procrit by Ortho Biotech but manufactured by A geo)
  • GM-CSF (Granuloc te Macrophage-Colo ⁇ y Stimulating Factor)
  • Formulation Lyophilized solution which feconsrJnned with sterile water (stored at refrigerated temperatures for ⁇ 6 hours) o ⁇ 0.9% benzyl alcohol (can be stored for ⁇ 20 days at refrigerated TABLE A temperatures) and administered intravenous.
  • the lyophilized single use product contains either 0.25 mg/mL or 0.50 mg/mL GM-CSF, 40 mg/ml mannitol, 10 mg/ml sucrose, and 12 mg ml tromethamine (final pH is 7.4 +/- 03).
  • the reconstituted solution is then diluted into a 0.9% NaCl bag for IV administration (note if final GM-CSF is below 0.01 mg/mL add human albumin to 0.1% to prevent adsorption to the IV bag.
  • G-CSF G-CSF (Granulocyte Colony Stimulating Factor)
  • the protein has an amino acid sequence identical to the human protein except for an additional N-terminal mcthionine (necessary for expression in E. coli).
  • the human protein is glycosylated but the recombinant Neupogen is not
  • Proleuldn has a molecular weight of 1 ,300 daltons and differs from the natural human protein (is not giycosylated, the N-terminal alanine is removed, and has a serine substituted for the free cysteine at position 125)
  • Formulation Lyophilized formulation which is reconstituted with 0.9% benzyl alcohol (supplied) and aclministered intramuscular or subcutaneous.
  • the lyophilized vial contains 5 mg Somatrem, 40 mg mannitol and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic) and is reconstituted with 1 to 5 mL of 0.9% benzyl akohoL
  • the lyophilized product is stored at refrigerated temperatures, the reconstituted product is good for 14 days at refrigerated temperatures.
  • Inhalation solution (aerosol mist produced by a compressed air driven nebulizer system). Comes in a single-use 2 -5 toL ampule containing 1.0 mg/mL DNase, 0.15 mg/ ⁇ nl- calcium chloride dihydratc, and 8.77 mg/ml sodium chloride, at a pH of 6.3. The solution is stored at refrigerated temperatures and should not be exposed to light.
  • M-CSF Macrophage-Colony Stimulating Factor
  • Epoetin Beta (Erythropoietin)
  • Human Serum Albumin Product name Produced by Indication: Human use, Date of approval: Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information:
  • Epoetin alfa Thousand Oaks, CA failure including patients on dialysis and not on (rSO) dialysis, and anemia in Retrovi ⁇ *treated HlV-infected patients ( _ne 1909); treatment of anemia caused by chemotherapy in patients with non-myaloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autoiogous blood __ ___ _ donation adjirvant (DecemberJ 996) _
  • Epoetin alfa NJ failure including patients on dialysis and not on (rEPO) dialysis, and anemia in Retrovfr*trea_ed HlV-infeded patients (December 1990); treatment of anemia caused by dierno erapy in patients with non-myd ⁇ id malignancies (April 1993); prevention of anemia associated with surgical blood lots, autologcus blood donation adjuvant (December 1996) [PROCRIT was approved for marketing under Amgtn's epoetin alfa PLA.
  • CanoBopm 1 Pha ⁇ r ⁇ a & Upjohn human short stature in children due to growth hormone somatropin Kalam*zDo, A ⁇ l growth deficiency (March 1995) (rONA origin) hormone for injection
  • Prtrtropt ⁇ * Genentech human human growth hormone deficiency in children somatrem 5. San Ftan ⁇ sco, CA growth (October 1985) for injection hormone
  • RetrraseTM Boehringer Mannheim tissue treatment of acute myocardial infarction (October 1996) reteplase Gaithet ⁇ urg,MD plasminogen Centocor factor Mah-m, PA
  • ISIS 2922 Isis Pharmaceuticals antisense cytomegalovi ⁇ s retin ris Phase III fomivirsen Carlsbad, CA
  • NEUPOCCN* A gen colony treatment and prevention of application
  • PRO 542 Progenies Pharmaceuticals HIV infection Phase 1 Ta ⁇ ytown, NY
  • DABsJW H ⁇ pkintmMA protein see also cancer, skin
  • interleukin-10 Schering-Plough interleukin rheumatoid arthritis Phase
  • ISIS 2302 Isis Pharmaceuticals antisense rheumatoid arthritis Phas d Carlsbad, CA (see also digestive, skin, transplantation) TABLE A
  • CA-EPO Hoechst Marion Roussel erythropoierin anemia associated with Phased Kansas City, MO chronic renal failure Transkaryotic Therapies Cambridge, MA ogenate-N Bayer dotting hemophilia A Phase ! rFVIII Berkeley, CA factor
  • Aastrom Aastrom B Kciences cellular cancer immunosuppression/ Phase II CeU ProdocMn A ⁇ Abor.Ml therapy blood and immune system System recovery for patients receiving stem and progenitor ablative chemotherapy cell expansion from bone mamow and umbilical cord Wood
  • AfP-ScmTM Immunomedics MAb extent of disease staging of liver Phased teehnetiuffl-99m- Moms Wains, NJ and germ cell cancers FAb' fragment (germctl allogeneic 5yStemix cellular advanced leukemia, rymphoma, Phase 1 hematopoietic Palo Alto, CA therapy r ⁇ yelodysplastic syndromes stem cell tran .plantation
  • DAHu.gamma 15- Chiron Viagene gene therapy disseminated Phase! iraruduced San Diego, CA malignant melanoma autologou* tumor cells; ITAT daniplestim Static growth factor mobilization of peripheral Phased! SkokictL blood stem DCb dendritic cell Denditon cellular advanced prostate cancer Phase 11/111 therapy Mountain Vew, CA therapy multiple myeloma Phase 1
  • KSPPC-96 Antigenics heat shock melanoma, pancreatic, Phase! autologous Ne yorf ⁇ NY protein renal cell cancers tumor derived
  • IDEOInBB IDEC Pharmaceuticals MAb non-Hodgkir ⁇ B-cell lymphoma Phase VII San Diego, CA
  • IDEC-Y288 IDEC Pharmaceuticals MAb ⁇ on-Hodgldn's B-cell lymphoma Phase l/ll San Diego, CA TABLE A
  • GM SF factor prophylaxis of chemotherapy-induced neutropenia in acute myelogenous leukemia
  • LymphoScanTM Immunomedics MAb extent of disease staging of Phase III tech ⁇ etium-99m- Morris trains, NJ non-Hodgx 's B-cell lymphoma, bectumomab detection of residual disease (lymphoma) following radiatiorVchemotherapy
  • OncoRad* ra CYTOCEN MAb targeted radiotherapy for prostate Phase d CYT-356.Y.90 Princeton, NJ malignancies
  • Sigoslx* Ares-Serono and interleukin hematologkal conditions Phase l/H recombinant Serono Laboratories (r ⁇ yelodvsplastic syndromes, cancer) interleukl ⁇ -6 Norwell, MA (r-IL-6) TABLE A
  • TBC CEA Therion Biologies vacant colorectal and lung cancers Phase VII (vaccinia virus Cambridge. MA expressing carcinoembryonic antigen)
  • BetaRx-H VivoRx cellular insulin-dependent diabetes Phasel encapsulated Santa Monica, CA therapy human isles
  • I51S2302 Is ⁇ Pharmaceuticals antisense Crohn's disease, ulcerative colitis Phased Carlsbad. C ⁇ (see also autoimmune, skin, transplantation)
  • Tc-99m apcitide Londonderry NH anri-CD18 Genentech MAb acute myocardial infarction Phase humanized MAb 5. San Francisco, CA
  • BioByPa ⁇ TM GenVec gene therapy cardiovascular disease Phase 1 therapeutic Rockville. MD including cardiac artery disease angiogenesis and peripheral vascular disease,
  • VEC cardiac artery bypass grafts
  • CPC-1 11 Cypros Pharmaceuticals cellular coronary bypass surgery Phase C-risbad.
  • CA therapy (see also blood) factor Vila Corvas deep vein thrombosis, pulmonary Phase l inhibitors San Diego, CA embolism, unstable angina, myocardial infarction
  • Bothel WA see also neurologic other) ⁇ legiflhTM COR Therapeutics percutaneous trar ⁇ himinal application eptifibatide S. San Francisco, CA coronary angioplasty. submitted (llh/llla platelet Schering-Plough unstable angina aggregation Madison, NJ inhibitor) acute myocardial infarction Phase! inter leu kin-10 Schering-Prough interleukin ischemic reperfua'on injury Phase ! (IL-10! Madison, NJ (see also ⁇ IDVHIV, autoimmune, digestive, neurologic respiratory, skin) lanoteplase Bristol-Myers Squibb t-P ⁇ acute myocardial infarction Phase 111 ftmcefon, NJ
  • VEG 121 Scios growth cardiovascular disorders Phasel (vascular Mountain View, CA factor endodietial growth factor)
  • hepatitis C Phase 111 l ⁇ tron* A Schering-Plough interferon relapsed hepatitis C application XebetolTM Madison, NJ submitted interferon alfa-2b (recombinant)/ naive hepatitis C (not previously Phase III ribavirin treated with interferon) hepatitis C (PEG-tntron A/Rebetol) Phase l
  • LhADt* Ares-Serono and recombinam female infertility— foHicular support, Phase d/Ill recombinam Serono Laboratories fertility stimulation of follicular development human leuiinizing Norwel MA hormone hormone (r-hLH)
  • FIBIA5T* Sdos growth stroke Phase d/Ill trafermin Mountain View, CA factor bee a o heart) Wyeth-Ayerst Laboratories Philadelphia, PA
  • NeuroCeflf-HD Diacrin cellular Huntington's disease Phase l (cellular Charkstown, MA therapy completed transplantation Genzyme Tissue Repair therapy) Catrib ⁇ dg-, A
  • Influenza rHAO Protein Sdences vacdne prevention of influenza Phase n Vacdne Maiden, CT influenza vaccine influenza virus Aviro ⁇ vacdne prevention of influenza Phase Id vaccine Mountain View, CA
  • NCUPOCtN* A gen colony multilobar pneumonia, Phase IU
  • PIV vaccine Vvyeth- derie continuous prevention of parainfluenza Phase l live, attenuated Vaccines & Pediatrics ceil line virus-mediated lower respiratory Philadelphia, PA vacdne disease in infants
  • ISIS 2302 Isis Pharmaceuticals antisense psoriasis Phase d Carlsbad, CA (see also autoimmune, digestive, transplantation) k ⁇ rattnoeytf Human Genome Sciences growth wound healing Phase ! growth factor-2 Rodeville. MD fa ⁇ or (see also other) ( GF-2J
  • IStS 2302 isis Pharmaceuticals antisense renal transplant rejection Phase d Carlsbad, CA (see also autoirnraurg, digestive, skin)
  • biopharmaceuticals which include, for example, any proteins, polypeptides, enzymes, irnmunoglobulins, polynucleic acids, and plasmids or other biopolymers.
  • biopharmaceuticals to be included in the crystal formulations of the present invention include the following: insulin, glucagon, Glucagon-Like Peptide- 1 (7-37)OH (GLP-1), human growth hormone, leptin, follicle-stimulating hormone (FSH), ribozyme, and analogs thereof .
  • the API's useful with the present invention include those which themselves may form crystalline products, as well as those which do not.
  • any proteins can be prepared as microcrystalline suspension products, but the results have frequently been unsatisfactory using existing technology.
  • inclusion of these biomolecules into a host crystal system in accordance with the present invention overcomes this limitation on crystallization.
  • the invention further finds utility even with API's that are readily crystallized, such as insulin.
  • the incorporation of such API's into a single crystal lattice can be used to enhance stability or provide means of delivery that have different characteristics.
  • Solvents for preparation of the saturated and supersaturated crystal lattice component include, but are not limited to, water, alcohols (e.g., ethanol, isopropanol), other organic solvents, acids, bases, and buffers.
  • the crystals of the present invention are prepared to have a predetermined amount of active pharmaceutical ingredient.
  • the desired amount of active pharmaceutical ingredient will depend on typical considerations, such as the effective amount of API used for administering to a patient.
  • the concentration of API in the crystal is controlled, such as by previously described means, to yield crystals which are readily used in preparing pharmaceutical formulations for administration.
  • the active pharmaceutical ingredient can be incorporated into the crystals at any of a wide variety of molar or weight percentages.
  • Preferred percentages can be easily selected by a skilled artisan taking into account the usual considerations for later formulation of the desired pharmaceutical compositions, depending on the application, route of delivery, and desired pharmacological profile. Preferred percentages include, for example, concentrations of 0.01 - 1 weight percent. As used herein, all weight percentages are given as the percent based on the weight of the crystal including the crystal lattice component, the active pharmaceutical ingredient and any other components included within the crystals, unless stated otherwise.
  • the crystals may be prepared at varying size distributions, similarly depending on the subsequent formulating to be done with the crystals, or on crystal growth parameters.
  • the crystals may be harvested and then sorted directly to desired size ranges, or may first be processed, such as by grinding or milling, and then sorted such as by sieving.
  • a desired amount of active pharmaceutical ingredient may be obtained simply by obtaining a determined weight of crystals containing the active pharmaceutical ingredient at a known weight concentration.
  • the useful size or weight range of the crystals of the present invention accordingly varies widely, depending on such factors as the inclusion level of the active pharmaceutical ingredient, the dosage amount for the active pharmaceutical ingredient, and the method of delivery of the crystals.
  • suitable crystals may have an average size distribution of 1 ⁇ m to 1 mm .
  • the crystals of the present invention will typically be used in a formulation comprising a large number of crystals. It is a feature of the present invention that the active pharmaceutical ingredient is included within the crystal lattice component in a predictable, oriented fashion. This leads to a uniform concentration of the active pharmaceutical ingredient as a molar, and therefore weight, percentage of the crystals.
  • a composition of crystals having a substantially uniform weight concentration of active pharmaceutical ingredient as between crystals.
  • substantially uniform weight concentration refers to the fact that the weight concentration of active pharmaceutical ingredient in the various crystals is sufficiently uniform that an acceptably accurate weight of active pharmaceutical ingredient can be obtained based on the weight of the crystals and the average concentration of active pharmaceutical ingredient in such crystals.
  • a composition of crystals in which the size distribution of active pharmaceutical ingredient does not vary between crystals by more than about 20 percent.
  • alternate embodiments may be equally useful, including mixtures of different size crystals.
  • a desired quantity of active pharmaceutical ingredient is then accurately obtained by measuring a weight amount of crystals which, given the concentration of active pharmaceutical ingredient, yields the selected weight of active pharmaceutical ingredient.
  • the crystals and included API's are useful in the crystal form for both the stabilization and storage of the API and for the administration of the API to a patient.
  • patient refers to either humans or non-humans, depending on the nature of the active pharmaceutical ingredient.
  • the crystals may be used as such, and in one aspect of the present invention the crystals consist essentially of simply the crystal lattice component and the API. Alternatively, the crystals include the crystal lattice component and the API in combination with other pharmaceutically-acceptable adjuvants also contained within the crystals.
  • the crystals of the present invention are preferably formulated as pharmaceutical materials for ultimate delivery in solid or liquid form.
  • the crystals are typically formulated with common, compatible, pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof.
  • pharmaceutically-acceptable adjuvants such as excipients, diluents, carriers or mixtures thereof.
  • pharmaceutically-acceptable refers in this context to the excipients, diluents or carriers, as well as coatings or other components referred to elsewhere, being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • excipients, diluents, and carriers that are suitable for such dosage forms are well known in the art, and include the following: suspension additives such as tonicity modifiers, buffers, precipitants, and preservatives; fillers and extenders such as starch, lactose, dextrose, sucrose, sorbitol, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol and glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. Additionally
  • the crystals may be coated to achieve various effects.
  • the crystals are coated with the same crystal lattice component which forms the underlying crystal, but without the included API. This assures that the coating and the underlying crystal have compatibility.
  • the coating is then applied at a thickness which provides the desired effect, such as further protection of the active pharmaceutical ingredient, bulking of the crystal for handling, and/or effecting a sustained or delayed release of the active pharmaceutical ingredient.
  • the same effects can be accomplished by coating the crystals with other compatible coating compositions, such as those which are well known in the pharmaceutical coating art.
  • the crystals can also be coated so as to release the active pharmaceutical ingredient only or preferably in a particular part of the intestinal tract or other route of administration, possibly over a period of time. This is accomplished, in known fashion, using coatings, envelopes, and protective matrices made, for example, from polymeric substances or waxes.
  • the crystals and included API's may be packaged and administered to patients in discrete pharmaceutical dosage forms.
  • the crystals may be used as such in solid form, or may be formulated into liquid solutions or suspensions prior to use.
  • the compositions may accordingly be administered by various routes, for example, by the oral, rectal, vaginal, ocular, buccal, nasal, pulmonary, iontophoretic, topical or parenteral routes. Such compositions form part of the present invention and are prepared in manners well known in the pharmaceutical art.
  • the API's of the present invention are effective over a varied dosage range.
  • compositions are formulated in one embodiment as a unit dosage form.
  • unit dosage form refers to physically discrete units, such as tablets, capsules, and suspensions in vials or cartridge/pen systems suitable as unitary dosages, particularly as unitary daily dosages.
  • Each discrete unit contains a predetermined quantity of active pharmaceutical material calculated to produce the desired effect, e.g., a prophylactic or therapeutic effect.
  • the amount of active pharmaceutical ingredient contained in a given dosage unit can be varied depending on the manner of delivering the crystals.
  • a single dosage unit in tablet form may contain 1/4, 1/3, 1/2 or 1 times the unit dose for the active pharmaceutical ingredient, according to which 1 to 4 tablets would be administered to achieve a unit dose of the active pharmaceutical ingredient.
  • a pharmaceutical product in dosage form comprising a pharmaceutical delivery unit including a dosage amount of active pharmaceutical ingredient.
  • the API is contained within the crystal lattice component, and a sufficient amount of crystals is included within the delivery unit to constitute the dosage amount of the API.
  • the dosage amount of pharmaceutical may be obtained by provision of one or more crystals of the present invention.
  • One form of the product consists essentially of a dosage amount of the crystals.
  • the pharmaceutical product consists of the dosage amount of the crystals.
  • the ultimate delivery forms may include, for example, tablets, soft and hard gelatin capsules, pellets, granules, marumes, lozenges, sachets, cachets, elixirs, suspensions, ointments, suppositories, injection solutions and suspensions, nonpareils, spheres and sterile packaged powders.
  • the crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants, including excipients, diluents and carriers, as already described.
  • One preferred form of the pharmaceutical product consists essentially of the crystals, and an alternate form consists of the crystals and the pharmaceutically-acceptable adjuvants.
  • the delivery forms are prepared by conventional techniques such as disclosed in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, PA (1995), which is incorporated herein by reference, or other treatises available to the skilled artisan.
  • Compressed tablets for example, are prepared by well-known means which are conventional in the art.
  • the tablets may be prepared by wet or dry granulation methods or by direct compression, and may be produced by any of a wide variety of tabletting machines. Tablet formulations usually incorporate diluents, binders, lubricants and disintegrators, as well as the crystals with included API's.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • Certain solid pharmaceutical dosage forms of the present invention may be coated in conventional fashion with a wide variety of materials utilizing various processes.
  • the products of the present invention may be sugar coated or film coated in accordance with well-known techniques.
  • the coatings serve an aesthetic purpose as well as a practical one. Coatings can mask an unpleasant taste or odor, can increase ease of ingestion by the patient, and can serve to improve the ultimate appearance of the dosage form. Similarly, coatings can protect the product from the effects of air, moisture and light, can improve product identification, and can facilitate handling in packaging and fill lines during manufacture.
  • Various adjuvants may be included in the coating formulations as is well known in the art. These include, for example, permeability enhancers, plasticizers, antitacking agents and the like.
  • permeability enhancers include, for example, plasticizers, antitacking agents and the like.
  • a discussion of coating techniques and adjuvants is presented in United States Patent No. 5,015,480, issued to Childers et al. on May 14, 1991, the pertinent portions of which are hereby incorporated herein by reference. Further information pertinent to coating processes and equipment may be obtained from Remington's Pharmaceutical Sciences, supra. Tablets are often coated with sugar as a flavorant and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet.
  • the compounds may also be formulated as chewable tablets by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well- established practice.
  • Instantly dissolving tablet-like formulations are also now frequently used to assure that the subject consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some subjects.
  • a lubricant is used in a tablet formulation to prevent the tablet and punches from sticking in the die of the tabletting machine.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances which swell when wetted to break up the tablet and release the crystals. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
  • Enteric formulations are used to protect crystals and the included API's from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
  • the crystals with included API's may similarly be formulated into capsules for administration.
  • Such capsules are prepared utilizing conventional encapsulating methods.
  • a general method of manufacture involves preparing the crystals for use in capsules, such as by milling the crystals to a suitable size.
  • the crystals are blended with desired excipients, diluents or carriers, and the resulting mixture is filled into suitably-sized capsules, typically hard gelatin capsules, using conventional capsule-filling machines.
  • the usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly.
  • Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are also in wide use.
  • the crystals can also be similarly formulated as elixirs or suspensions for convenient oral administration or for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.
  • the inventive crystals enable the design of sustained-release formulations based upon various factors to yield both the desired amount of active pharmaceutical ingredient and the desired pharmacokinetic profile for delivery of the active pharmaceutical ingredient.
  • the choice of the crystal component and the process used to grow the crystals of excipient host and guest active pharmaceutical ingredient can be selected and/or modified to adjust parameters such as the delivery rate of the active pharmaceutical ingredient upon use of the formulation.
  • the active pharmaceutical ingredient is incorporated into the crystal matrix at a selected rate, typically as only a small weight percentage of the overall crystal. This permits moderate and uniform rates of release.
  • Various approaches may be used to accomplish a delayed or sustained release of active pharmaceutical ingredient from the crystals.
  • the crystals of the desired size are combined with a compatible preservative and the mixture is injected subcutaneously or surgically implanted to provide a prolonged payout as the crystals dissolve as a result of contact with the surrounding body tissue and fluid.
  • the concentration of the active pharmaceutical ingredient in the crystals is reduced in order to effect a sustained release over time.
  • larger crystals may be used to provide for more prolonged payout of the active pharmaceutical ingredient.
  • coatings on the crystals are used to affect the rate of release of the active pharmaceutical ingredient. Such coatings may comprise the same crystal lattice component but without the included active pharmaceutical ingredient, as well as other coating compositions useful for this purpose.
  • the crystals of the present invention can be used to isolate and/or store the active pharmaceutical ingredient for later reconstitution into solution.
  • the crystals may be stored for extended periods of time prior to reconstitution in view of the added stability accorded the API's by the encompassing crystal lattice component.
  • the crystals are then combined with pharmaceutically-acceptable excipients, diluents or carriers to prepare the solutions for subsequent administration.
  • the crystals are readily dissolved or suspended in appropriate diluents, which may be selected, for example, from the list previously provided with regard to diluents used to initially prepare the crystals.
  • Such solutions of dissolved crystals provide the active pharmaceutical ingredient free of the previously encompassing crystal lattice component.
  • the solutions are useful, for example, for oral administration, parenteral use, or as suppositories.
  • the crystals may be formulated in a pharmaceutically-acceptable diluent such as physiological saline (0.9%), 5% dextrose, Ringer's solution, and the like, along with other additives to reduce the solubility of the crystals in suspension.
  • the resulting pharmaceutical formulations provide an active pharmaceutical ingredient which is included within the host crystal and has enhanced stability and shelf-life.
  • the present invention therefore satisfies the desire to provide certain pharmaceuticals having an acceptable, room-temperature shelf-life.
  • the desired shelf-life can be as little as one month, or may be at least one year, two years or more.
  • the pharmaceutical molecules are generally isolated from one another and from the environment by the surrounding crystal lattice.
  • the containment of the API in the solid crystal lattice also fixes the conformational orientation. This eliminates most of the potential degradation mechanisms, such as polymerization, oxidation, deamidation and proteolysis, that could otherwise reduce the stability of the pharmaceutical.
  • Methods demonstrating stability include but are not limited to high- performance liquid chromatography for purity and potency, FT-IR for secondary structure, in-vitro and in-vivo bioassays, and pharmacokinetic profiles.
  • the crystals of the present invention are readily prepared and are useful in containing the included API in an isolated, oriented position within the lattice.
  • the utility of the present invention is demonstrated in the following examples, which are illustrative in nature, and are not to be considered limiting of the scope of the present invention.
  • green fluorescent protein was incorporated into deionized ⁇ -lactose monohydrate.
  • GFP was selected because it is known to fluoresce only in its native conformation. Upon denaturation, the interior of the ⁇ -barrel of the molecule is exposed and the fluorescence of the p-hydroxybenzylideneimidazolinone chromophore is rapidly quenched.
  • Typical crystal growth conditions involved the addition of 8 volumes of an approximately 1 mg/mL (approximately 37 ⁇ mole) solution of GFP in 10 mM tris-HCl, pH8 and 10 mM EDTA to 100 volumes of a supersaturated aqueous solution (approximately 1.15 M) of deionized ⁇ -lactose monohydrate. The mixed solution was allowed to stand for 3-4 days at room temperature in a 24-well plate.
  • Crystals were harvested between 1-3 days and displayed a hatchet morphology as shown in Figure 1 with a broad base (010) further bounded by ⁇ 100 ⁇ , ⁇ 110 ⁇ , ⁇ 1- 10 ⁇ , and ⁇ 0-11 ⁇ . Small (0-10) and ⁇ 1-50 ⁇ faces are also occasionally present. When illuminated with a long wavelength UV lamp, the crystals exhibited a bright green fluorescence localized within a sharply defined pyramid corresponding to the (010) growth sector. This indicates that GFP is selectively recognized and overgrown by the (010) face in preference to the others. More importantly, it is evidence that the GFP is in its native conformation. The level of GFP to lactose is approximately 0.008% (w/w).
  • GFP fluorescence intensity was measured as a function of time and temperature in three environments: saturated aqueous ⁇ -lactose solution, lyophilized ⁇ -lactose, and crystalline ⁇ -lactose monohydrate. As shown in Figure 2, both the solution and lyophilized preparations lost nearly half of the fluorescence intensity at 333°K within one hour. The crystal showed no change at 333°K or even 343°K.
  • Example 2 To investigate the potential for incorporation of a biopharmaceutical into crystals of biocompatible excipients, studies were conducted using rhodamine- labeled glandular glucagon and lactose.
  • the rhodamine label was used to facilitate the visualization of glucagon in the host crystals.
  • Typical crystal growth conditions involved the addition of 5 volumes of a supersaturated solution of deionized ⁇ -lactose monohydrate to 1 volume of an approximately 1.5 mg/mL (approximately 300 to 400 ⁇ mole) of rhodamine-labeled glucagon in purified water.
  • the mixed solution was allowed to stand at room temperature in a 24-well plate. Crystals were harvested between 1-3 days and displayed a hatchet morphology with a broad base. With the rhodamine label, glucagon inclusion was visible in the crystals as a well-defined pyramid corresponding to the (010) growth sector.
  • the level of inclusion was determined to be approximately 0.1% (w/w).
  • In-vitro dissolution experiments were performed on the glucagon/lactose crystals to evaluate potential for in-vivo, sustained-release pharmacokinetics. The release of rhodamine-labeled glucagon into solution was followed by fluorescence spectroscopy. In a typical experiment, 1-2 crystals were added to 100 microliters of phophate buffered saline solution at room temperature and the increase in fluorescence of the solution was monitored over time. The release of glucagon from the dissolving crystals was generally complete after 24-48 hours depending on crystal size and was linear until the last few hours of dissolution.
  • Example 3 To demonstrate the universality of this technology for incorporation of a diversity of biopharmaceuticals into crystals of biocompatible excipients, studies were conducted using biosynthetic human insulin and insulin analogs, V8-GLP-l(7-37)OH, a glucagon-like insulinotropic peptide- 1 analog, exendin, and human growth hormone in deionized ⁇ -lactose monohydrate or phthalic acid.
  • V8-GLP Information regarding V8-GLP is available in United States Patent No. 5,705,483, issued to Galloway and Hoffman on January 6, 1998, which patent is hereby incorporated herein in its entirety.
  • exendin see, e.g., R. Goke, H.C. Fehmann, T. Linn, H.
  • Exendin- 4 is a High Potency Agonist and Truncated Exendin-(9-39)-amide an Antagonist at the Glucagon-like Peptide l-(7-36)-amide Receptor of Insulin-secreting Beta- cells," J. Biol. Chem. 1993, Sep 15, 268(26), pp. 19650-5, which reference is hereby incorporated herein in its entirety.
  • Typical crystal growth conditions involved the addition of 1 volume of an approximately 10 mg/mL rhodamine- or Texas red-labeled peptide or protein in 0.1M phosphate-buffered saline solution (PBS, pH7.4) to 10 volumes of a supersaturated ⁇ -lactose solution or phthalic acid solution.
  • PBS phosphate-buffered saline solution
  • Supersaturated solutions of purified ⁇ -lactose were obtained by adding 0.41 grams of ⁇ -lactose to 1 mL of purified water, allowing to dissolve in a 50-70°C water bath, and cooling to room temperature.
  • Supersaturated solutions of phthalic acid were prepared by adding 0.05 grams of phthalic acid to 1 mL of either 70/30 (v/v) water/acetonitrile or 90/10 water/ethanol, allowing to dissolve in a 50-70°C water bath, and cooling to room temperature. Larger volumes of supersaturated solutions are obtained by using the same solute-to-solvent ratio.
  • the shape of the crystals formed was dependent on the solvent system used for the phthalic acid.
  • the crystals formed with phthalic acid in water/ethanol were long, petal-shaped clusters.
  • the crystals formed with water/ethanol were smaller and rhombic.
  • Crystals of labeled-insulin/lactose were dissolved in PBS and analyzed by HPLC.
  • the level of insulin inclusion was determined to be approximately 0.1%. This process is scalable from 100 ⁇ L to several liters.
  • the larger volume crystallizations were performed using glass beakers, or other appropriate large containers, covered with watch glasses.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pharmaceutical compositions comprising crystals of a pharmaceutically-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation. The crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the active pharmaceutical ingredients to a patient. The crystals are typically combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing predetermined amounts of the pharmaceuticals. Also provided are methods for preparing the crystals, and methods for storing and administering the active pharmaceutical ingredient either included within the crystals or upon reconstitution of the crystals to a solution.

Description

PHARMACEUTICAL MATERIALS AND METHODS FOR THEIR PREPARATION AND USE
BACKGROUND OF THE INVENTION
Field of the Invention:
The present invention relates to pharmaceutical formulations involving the inclusion of an active pharmaceutical ingredient ("API") in a pharmaceuticaUy- acceptable single crystal matrix. More particularly, the crystals contain growth- sector specific, oriented inclusions of active pharmaceutical ingredients which are isolated. The active pharmaceutical ingredients have higher stability and shelf-life, and can be delivered in conventional dosage forms. This invention has general application to active pharmaceutical ingredients, and in one aspect has particular application to biopharmaceuticals. As used herein, the term "biopharmaceuticals" is used to refer to a subset of API's which are polymeric in nature, including for example, proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids. Description of the Prior Art:
There is a continuing need for pharmaceutical compositions which are capable of maintaining the quality and efficacy of the API during storage and delivery. The loss of potency of an API is a critical concern in assuring that viable, effective drugs are delivered to patients. It is similarly desirable to have formulations which do not require special packaging or handling. FuVther, it remains a constant goal to provide active pharmaceutical ingredients in a form which facilitates their use by the consumer, such as through convenient dosage forms. The present invention addresses these and other issues concerning pharmaceutical compositions and formulations.
Although not limited to biopharmaceuticals, the usefulness of the present invention is well exemplified with respect to biopharmaceuticals, many of which demonstrate the problems encountered in prior-art approaches. Ensuring long-term stability and maintaining activity of biopharmaceuticals is a prevalent concern. The chemical complexity and conformational fragility of protein drugs, for example, make them highly susceptible to both physical and chemical instabilities and threaten their emergence into the marketplace. Denaturation, adsorption with container walls, aggregation, and precipitation can result from non-covalent interactions between a drug and its environment. Insulin, for instance, has been shown to adsorb onto the surfaces of glass and plastic containers, and to have interactions at air-water interfaces, leading to denaturation, aggregation and precipitation. For example, upon denaturation human growth hormone (HGH) forms dimers and higher molecular weight aggregates, and glucagon in solution has been shown to readily gel or aggregate when subjected to mechanical stress. As a further example, researchers have distinguished nine major reaction mechanisms by which proteins degrade, including hydrolysis, imide formation, deamidation, isomerization, racemization, diketopiperazine formation, oxidation, disulfide exchange, and photodecomposition. The rates of these deleterious processes depend in large measure on the protein and its environment. The primary chemical degradation products of glucagon, for example, include oxidation of Met (27), deamidation of Gin (24), and acid-catalyzed hydrolysis at Asp (9), Asp (15) and Asp (21). HGH undergoes chemical decomposition via oxidation at Met (14) and deamidation at Asn (149).
A critical challenge of product development science in the pharmaceutical industry therefore has been devising formulations that maintain the stability of the active pharmaceutical ingredient over an acceptable shelf-life. This has been especially difficult to achieve for certain API's which are unstable in solution or with respect to many common formulation processes. Developing techniques for stabilization and storage looms as a great impediment to the pharmaceutical industry. Formulation scientists have consequently used a variety of techniques to enhance the stability of API's while maintaining other important product characteristics such as biocompatibility, absorption, pharmacokinetics, efficacy and excretion.
One technique used in formulating biopharmaceuticals has been lyophilization of the biopharmaceutical solution in the presence of excipients, buffers and/or bulking agents. However, even lyophilized preparations must typically be stored under refrigeration, a requirement which is neither technically nor economically feasible in many markets and inhibits flexibility of patient use. There has therefore been a continuing demand for formulations of many biopharmaceuticals which would permit their storage at ambient temperatures. This would permit more rapid development of products, increasing flexibility in shipping, storing and carrying the drug products, and allowing introduction and use of such products in markets where refrigeration is too costly. Moreover, the increased stabilization of biopharmaceuticals would naturally improve the general use of the biopharmaceuticals where shelf life is an important consideration, whether or not refrigeration or other concerns are at issue. The prior art use of excipients in the lyophilization of biopharmaceuticals has been directed away from inclusion of the biopharmaceuticals in single crystals in the manner of the present invention. It has been widely assumed that amorphous glasses are critical in the stabilization of biopharmaceuticals by such excipients in lyophilized form, and it has been suggested that the drug molecules must exist in amorphous regions between the crystalline domains. See, e.g., M. J. Pikal, "Freeze Drying of Proteins", to be published in Peptide and Protein Delivery, 2nd Ed., V. H. L. Lee, Marcel Dekker, Preprint, 1995. Implicit in this reasoning is the conclusion that the biopharmaceuticals could not exist as guests within single crystals.
In the process of lyophilization, typically an aqueous solution containing a biopharmaceutical with a limited amount of excipient(s) is frozen and then dried under vacuum to produce solids of sufficient stability for storage and distribution. Excipients are added to prevent blow out of the product, to provide stability during lyophilization and/or dissolution, and to enhance compatibility for parenteral use. Various excipients used with lyophilization have included salts, metal ions, polyalcohols, surfactants, reducing agents, chelating agents, other proteins, amino acids, fatty acids, and phospholipids. The more frequently used excipients include mannitol, alanine, glycine, sorbitol, lactose, arginine, and maltose. The results obtained with such excipients, however, have usually been inconsistent. Most lyophilized biopharmaceuticals are amorphous powders that have no specific structure, and as a result, the amount and location of the incorporated biopharmaceutical varies widely for the product particles. Also, they are typically readily dissolved, rendering them unsuitable for use as a sustained-release material. Further, there is no isolation of the pharmaceutical molecules from the environment or one another, leaving them susceptible to degradation by various mechanisms. Studies have shown that lyophilization of excipients can typically damage proteins rather than protect them. See, e.g., J. F. Carpenter, J. H. Crowe, "Infrared spectroscopic studies of the interaction of carbohydrates with dried proteins", Biochemistry 1989, 28, 3916-3922; J. F. Carpenter, S. Prestrelski, T. Arakawa, "Separation of freezing- and drying-induced denaturation of lyophilized proteins by stress-specific stabilization: I. Enzyme activity and calorimetric studies," Arch. Biochem. Biophys. 1993, 303, 456-464. K. Izutsu, S. Yoshioka, Y. Takeda, "The effects of additives on the stability of freeze-dried β-galactosidase stored at elevated temperatures", Int. J. Pharm. 1991, 71, 137-146. K. Izutsu, S. Yoshioka, T. Teroa, "Decreased protein-stabilizing effects of cryoprotectants due to crystallization", Pharm. Res. 1993, 10, 1232-1237. Crystallized pharmaceuticals have been used in some instances, but there have been inherent limitations. Some API's , e.g. insulin, can be crystallized themselves, and are useful in that form for administration to patients. However, the majority of biopharmaceuticals either do not crystallize or the crystallization is very difficult, particularly on a commercial scale. Further, crystallization procedures are limited to the use of pharmaceuticaUy-acceptable ingredients and process conditions that do not adversely affect the active pharmaceutical ingredient, thus further constraining the ability to obtain desired microcrystalline suspensions.
The fact that macromolecules are routinely isolated in sub-millimolar concentrations in a variety of crystals is known. See, e.g., K. Strupat, M. Karas, F. Hillenkamp, Int. J. Mass Spec. Ion Proc, 111, 89-102, 1991. Also, certain aromatic acids have been employed as hosts for biopolymer guests in crystals for use in matrix-assisted laser desorption ionization (MALDI) mass spectrometry, but not for the purposes of the present invention. See, Review by F. Hillenkamp, M. Karas, R.C. Beavis, B.T. Chait, Anal. Chem, 63, 1 193A-1203A; S. Borman,
Chem. Eng. News, 23-25, June 19, 1995. However, crystallization conditions in these studies were optimized for characterization of the incorporated biopolymers. There were no investigations into optimizations that would be relevant to pharmaceutical preparations or operations such as homogeneity of the concentration of the inclusions, process scale-up, process robustness, chemical and physical stability of the preparations, suspendability in biocompatible solutions, preservative requirements and compatibility, container/closure system compatibility, and pharmacokinetic profiles.
The difficulty in obtaining suitable single crystals of some biopolymers has encouraged structural chemists to partially orient such molecules with electric, magnetic, or flow fields, by dissolution in liquid crystals or stretched gels, and as monolayers. In a similar effort, the isolation of biopolymers in a single crystal matrix has recently been studied in an effort to use such crystals for structural analysis of the biopolymers. Such isolation technique is described in "Single Crystal Matrix Isolation of Biopolymers," J. Chmielewski, J.J. Lewis, S. Lovell, R. Zutshi, P. Savickas, C.A. Mitchell, J.A. Subramony, and B. Kahr, J. Am. Chem. Soc. 1997, 119, 10565-10566. However, this article simply demonstrates that certain biopolymers are oriented by the host lattice, and the article suggests the use of such crystals for analyzing spectral anisotropies in biological molecules which could not otherwise be crystallized. This article does not discuss or suggest the use of this technique for enhancement of stability or sustained release of pharmaceuticals, or their administration to patients. Further, the proteins studied were not of pharmaceutical interest, the crystal materials described in this article, namely phthalic acid, gentisic acid and sinapic acid, were not selected or evaluated for biocompatibility, and the crystal sizes were not optimized for particular routes of administration. Therefore, the produced crystals with included biopolymers would not be suitable for administration to patients.
Other prior art procedures have required the use of polymers that are difficult to prepare, require harsh preparation conditions that can be harmful to the API's, and yield inconsistent results. For example, United States Patent No. 5,075,291 describes a process for preparing a uniformly-dispersed, pharmaceutically-active material in a crystalline sugar alcohol matrix. However. this process requires the addition of the API into a molten sugar alcohol with considerable mechanical agitation. Many API's and virtually all biopharmaceuticals would not be stable in the extreme temperature of 110°C and the physical stresses of a high-shear vortex mixer used for agitation. The present invention does not require these extremes of temperature and physical agitation. Also, the process of the present invention slowly includes the API into the growing crystal lattice in specific growth sectors, instead of homogeneous mixing and entrapping of the active pharmaceutical ingredient in a viscous melt.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to pharmaceutical compositions comprising single crystals of a pharmaceuticaUy-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation. The crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the API's to a patient. The crystals may be coated or combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing dosage amounts of the API's. Alternatively, the crystals are prepared as depot formulations which may be administered, as by subcutaneous injection or implantation, to provide a long-term payout or sustained release of the active pharmaceutical ingredient. The present invention further provides methods for preparing the crystals and for storing and administering the active pharmaceutical ingredient either in crystal form or upon reconstitution to a solution.
Accordingly, it is an object of the present invention to provide single crystals which include API's in a growth-sector specific orientation. It is a feature of the invention that the API's are included at predictable, uniform concentrations that permit use of the crystals in formulating dosage amounts of the API's.
Another object of the present invention is to provide compositions comprising API's included in single crystals to provide improved stability and shelf-life. The active pharmaceutical ingredients may therefore be stored for extended periods of time prior to use either as crystals or as reconstituted solutions. It is a further object of the present invention to provide single crystals with included API's to provide quick, delayed-release or sustained-release formulations for flexibility in pharmacokinetic profiles in delivery of the API's to patients.
Another object of the present invention is to provide pharmaceutical delivery units including an amount of single crystals sufficient to provide a dosage amount of the included active pharmaceutical ingredient. Alternatively, the pharmaceutical delivery units include a quantity of crystals sufficient to provide a prolonged payout of the active pharmaceutical ingredient. The crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants including excipients, diluents and carriers.
A further object of the present invention is to provide methods for preparing compositions comprising single crystals with growth-sector specific inclusions of API's.
It is another object of the present invention to provide methods for the storage and administration of API's utilizing inclusion of the API's within single crystals. Other objects, features, and advantages of the present invention will be apparent to those skilled in the art from the following description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photomicrograph illustrating fluorescence of a single crystal of green fluorescent protein in α-lactose monohydrate (1.8 (h) x 0.8 (w) x 0.5 (d) mm3) with an idealized representation of habit. The sides of the crystal in the photomicrograph are bright due to internal reflection.
Figure 2 is a graph of the fluorescence decay of the green fluorescent protein at 333°K in several environments: mixed crystal in α-lactose monohydrate (triangle), saturated lactose solution (square), and lyophilized α-lactose monohydrate (diamond).
DESCRIPTION OF THE PREFERRED EMBODIMENT
For the purposes of promoting an understanding of the present invention, reference will now be made to the embodiments described hereafter. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such modifications and applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art to which the invention relates.
The present invention utilizes single-crystal matrix inclusion of active pharmaceutical ingredients ("API's") to achieve advantageous storage and delivery of the API's. This invention has application to a wide range of API's to provide enhanced stability and/or delivery of the active pharmaceutical ingredients. For some applications, such as for many biopharmaceuticals, the invention is particularly advantageous in providing greater stability over time and in providing alternative delivery and sustained release formulations to patients . The small molecule host crystals comprise a crystal lattice component which includes the API's in an oriented, growth-sector specific manner. The crystals and included API's are prepared to be pharmaceutically acceptable and pure, thereby being useful for administration to patients to be treated with the API's. As used herein, the term "pharmaceuticaUy-acceptable" refers to sufficient quality to meet regulatory and compendial requirements for administration to humans and/or animals. The crystals provide a regular, predictable inclusion of the guest active pharmaceutical ingredient, and the crystals can consequently be used for obtaining a predetermined amount of the active pharmaceutical ingredient for delivery to a patient. In one aspect, the host crystal gradually dissolves upon contact with body tissue or fluids, and is therefore useful as a system for delivery of the active pharmaceutical ingredient into the body. Alternatively, the crystals and included active pharmaceutical ingredient may be reconstituted into a solution for administration to a patient.
The active pharmaceutical ingredient molecules are generally isolated from one another and are insulated from the environment by the host crystal. This leads to reduced susceptibility of the API to degradation, and therefore enhanced stability and shelf-life. Also, the use of appropriate host crystal compounds, or selected dosage forms, permits the design of quick, delayed, or sustained-release formulations for delivery of the active pharmaceutical ingredient. Sustained- release formulations are particularly advantageous for treatment of chronic conditions as they provide a consistent amount of drug delivery over a long period of time to improve ease of use and patient compliance in administering the API.
The crystals preferentially incorporate the active pharmaceutical ingredient on certain faces, thereby providing a growth-sector specific inclusion and orientation to the API's. As used herein, the term "growth-sector specific inclusion and orientation," and equivalent terminology, refers to the fact that the API molecules are included primarily at certain faces of the crystal matrix. The growth-sector specific inclusion and orientation can be determined by one skilled in the art, as demonstrated in the examples herein, by fluorescence microscopy and anisotropy measurements, single crystal desorption mass spectrometry, and autoradiography of 14C-labeled material. In one embodiment, at least about
0.001% (on weight/weight (w/w) basis) of the pharmaceutical is included within specific faces of the crystal matrix, and in another embodiment at least about 0.1% (w/w) and up to about 10%. The crystal parameters, including the particular crystal lattice component for a given API, the concentration of API, the use of crystal adjuvants, and the crystallization conditions, are selected to achieve the growth-sector specific inclusion and orientation of the API within the crystals.
The method of the present invention broadly involves the including of the active pharmaceutical ingredient into the single crystal matrix formed from a pharmaceutically-acceptable crystal lattice component. As used herein, the term "included" in the crystals refers to the active pharmaceutical ingredient being chemically adsorbed within the crystal lattice as the crystal is formed. This inclusion of the active pharmaceutical ingredient molecules is distinguished from crystallization of the API molecules with one another, and from simple and random entrapment of the API molecules by the formed crystal. The crystal product of the present invention is ordered, in contrast to the amorphous material produced by other approaches. The API is incorporated in the crystal in relation to its degree of affinity for the crystal lattice molecules. The crystal lattice component is therefore selected to be both chemically and physically compatible with the API such that the API is received by the crystal during formation, and remains stable and efficacious while within the crystal and upon release therefrom. In a typical approach, the including of the active pharmaceutical ingredient involves combining the crystal lattice component, the active pharmaceutical ingredient and a pharmaceutically-acceptable adjuvant in a liquid state. The crystal lattice component is then crystallized under pharmaceutically-acceptable conditions to form the inventive crystals. For example, one method uses spiking of the API into a saturated or supersaturated solution of the crystal lattice component in a suitable organic and/or aqueous solvent system. Alternately, the saturated or supersaturated solution of the crystal lattice component may be spiked into the API solution. Other components may also be added to the solution, including compounds which facilitate or modify crystal growth or which are desired for incorporation in the final formulation. The solution may be seeded using any of a variety of conventional techniques.
In one approach, the solution is allowed to evaporate and/or equilibrate to cooler conditions for growth of the crystals. The crystals are then grown as the solvent is slowly evaporated away and/or the solution is cooled, with the evaporation and temperature gradient conditions being selected dependent on such factors as the solvent system and the desired crystal size. The crystals containing the active pharmaceutical ingredient are harvested from the remaining solution and are preferably washed to remove surface contamination. This procedure yields crystals which include the active pharmaceutical ingredient at a predictable concentration and facial orientation.
In accordance with the present invention, crystals are grown under pharmaceutically-acceptable conditions. As used herein, the term "pharmaceutically-acceptable conditions" refers to the use of crystal and API compounds which are pharmaceutically-pure, and for which such pharmaceutical purity is maintained in the final crystals. The crystal and API compounds are pharmaceutically pure, or have pharmaceutical purity, if they are of sufficient purity to be suitable for administration under applicable FDA or other administrative regulations regarding purity. The term pharmaceutically-acceptable conditions further refers to the use of crystallization conditions through which the API compounds retain pharmaceutical efficacy in the final crystals and upon subsequent administration to patients.
The present invention readily allows the inclusion of API's by affinity with the small host molecules in the growing crystal lattice. This overcomes many of the limitations associated with previous approaches. The processing involved with preparing the present crystals does not expose the API's to harsh conditions, thereby substantially reducing or avoiding the possible degradation or disruption of the structural aspects of the API which could occur with prior art techniques. The inventive crystals have an added advantage in that they do not interfere with normal analytical methodologies used for characterizing the pharmaceutical product. The small host molecules can be easily separated on the basis of molecular size, which is not the case for prior art techniques which use polymers that interfere with analytical methodologies.
The API molecules are incorporated into the host crystals typically at rates of at least about 0.001% (w/w), preferably at least about 0.1%, and more preferably about 1% to about 10% (w/w). Alternatively, the API molecules are included at rates of at least about 0.01 %, and as much as at least about 1 % (w/w). The limited molar concentration of the active pharmaceutical ingredient in the host crystals means that the active pharmaceutical ingredient molecules are generally isolated from one another in the crystals. Isolation of the API molecules is particularly advantageous for those molecules, such as certain biopharmaceuticals, which could otherwise react with one another (e.g., by polymerization) or the surrounding environment. The degree of isolation can be verified by those skilled in the art using atomic force microscopy or reaction fluorescence energy techniques. The present invention has a particular application to guest-host systems in which the guest API molecules are reactive with one another, but in which these molecules are sufficiently isolated from one another in the crystals as to substantially prevent such interaction. Consequently, the invention provides containment of the API molecules in the solid state crystals and provides for the API to be comformationally stable.
The method preferably involves preparing a mixture of crystals of substantially uniform size. This may include processing of the harvested crystals, such as by grinding or milling, to reduce the crystals to a substantially uniform size. Greater uniformity can be achieved by sorting the processed crystals, such as by sieving. A preferred method further includes obtaining crystals which have a substantially uniform concentration of pharmaceuticals, for example, about 1% (w/w) of pharmaceuticals, that do not vary between crystals by more than 10 percent.
The method of the present invention may further include formulating the crystals into pharmaceutical preparations. For example, the collected crystals may optionally be coated with a suitable composition. Coated or uncoated crystals may be blended with one or more pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof. The blended crystals and adjuvant(s) are then formulated into pharmaceutical delivery units. In one embodiment, each unit includes a predetermined amount of the pharmaceutical. Alternatively, the crystals are combined in a delivery unit intended to deliver multiple or sustained dosing of the API over a period of time, such as by subcutaneous implantation of the delivery unit. A further aspect of the method of the present invention involves reconstituting the crystals to liquid form. In accordance with this method, the harvested crystals are dissolved in a suitable diluent for the crystal lattice component. The dissolution of the crystals releases the API from the crystals. The resulting solution may include other adjuvants, such as excipients, diluents or carriers, and the mixture is formulated under conventional procedures to desired delivery forms. In a particular aspect of the present invention, the crystals are used to store the pharmaceutical for a period of time, such as at least one month, or at least one year, and the crystals are subsequently dissolved to use the active pharmaceutical ingredient. The present invention involves the use of any of a wide variety of pharmaceutically-acceptable host crystal systems that can incorporate API's in a growing crystal lattice. The crystal lattice component is selected to be compatible with the guest API, and to be suited to the use of the resulting formulation for storage and administration. Selection of the crystal lattice component will involve consideration of such factors as affinity for the API, crystal size distribution and morphology, and desired pharmaceutical concentration and delivery rate, as well as other factors well known in the art of pharmaceutical delivery systems. The crystal systems must consistently incorporate the guest active pharmaceutical ingredient in terms of concentration and placement within the crystal lattice. The crystals also must grow under conditions which will not degrade or otherwise adversely affect the viability of the active pharmaceutical ingredient.
Preferred host crystal materials are those that have a high affinity for the included API. It appears that the oriented inclusion of the API's is related to the affinity between the crystal lattice component and the API. The affinity between these materials is therefore important in obtaining the desired inclusion of the API's, and also permits control of the inclusion based upon this affinity. For example, the concentration of the pharmaceutical in a crystal can be controlled by selecting the host component to have an affinity for the API which yields the desired inclusion rate. Also, mixtures of host materials, or of host materials and other excipients, can be used to provide an affinity yielding the desired inclusion level. In one aspect of the present invention, the API's are incorporated at levels of at least about 0.001% (w/w of guest±ost), more preferably at least about 0.1% (w/w).
The preferred host crystal materials will also be very stable and readily crystallizable, and will maintain their "order" or crystal morphology when including a guest molecule, particularly large biomolecules. The use of particular host crystal components will also depend on such factors as how small or large the crystals can be produced and how readily they dissolve. For various routes of administration, it is desirable to have very small crystals (e.g., pulmonary), moderately sized crystals (e.g., injectable), or very large crystals (e.g., implantation and long term payout). The useful crystal sizes will therefore vary accordingly, ranging from submicron to millimeter sizes. In one aspect of the present invention, the preferred crystals are in the order of 5-100 microns in size.
The useful host crystal systems are therefore diverse, and include various small molecule crystal systems which meet the desired criteria. Examples of pharmaceutically-acceptable crystal lattice components include sugars, polyhydroxy alcohols, single and polyamino acids, vitamins, salts, metals, preservatives, aromatic compounds especially aromatic acids, purified natural products, and polymers. Preferred crystal lattice components include, for example, sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, and potassium citrate. Also, compatible mixtures of these materials are also useful, and can be selected to obtain the desired rate of inclusion of the pharmaceutical, or to achieve desired characteristics, such as dissolution rate and pharmacokinetic profile, for the product crystals.
The crystal lattice components are selected to achieve the desired pharmacokinetics for the final crystals. As pertains to the present invention, the term "pharmacokinetics" is used to refer to the profile of the delivery of active pharmaceutical ingredient from the crystals into the circulatory system. This will depend primarily on the concentration of the active pharmaceutical ingredient in the crystals, as well as parameters of the active pharmaceutical ingredient itself. While given crystal lattice components will have associated inclusion and dissolution characteristics, these can be modified by including other crystal lattice components, other API's, or a variety of excipients. Thus, single crystals having two different, co-crystallized lattice components will typically be characterized by pharmacokinetic profiles different from crystals prepared with either of the crystal lattice components alone. Similarly, including excipients or other API's will provide altered rates of inclusion or dissolution for the resulting crystals, providing an associated modification in the pharmacokinetic profile for the resulting crystals. In a related aspect, the present invention involves the use of mixtures of crystals having different pharmacokinetics in order to achieve desired payout profiles. For example, a pharmaceutical product can be obtained by combining two different types of crystals, one type of crystal using a first crystal lattice component characterized by a first pharmacokinetic profile, and the second type of crystal using a second crystal lattice component characterized by a second pharmacokinetic profile. The mixture of crystals will give a payout of API that is different from either of the individual payouts for the two crystal types. The included API's are similarly diverse, limited simply by the requirements of compatibility with the host crystal and the crystal growth conditions. The active pharmaceutical ingredient cannot be unacceptably degraded or otherwise adversely affected by the conditions under which the crystals are formed. Also, the active pharmaceutical ingredient should remain stable for an extended period of time while included within the host crystal, and pharmaceutically efficacious upon release from the crystal.
Given the foregoing criteria, examples of API's useful in accordance with the present include: antibiotics (such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin), fluoxetine, raloxifene, olanzapine, and nizatidine. A more complete list of API's useful in accordancw with the present invention would include those identified in the following Table A.
TABLE A
Marketed Recombinant Protein Products
Tissue Piasminogen Activator, T-PA
• Product name: Acϋvase (Generic name: A epase)
• Produced by: Genentech
• Indication: Hunan use, Acute myocardial infarction
• Date of approval: Nov 87, Patent expires on Dec 2000.
• Formulation: Intravenous injection- Lyophilized powder which is reconstituted with sterile water (supplied) to 1 mg/mL and results in a final pK of 7.3. Can not be reconstituted with preserved water due to precipitation. The 1 mg mL solution can be diluted 1 : 1 with 0.9% NaCl or D5W and help for 8 houπ at room temperature. TPA is incapable with preservatives.
Ingredients 100 pig vial 50 mg vial 20 mp vial
T-PA 100 mg 50 mg 20 mg
L-Argiπine 3.5 g 1.7g 0.7g
Phosphoric acid lg 0.5g 0_2g
Polysotbate 80 <l l mg 4 g <1.6 mg
Vacuum No Yes Yes
• Expression System: Mammalian cell line (Chinese Hamster Ovary cells)
• Refolding Condition*:
• Structure: Olycoprotein of 527 amino acids, sequence from human melanoma cell line, activity of
• Additional Information: Sales > $100 million. Cost of therapy $2,750 (100 mg).
Interferon Gamma-lb
• Product name: Acammune
• Produced by: Genentech
■ Indication: Human use, chronic gianulomatous disease - • Date of approval: Dec 1990
• Formulation: Single dose solution formulation (0.5 mL), subcutaneous injection. Each 0.5 mL contains lOOμg interferon gamma- lb, 20 mg mannitol, 036 mg sodium succinate, 0.05 mg polysorbate-20 in sterile water.
• Expression System: E. coli
• Refolding Conditions:
• Post-Transitional Modifications:
• Structure: Single chain; Human sequence, 140 amino acids, 16,465 molecular weight, noπ-eovalent dimeric form in solution, activity of 30 million unita/mg.
• Additional Information: 14% injection site irritation vs. 2% in placebo. Cost S 140 for 50μg.
Interferon al a-n3 (natural source, not recombinant)
• Produet name: Aileron N
• Produced by: Interferon Science (New Brunswick, NJ)
• Indication: Human use, Genital Warts
• Date of approval: Jun 90
• Formulation: Preserved solution formulation (each mL contains 5 million IU of interferon alfa-n3 in phosphate buffered saline containing 3.3 mg phenol and 1 mg human albumin). Injected intralesional twice weekly for up to 8 weeks (50μL injected into each wart, 500μL total dose per treatment).
• Expression System: Natural source - human leukocytes which arc exposed to an avian vims in order to produce interferon.
• Refolding Conditions: None
• Structure: Approximately 166 amino acids with a molecular weight tanging from 16 to 27 I Da, specific activity of 20,000 I Vmg or greater.
• Additional Information: Cost $142 per mL.
Beta Interferon la
• Product name: Avonex
• Produced by: Biogen (Cambridge, MA)
• Indication: Human use, Multiple Sclerosis
• Date of approval: May 95 ιy
TABLE A
• Formulation: Lyophilized powder (stored refrigerated or at Z5°C for < 30 days) which is reconstituted with sterile water (supplied, l.lmL) to 30 μg mL beta interferon l , 15 mg/mL human albumin. 5.8 mg ml NaCl, 5.7 mg/ml dibasic Na phosphate, 1.2 mg/ml monobasic sodium phosphate, and has a pH of approximately 7.3 (recon sohmcra is stable for 6 hours at refrigerated temperatures). Weekly intramusculai injection by patient or doctor (dosed for 1-2 years in clinical trials).
• Expression System: Mammalian cells (Chinese Hamster Ovary cells)
• Refolding Conditions:
• Structure: Glycσprotein (single N-linked complex carbohydrate), 166 amino acids with a predicted molecular weight of 22,500 daltons, human sequence, has a specific activity of 200 million units per mg protein.
• Additional Information: Cost $ 180 per vial (33μg)
Interferon beta-lb
■ Product name: Betaseron
• Produced by: Bexlex Laboratories (Wayne, NJ and Chiron, Emeryville, CA)
• Indication: Human use, Multiple Sclerosis
• Date of approval: July 93.
■ Formulation: Lyophilized product (stored refrigerated) which is reconstituted with 0-54% NaCl (supplied] to 0.25 mg/mL i__te.fa.on beta-lb, 12.5 mg mL human albumin, 12.5 mg/ml dextrose, and has a pH of approximately 7.3 (recon solution is stable for 3 hours). Injected subcutaneously every other day (chronic use).
• Expression System: E. coli
• Refolding Conditions:
• Structure: 165 amino acids with an approximate molecular weight of 18,500 daltons, human sequence bui with a seπne or cysteine substitution at residue 17. Recombinant form does not contain the carbohydrate moiety found in d e natural material. Has a specific activity of 32 million units per mg protein.
• Additional Information: Sales > $500 million. Cost of therapy is $13,140 (based on 025 mg/injection, dose every other day for 1 year; equals 46 mg protein).
Interferon alfa-2b
• Product name: Intron A
• Produced byi Schering-Plough (Madison, NJ)
• Indication: Human use, Hairy cell leukemia, genital warts, Hepatitis, Melanoma, Kaposi's sarcoma
• Date of approval: June 86
• Formulation: Comes in a lyophilized and a solution formulation. The lyophilized formulations when reconstituted with 0.9% benzyl alcohol (supplied) contains either 0.015, 0.025, 0.05, 0.90, or 0.125 mg/ml. Interferon alfa-2b, 20 mg/ml glycine, 2.3 mg/ml sodium phosphate dibasic, 0-55 mg/ml sodium phosphate monobasic, and 1 mg/ml human albumin, The solution formulations contain either 0.05, 0.114, or 0.1 5 mg/mL Interferon alfa-2b, 20 mg/ml glycine, 2.3 mg ml sodium phosphate dibasic, 0.55 mg/ml sodium phosphate monobasic, 1 mg/ml human albumin, 1.2 mg/mL methylparaben, and 0.12 mg/ml propyparaben. These formulations be injected intramuscαlar, subcutaneous, or intralesiσnal. All formulations and reconstituted products are stored at reftigerated temperatures.
• Expression System: E. coli
• Refolding Conditions:
• Structure: Water soluble protein a molecular weight of 19,271 daltons. The Interferon alfa-2b gene is derived from human leukocytes.
• Additional Information: Sales > $500 Million. Cost of therapy is $ 16,445 (5 million units every day for 1 year, this is equal to 9 mg protein). Specific activity is 200 million units per mg protein
Interferon alfa-2a
• Product name: Roferon-A
• Produced by: Hofrmann-La Roche (Nutley, NJ)
• Indication: Human use. Hairy cell leukemia, Kaposi's sarcoma, myelagenous leukemia
• Date of approval: June 1986
• Formulation: Multi-use and lyophilized formulation indented for intramuscular or subcutaneous administration. Multi-use formulation contains either 0.015, 0.045, 0.090, 0.18 mg/mL Interferon alfa-2a, 9 mg/ml NaCl. 5 g/ l human albumin, and 3 mg/ml phenol. The lyophilized formulation reconstituted with 3 mL of supplied diluent (6 mg ml NaCl, .3 mg/ml phenol) consists of 0.03 mg/ml Interferon alfa-2*, 9 rag/ml NaCl, 1.67 mg/ml human albumin, and 3.3 mg/ml phenol.
■ Ezprcarioα System: £. coli (utracyclinc promoter). 2 Q
TABLE A
• Refolding Conditions:
■ Structure: Protein of 165 amino acids having a molecular weight of 19,000 daltons
• Additional Information: Cost of therapy is $59,200 (28mg protein over 1 year). Specific activity is 200 million international units per mg protein.
Human Growth Hormone (Somatropin) Product name: BioTropin Produced by: Bio-Technology General (Iselin, NJ) Indication Human use, Growth Deficiency Date of approval: May 95 Formulation; Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information:
Human Growth Hormone (Somatropin) Product name: Genotropin
Produced by: Pharmacia and Upjohn (Kalamazoσ, MI) Indication: Human use, Growth Deficiency Date of approval: Aug 95 Formulation: Expression System: Refolding Conditions: Structure: Additional Information:
Human Growth Hormone (Somatropin)
• Product name: Humatrope
• Produced by: EU Lilly (Indianapolis, IN)
• Indication: Human use, Growth Deficiency
• Date of approval: March 87
• Formulation: Lyophilized product which is reconstituted with sterile water containing 0.3% m-cresoL 1.7% glycerin (supplied) to 2 mg/inL hGH and has a final pH of approximately 7.5, subcutaneous or intramuscular _uin_Jnistratioα. Each 5 mg lyophilized vial contains 5 mg hGH, 25 mg mannitol, 1.13 mg dibasic sodium phosphate, and 5 mg glycine.
• Expression System: E. coli.
• Refolding Conditions:
• Strncture: 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary- derived material.
• Additional Information: Cost $210 per 5 mg hGH.
Human Growth Hormone (Somatropin) Product name: Norditropiπ Produced by: Novo Nordisk (Princeton, NJ) Indication: Human use, Growth Deficiency Date of approval: July 1 Formulation: Expression System: Refolding Conditions:
Port-Trat itiαnal Modification*:
Structure:
Additional Information:
Human Growth Hormone (Somatropin)
• Product name: Nutropin and Nutropin AQ
• Produced by: Genentech
• Indication: Human use, Growth Deficiency ^
TABLE A
• Date of approval: March 1994
• Formulation: Lyophilized product which is reconstituted with bacteriostatic water (0.9% benzyl alcohol, supplied) to 5 mg/mL hGH and has a final pH of approximately 7.4, subcutaneous or iritramuscular administration. Each 5 mg lyophilized vial contains 5 g hGH, 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg monobasic and 1.3 mg dibasic), and 1.7 mg glycine.
• Expression System: E. coli, expressed with a leading secretion signal precursor which directs the protein to the plasma membrane of the cell where the sequence is removed and the native protein is secreted into the periplas so that the protein if folded appropriately as it is synthesized
• Refolding Conditions: None, expressed folded in £. coli.
• Structure: 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary- derived material.
« Additional Information: Cost $420 per 10 mg hGH. β-Glucocerebrosidase (imiglucerase)
(β-D.glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45)
• Product name: Cerezyme
• Produced by: Genzyme (Cambridge, MA)
• Indication: Human use, Gaucher's disease
• Date of approval: May 94
• Formulation: Lyophilized product (212 units ghicocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysotbate-80; stored refrigerated) is recomtituted with 5.1 mL of sterile water, final pH is approximately 6.1. The reconstituted material is combined with 100 to 200 mL of 0.9% NaCl and administered intravenously.
• Expression System: Mammalian cell culture (Chinese Hamster Ovary cells)
• Refolding Conditions:
• Structure: Moπomcric glycσprotein of 497 amino acids, containing 4 N-linked glycosylation sites, molecular weight is 60,430 daltons. Recombinant protein differs from human placental ghicocerebrosidase by a arginine substituted for histidine at position 495 and the glycosylation sites have been modified to terminate in mannose sugars (which are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease).
• Additional Information: Orphan Drug, sales > S100 million- Cost of therapy is $351,130 (1 year).
Hepatitis B Surface Antigen
Product name: Engerix-B
Produced by: SπώhKline Beechman (Philadelphia, PA)
Indication: Human use, Hepatitis B
Date of approval: Sept 89
Formulation: Suspension (20μg/mL hepatitis B surface antigen adsorbed onto 0.5 mg aluminum, 1:20,000 thimerosal, 9 mg/ml NaCl, 1.7 mg/ml sodium phosphates). IJcrO^ uscular administration.
Expression System: A portion of the hepatitis B virus gene, coding for hepatitis B surface antigen, in cloned into yeast (Sacccharom cβs cerevisiae)
Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information: Formulation contains no more than 5% yeast proteins.
Hepatitis B Surface Antigen
Product name: Recombivax HB Produced by: Merck (Whi house Station, NJ) Indication: Human use, Hepatitis B prevention Date of approval: July 1986
Formulation: Suspension (lOμg/ml hepatitis B surface antigen adsorbed onto 0.5 mg aliiminuirj, 1:20, 00G thimerosal). Intramuscular administration.
Expression System: A portion of the hepatitis B vims gene, coding for hepatitis B surface antigen, In cloned into yeast (Sacc haromyces csrevύiae)
Refolding Conditions:
Structure:
Additional Information: Formulation contains no more than 1% yeast proteins.
Erytbropoietin (rEPO) TABLE A
• Produet name: Epogen or Epoetin alfa (Also sold under the name Procrit by Ortho Biotech but manufactured by A geo)
• Produced by: Amgen (Thousand Oaks, CA)
• Indication: Human use, Anemia
• Date of approval: June 89, Patent expires in 2004 (December .
« Formulation: Two solution foπnulations, single dose and multi-dose. Single-dose is preservative free and each mL contains 2000, 000, 4000, or 10000 units Epogen, 2-5 mg human albumin, 5.8 mg sodium citrate, 5.8 mg NaC and 0.06 mg citric acid in water for injection, pH 6.9 +/- 0.3. The preserved multi- dose product contains 10,000 units Epogen, 2.5 mg human albumin, 1 -3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid and 1 % benzyl alcohol per mL of solution, pH is 6.1 +/- 0.3. Both solutions are stored refrigerated.
• Expression System: Mammalian cell
• Refolding Conditions:
• Structure: Glycoprotein of 1 5 amino acids having a molecular weight of 30,400 daltons, sequence identical to that of the human protein.
• Additional Information: Sales > $500 million, Cost $ 120 for 10,000 units.
Human Insulin
• Product name: Hutnulin
• Produced by: Eli Lilly (Indianapolis. IN)
• Indication: Human use, Diabetes
• Date ofappπ_val: Oct 82
• Formulation:
» Expression System: E. Coli
• Refolding Conditions:
• Structure:
• Additional Information: Sales > $500 Million.
Human Insulin
• Product name: Novolin
• Produced by: Novo Nordiak (Princeton, NJ)
• Indication: Human use, Diabetes
• Date of approval: July 91
• Formulation:
• Expression System:
• Refolding Conditions:
• Post-Transitional Modifications:
• Structure:
• Additional Information:
LysPro Human Inaulin
• Product name: Humulog
• Produced by: Eli Lilly (Indianapolis, IN)
• Indication: Human use, Diabetes
• Date of approval: June 1996
• Formulation:
« Expression System:
• Refolding Conditions:
• Post-Transitional Modifications:
• Strncture:
• Additional Information:
GM-CSF (Granuloc te Macrophage-Coloπy Stimulating Factor)
• Product name: Leukine
• Produced by: Immunex (Seattle, WA)
• Indication: Human use, Bone marrow transplantation, Hodgkin's Disease, Leukemia
• Date of approval: Mar 91
« Formulation: Lyophilized solution which feconsrJnned with sterile water (stored at refrigerated temperatures for < 6 hours) oτ 0.9% benzyl alcohol (can be stored for < 20 days at refrigerated TABLE A temperatures) and administered intravenous. After reconstitution, the lyophilized single use product contains either 0.25 mg/mL or 0.50 mg/mL GM-CSF, 40 mg/ml mannitol, 10 mg/ml sucrose, and 12 mg ml tromethamine (final pH is 7.4 +/- 03). The reconstituted solution is then diluted into a 0.9% NaCl bag for IV administration (note if final GM-CSF is below 0.01 mg/mL add human albumin to 0.1% to prevent adsorption to the IV bag.
• Expression System: Yeast (S. Cerevisiae)
• Refolding Conditions: None, expressed folded.
• Structure Glycoprotein of 127 amino acids characterized by 3 primary molecular species having molecular masses of 19,500, 16800, and 15500 daltons. The primary sequence differs from natural humari GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from native.
• Additional Information: Specific activity is 5 X 107 colony forming units per g protein. Sargramostim is the proper name for yeast-derived recombinant GM-CSF. Cost for a 0.5 mg GM-CSF vial is $178.
G-CSF (Granulocyte Colony Stimulating Factor)
• Product name: Neupogen
• Produced by: Amgen (Thousand Oaks, CA)
• Indication: Human use, Neutropenia, bone marrow transplantation, anemia ■ Date of approval: Feb 91
• Formulation: Single-use solution formulation containing 0.3 mg/mL G-CSF, 10 mM sodήim acetate, 5% mannitol, and 0.004% Tween-80 at a pH of 4. The product is to be stored at refrigerated temperatures and no more than 24 hours at room temperature. If required, Neupogen can be diluted with D5W (no not dilute with saline at any time; product may precipitate), at concentrations below 5 to 15μg/mL, add human albumin to 2 mg/mL to prevent adsorption to IV bag.
• Expression System: E. coli.
• Refolding Conditions:
• Structure: A 175 amino acid protein with a molecular weight of 18,800 daltons. The protein has an amino acid sequence identical to the human protein except for an additional N-terminal mcthionine (necessary for expression in E. coli). The human protein is glycosylated but the recombinant Neupogen is not
• Additional Information: Sales > $500 million. Filgrastim is the name give to recombinant methionyl human G-CSF. Cost of therapy (lung cancer) is $2,130 (4.2 mg protein over 14 days). Specific activity is 30 million units per mg protein.
Satumomab Pen etide
• Product name: OncoScint CR/OV
• Produced by: Cytogen (Princeton, NJ)
• Indication: Human use, Colorectal and ovarian cancers
• Date of approval: Dec 92
• Formulation:
• Expression System:
• Refolding Conditions:
• Post-Transitional Modifications:
• Structure:
• Additional Information:
Interleuidπ-2
• Product name: Proleukm (generic name: Aldr_.ini.rin)
• Produced by: Chiron (Emeryville, CA)
• Indication: Human use, Renal cell carcinoma
• Date of approval: May 1992
• Formulation: Single-use lyophilized formulation which is reconstituted with 1.2 mL sterile water and administered intravenously. Each reconstituted product contains 1.1 mg/mL Proleukin, 50 mg/ml mannitol, and 0.18 mg/ml dibasic sodium phosphate (pH is 7.5 -*-/• 0.3). Lyophilized product is stored at refrigerated temperatures, reconstituted product is stable up to 48 hours at refrigerated to room temperatures, but should be stored in refrigerator due to lack of preservatives. Addition of preservatives results in increased aggregation, addition of human albumin alters pharmacology.
• Expression System: E. coli (tetracycline promoter).
• Refolding Conditions: . 4
TABLE A
• Structure: Proleuldn has a molecular weight of 1 ,300 daltons and differs from the natural human protein (is not giycosylated, the N-terminal alanine is removed, and has a serine substituted for the free cysteine at position 125)
• Additional Information: Specific activity is 18 mutton international units per 1.1 mg protein. Cost is S395 per 1 -3 mg protein.
Somatrem
• Product name: Protropin
• Produced by: Genentech (S. San Francisco, CA)
• Indication: Human use, Growth deficiency
• Date of approval: Oct 1985, patent expired on Oct 1992.
• Formulation: Lyophilized formulation which is reconstituted with 0.9% benzyl alcohol (supplied) and aclministered intramuscular or subcutaneous. The lyophilized vial contains 5 mg Somatrem, 40 mg mannitol and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic) and is reconstituted with 1 to 5 mL of 0.9% benzyl akohoL The lyophilized product is stored at refrigerated temperatures, the reconstituted product is good for 14 days at refrigerated temperatures.
• Expression System: E. coli.
• Refolding Conditions:
• Structure: Contains 192 amino acids with a molecular weight of 22,000 daltons. Identical to human sequence but contains an extra methionme at the N-terminua.
• Additional Information: Sales > $100 million. Cost of therapy is $13,110 (1 year, 313 mg protein)
DNase (deoxyribonπclease I)
• Product name: Pubnozyme
• Produced by: Genentech (S. San Francisco, CA)
• Indication: Human use, Cystic fϊbrosis
• Date of approval: Dec 1993
• Formulation: Inhalation solution (aerosol mist produced by a compressed air driven nebulizer system). Comes in a single-use 2 -5 toL ampule containing 1.0 mg/mL DNase, 0.15 mg/τnl- calcium chloride dihydratc, and 8.77 mg/ml sodium chloride, at a pH of 6.3. The solution is stored at refrigerated temperatures and should not be exposed to light.
• Expression System: Mammalian cells (Chinese hamster Ovary cells)
• Refolding Conditions:
• Structure: Glycoprotein of 260 amino acids having a molecular weight of 37,000 daltons. The primary sequence is identical to that of the native human enzyme.
• Additional Information: Sales > $ 100 Million. Cost is $32 for 2.5 mg of protein (1 ampule)
M-CSF (Macrophage-Colony Stimulating Factor)
• Product name Leucomax (generic name: Molgramostim)
• Produced by:
• Indication: Human use,
• Date of approval: FDA unapproved
• Formulation:
• Expression System:
• Refolding Conditions:
• Post-Transitional Modifications:
• Structure:
■ Additional Information:
Epoetin Beta (Erythropoietin)
• Product name: Marogea
• Produced by:
• Indication: Human use,
• Date of approval:
• Formulation:
• Expression System:
• Refolding Condition*:
• Post-Transitional Modifications: TABLE A
Structure:
Additional Information:
Polyribonucleoiide
Product name: Arπpligen
Produced by:
Indication: Human use,
Date of approval: FDA Unapproved
Formulation:
Expression System:
Refolding Conditions:
Post-TraπsitionaJ Modifications:
Structure;
Additional Information:
Human Serum Albumin Product name: Produced by Indication: Human use, Date of approval: Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information:
Septomonab?
Product name: Gentoxin
Produced by:
Indication: Human use,
Date of approval: Not FDA approved
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information;
Protein
Product name:
Produced by:
Indication: Human use.
Date of approval;
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information: TABLE A
A P P R O V E D B I O T EC H N O L O G Y D R U G S A N D VA C C I N E S
BMP« Company Category Inflation
Cβmvκ*» Merck recombinant vaccmatta of infartt begiimirfg t two monthj cf ^ Haemaphika b Whitehouse Station, Nl. vaccine against both invasive Haemophilυs Influenzas type b conjugate diseases (Hib) and hepatitis B (October 1996) (meningococcal protein conjugate) and hepatitis b (recombinant) vaccine
Eπgerix-8* SmithKline Beecham recombinant hepatitis B (September 1989) hepatitis B vaccine Philadelphia. PA vaccine (recombinant)
BΌGEN* A gen erythrαpoietin treatment of anemia associated with chronic renal
Epoetin alfa Thousand Oaks, CA failure, including patients on dialysis and not on (rSO) dialysis, and anemia in Retroviι*treated HlV-infected patients ( _ne 1909); treatment of anemia caused by chemotherapy in patients with non-myaloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autoiogous blood __ __ _ donation adjirvant (DecemberJ 996) _
PROcarr* Onho Biotech βrythfopoietin trftftrneft cf anemia associated with chronic renal
Epoetin alfa NJ failure, including patients on dialysis and not on (rEPO) dialysis, and anemia in Retrovfr*trea_ed HlV-infeded patients (December 1990); treatment of anemia caused by dierno erapy in patients with non-mydαid malignancies (April 1993); prevention of anemia associated with surgical blood lots, autologcus blood donation adjuvant (December 1996) [PROCRIT was approved for marketing under Amgtn's epoetin alfa PLA. Amgen mam/acures the product for Onho Biotech J Under an agreement between the two companies, Amgen licensed to Onto Pharmaceutical the U fights to epoetin *lfa for incBαticns for human use excluding dialysis and diagnostics,
CanoBopm"1 Phaπrα a & Upjohn human short stature in children due to growth hormone somatropin Kalam*zDo, AΛl growth deficiency (August 1995) (rONA origin) hormone for injection
Cent* Saronσ Laboratories growth evaluation of the ability of the somatotroph of the human growth Norwell, MA factor pituitary gland to secrete growth hormone hormone (December 1 90); ped tric growth hormone releasing factor deficiency (October 1997)
Con_J- » Sercno Laboratories recombinant female infertility (September 1997) recombinant human Norwell, MA fertility folliclβ-Λlmulating hormone hormone (r-FSH)
Hunutog™ Lilly re oTtbinant dabetes (|une l99δ] insulin llφro Indianapolis, IN insulin
Humatrepe* Bl Ulry human human growth hormone deficiency in chilton somatropin Mian-polls. IN growth (March 1 87) (rONA origin} hormone for injection TABLE A
APPROVED BIOTECHNOLOGY DRUGS AND VACCINES
Predict Product Name Company Categaty uιd.eaϋon
Hαmulln* Eli Lilly recombinant diabetes (October 1982) human insulin Indianapolis, IN insulin (recombinant DN A origin) tafageπe Amgen interferon treatment of chronic hepatitis C viral infection interferon alfacon- Thousand Oaks, CA (October 1997) krtiran • A Schering-Plough interferon hairy cell leukemia (June 1966); genital warts interferon alfa-2b Madison, Nf (June 1988); AlDS-rdaied KaposKs sarcoma (recombrπaπt) (November 1988); hepatitis C (February 1991); hepatitis 8 (July 1992); malignant melanoma (December 19S); follicular lymphoma in oonjunction with chemotherapy (November 1997)
KoGENate* Bayer Corporation, clotting treatment of hemophilia A (February 193) antihe ophiliac Pharmaceutical Division factor factor West Haven,Cτ
h i l injection
(recombinant DNA origin)
Novoirn* I Novo Nordisk recombinant insulin-dependent diabetes mellitus (Jury 1991) Lents*, human Pharmaceuticals insulin insulin zinc Princeton, N/ suspension (recombinan. DNA origin) TABLE A
A P P R O V E D B IOT EC H N O L O G Y D R U G S A N D VACC I N E S
Product Prodect
Name Company Category Indication
Novoln* N Nova Nordisk recombinant insulin-dependent diabetes mellitus duly 1 91) NPH, human Pharmaceuticals insulin insulin tøphane Princeton, Nl suspension IrecDmbinant DNA origin)
Novolme Novo Nordisk recombinant insulin-dependent diabetes mellitus (July 1 91) regular, human Pharmaceuticals insulin insulin injection Nnceton, NJ (recombinant DNA origin)
Nutrofήπ* Genentech human growth failure in children due to chronic rwal somatropin S. San Francisco, CA growth insufficiency, growth hormone inadequacy In children for injection hormone (March 1994); Turner's syndrome (December 1996); growth hormone inadequacy in adults (December 1997)
Nutropin ΛQ™ Genentech human growth failure in children due to chronic renal somatropin S. San Francisco, CA growth insufficiency, growth hormone inadequacy in children
(liquid) hormone (December 1995); Turner's syndrome December 1996); growth hormone inadequacy in adults (December 1 97)
OncoSάnP CYTOGEN MAb detection, staging and follow-up of colorectal and CRΛV Princeton, HI ovarian cancan; (December 1 92) satumorπab peπdedde
OrTTHOαONE Onho Biotech MAb reversal of acute kidney transplant rejection OKTO Λarfta N/ (June 1 86); reversal of heart and liver transplant murumonab-CD3 rejection (June 1993)
Proleuldn* Chiron iπterieukin renal call carcinoma (May 1992); metastatie melanoma aldesleukin firneryvifte, CA (January 1998) (interleukin-2) ftortiSdnt* CYTOGEN MAb detection, staging and follow-up of prostate capromab Princeton, NJ adenoearcinαma (October 1996) pentetate
Prtrtroptπ* Genentech human human growth hormone deficiency in children somatrem 5. San Ftanόsco, CA growth (October 1985) for injection hormone
Pulmozyaw* Genentech recombinant cystic fibrosb (December 1993); management of domase alpha, 5. San Francisco, CA DNase advanced cystic fibrosis (December 1996) recombinant
ΛecomWrBrte™ Baxter HeahhcanV clotting hemophilia A (December 1992) antihemophillc Hyi and Division factor factor recombinant Oendale, CA (rAHF) Genetics Inαrtute Cambridge. MΛ KOMBIVAX HB* Merck recombinant hepatitis 8 prevention (Jury 1 86) hepatitis 8 vaccine Whitehoυχ Scatkπ, N] vaccine (recombinant), MSD l fludan™ Hoechst Marion Roussel recombinant heparin-induced mrombocytopenia type II lepirudln Kansas City. MO anticoagulant (March 1998) (rDNAj for injection TABLE A
A P P R O V E D B I O T E C H N O L O G Y D R U G S A N D V A C C I N E S
Prσdn "~ "~ Product . _ _~
Name Company Category InJcatiOn
■egnnex* Ortho-McNtil growth lower extremity diabetic neuropathic ulcers becaplermin Pharmaceuticals factor (December 1997) R3fitan, N[
RβoPro* Cemocor MAb aπli-pbwl*t prevention of blood clots in the setting of abciximab Mahτm. PA high-risk percutaneous translumrπai coronary angioplasty Eli Lilly (December 1994); refractory unstable angina when Indianapolis, IN percutaneous coronary intervention is planned (November 1997)
Retrrase™ Boehringer Mannheim tissue treatment of acute myocardial infarction (October 1996) reteplase Gaithetώurg,MD plasminogen Centocor factor Mah-m, PA
Ritαan* Genentech MAb treatment of relapsed or refractory low-grade or rituximab & San Franάsco, CA foHicula CD20-positfve B-cell non-Hodg in's IDEC Pharmaceuticals ry phcma (November 1997); San Diego. CA
Rofcron*-A Hoffmann-la Roche interferon hairy cell leukemia (June 1966); AlD&related Kaposi's interferon alia-2a, Nυdtγ, NJ sarcoma (November 1 88); chronic rπyelogenous recombinant leukemia (November 1 95); hepatitis C (November 1996)
Saizen* Serono Laboratories human pecSatric growth hormone deficiency (October 1996) somatropin NorwelLMA growth (rONA origin) hormone for injection
Serosβm™ Serano Laboratories human treatment of AIDS-associated catabolismλvasting somatropin Norwell, MΛ growth (August 1 96); pediatric HIV failure to thrive (rONA origin) hormone (February 1998) for injeαion
Vαiuma* Boehringer Ingelheim MAb detection of small-cell lung cancer (August 1996) nofetumomab RidgcfiekL Cr NaoRx Sttαle, WA
Vtrtde* Gilead Sciences nu eotide cytomegalovina retinttis in AIDS patients (June 1 96) ddofovir injection Foster City, CA analogue
Zeπaptax* Hoffmaππ-La Roche MAb prevention of acute kidney transplant rejection daclizumab Nuύcγ. NJ (December 19971
The content αf this survey has been obtained through government and industry sources based on the latest information. The information may not be comprehensive. For more specific information about a particular product, contaα the Individual company directly.
PhRMA tntmet ddrtsc hϋμJhn w≠ ma α t
Provided as a Public Service by PhRMA. Founded in 1958 as me Pharmaceutical Manufacturer* Association.
Copyright C 1998 by the Pharmaceutical Research and Manufacturers of America. Peπwβicπ to raprim Is awarded if proper credit is given.
Leading the way In the search for cures
Pharmaceutical Research and Manufacturers of America 1100 Fifteenth Street N Washington, D.C. 20005 http://www.phfTria.org β Primed on recycled paper. 4/98 TABLE A
Biotechnology Medicines in Development
A I DS/H IV I N FECT IO N ! A N D R E L AT ED C O N D IT IO N S
Product Product Development Name Company Category Indication Status
AD- 39 »nd Tanox Brosystems MAb HIV infection, AIDS Phase II
AD-519 Hσus»n, TX combination
AD-439 MAb, Tanox βiαsystems MAb HIV infection, AID5 Phase II anti-HIV to V3 Houston TX loopo pl20 protein; neutralizing antibody
AD-519 MAb, Tanox Biosystems MAb HJV Infection, AIDS Phase II anti-HIV to C4 HOI/SJOΛ. TX region of gpl 20 protein; neutralizing antibody
Λlferaπ LDO* Interferon Sciences iπtisfefun AiDS-nlattd complex, AIDS Phase W interferon arfa-r_3 New Brunswick. N)
Alfcrwi N Interferon Sciences interferon HIV infection Phase III Injection* New Brunswick, NJ (see also infectious diseases) interferon alfa-fj co-infection (HIWHCV) Phase II
ΛLVΛC-MN Pasteur Merieux Connaught vaccine HIV infection Phase II
12-TMC Lyons, France
(vCP205) Virogenetics Λftβny, NY
Ampβgeπ* Hemispherx Siopharma interferon HIV infection Phase II New York, NY (see also cancer, infectious diseases, other) autologous gene- SyStemix gene therapy HIV infection Phase 1 modrfiεd Palo Alto. CA hematopoietic stem cells gene therapy Cell Cenesys gene therapy HIV infection Phase 11 faster C/ry, CA Hoechst Marion Roussel Kansas Clγ, MO gp120 VaxCon vacdne AIDS Phase d vaccine S. San Fftndsco, CA
HIVJTM Chiron Vagene gene therapy asymptomatic HIV-1 infection Phase d Rettovector™ San Diego, CA retroviral vector
HIV vacdne Chiron vaccine AIDS Phase d lj.pl 20) Emeryville, CA iπterie.lα'n-10 Schering-Plough intetteuJάn HIV disease Phase I (11-10) Madison, NJ (tee also autoimmune, digestive, heart, neurologic respiratory, skin) TABLE A
A I D S/H I V I N F E C T I O N A N D R E L AT E D C O N D IT I O N S
Product Product Development
Name Company Category Indication Status
ISIS 2922 Isis Pharmaceuticals antisense cytomegaloviπ s retin ris Phase III fomivirsen Carlsbad, CA
ISIS 13312 Isis Pharmaceuticals antisense cytomβgalovims reiinitis Phase ! Carlsbad. CA
LeuUne'" Immunex colony adjuvant to AIDS therapy, Phased sargramostim Seattle, WA stimulating HIV Infection, prevention of (GM-CSF) factor infection in HlVpatients (see also cancer! memanjne Neurobiological AIDS dementia complex and Phas d Technologies AlDS-related neuropathic pain Richmond. CA (see also diabetes)
MPl* Ribi ImmunoChem vaccine AIDS Phase ! i munomodulator Hamilton, MT (see also infectious diseases) . vaccine
NEUPOCCN* A gen colony treatment and prevention of application
Firgrastim Thousand Oaks, CA stimulating neutropenia in HIV patients submitted
(rC-CSF) factor (see also cancer, respiratory)
Ovidrel* Ares-Serono and recombinant Kaposl's sarcoma, AJDS-reiated Phase IΛ1 recombinant 5erono Laboratories gonadotropin hypogonadism human chorionic Notwtll. MA (see also infertility) gonadotropin (r-hCG)
PEC interleuidn-2 Chiton interleukin HIV infection in combination Phase π Emeryville, CA with Rarovii*
PMPA dea Sciences nudeotide HIV infection, AIDS Phase foster Cfy, CA analogue
Pwveon™ Citead Sciences nudeotide HiV efltecϋon, ΛlDS Phase ill adefσvir d!pivo__l Foster City, CA analogue
PRO 367 Progenies Pharmaceuticals HIV infection Phase 1 Tarrytσwn, NY
PRO 542 Progenies Pharmaceuticals HIV infection Phase 1 Taπytown, NY
ProleuUn* Chiron interleukin HIV infection in combination Phase Mil aldesleuldn Emeryville, CA with Retrovir* (ϊnierleul in-2) (see also cancer)
Rename Immune Response Corp. immune- HIV sercpositlve Phase III
HIV-1 hnmunogen Carlsbad, CA based therapy retroviral vector Chiron gene therapy HIV infection Phase 1/11 with 2 ribozymes Emeryville, CA
TBC-3B Therkm Biologi s vacant AIDS prevention Phase I (vaccinia virus Cambridge, MA expressing HIV genes env, gag and pal) TABLE A
AUTOIMMUNE DISORDERS
Product Product Developmnt Name Company Category Indication Status adenosine National Cancer Institute gene therapy severe combined Phase I deaminase- Bethesώ,MD immunodeficiency NCI TaiAi transduced autologous CD34+ PBCor umbilical cord/ placental blood cells adenosine National Cancer Institute gene therapy sever* combined Phase 1 deamiπase- Beώetda,MD immurvodeficiency NCI TRIAL transduced
T cells
AnergiXnMlA Anergen functional rheumatoid arthritis Phasel KedwoodCty, CA amigenics Immuno- therapy
AaervaXtn Anergen pepide rheumatoid arthritis Phased Redwood City, CA vaccine
Avakine" Centocor MAb rheumatoid arthritis Phase Ul chimtric a ri-TNF Malvem, PA (see also digestive) antibody
CD 0 ligaπd Biogen MAb lupus, immune thrombσcytopenic Phased antibody Cambridge. MA purpura clenolbd ab IDEC Pharmaceuticals MAb rheumatoid arthritis Phased San Diego. CA Srn hKlin* Baecham Philadelphia. PA
ConXπ1- Coπneπ'cs recombinant scleroderma Phased relaxiπ Pa\oAho,CA human protein
Enbrel Immunex recombinant rheumatoid arthritis Phase III tumor necrosis Seattle, WΛ soluble factor CTNF) Wyeth-Ayeπt Laboratories receptor receptor Philadelphia, PA hSGl.1 Alexion Pharmaceuticals MAb lupus, rheumatoid arthritis Phase l/ll New Haven. CT
IDEC131 IDEC Pharmaceuticals MAb systemic lupus erythematosus Phasel humanized MAb San Diego, CA
IL-2 fusion protein Seragen fusion severe rheumatoid arthritis Phase HI
DABsJW HαpkintmMA protein (see also cancer, skin) interleukin-10 Schering-Plough interleukin rheumatoid arthritis Phase
(IL-10) Madison, NJ [see also AIDSHIV, digestive, heart, neurologic respiratory, skin)
IR501 Immune Response Corp. vaccine rheumatoid arthritis Phase therapeutic Carlsbad, CA vaccine
ISIS 2302 Isis Pharmaceuticals antisense rheumatoid arthritis Phas d Carlsbad, CA (see also digestive, skin, transplantation) TABLE A
A U TO IM M U N E D ISO R D E RS
Product Product Devefopπienr
Name Company Category Indication Stalαa
MDX-33 Medtrex MAb autoimmune diseases, idiopathic Phase 1 Annandale. NJ mrombocytope ic purpura
O THOαONE Onho Biotech MAb treatment of CD4-mediat*d Phas d OKT4A toritan, N/ autoimmune diseases (tee alto transplantation)
QuβKtαldne Schering-Plough interleukin rheumatoid arthritis Phase 1 interleukin-* Madison, NJ
OL-4)
SMAITF"AJΛ'-CD3 Protein Design Labs MAb autoimmune diseases Phase I HuM291 Mountain View, CA (see also transplantation)
B L O O D D I S O R D ERS
Product Product Development Name Company Category Indication Status
CPC-111 Cypros Pharmaceut ae. cellular sickle cell disease Phas d Carlsbad. CA therapy (see also heart)
Factor VIII Transkaryotic Therapies gene therapy hemophilia A Phase 1 Cambridge, MA
CA-EPO Hoechst Marion Roussel erythropoierin anemia associated with Phased Kansas City, MO chronic renal failure Transkaryotic Therapies Cambridge, MA ogenate-N Bayer dotting hemophilia A Phase ! rFVIII Berkeley, CA factor
NovoSeven* Novo Nordisk clotting treatment of hemophilia B with Phase ! recombinant factor Pharmaceuticals factor and without antibodies against Vila Princeton. NJ factors VllMX
OpW" S matogen recombinant oxygen-carrying agent and Phase d recombinant human Boulder, CO human alternative ID red blood cell hemoglobin hemoglobin transfusion
IrHbl .D
Stimulation of red blood Cell Phase I formation
ReFacto* Cenetic* Institute dotting hemophilia A Phase 1 recombinant factor Cambridge. MA factor vπi
YM-337 MAb Yamanoudu USA MAb platelet aggregation Phase t White Plains, NY Protein Design Labs Mountain View, C TABLE A
CANCER AND RELATED CONDITIONS
Product Product Development
Name Compan Category Indication Status r
131 hTNT-l/B Technickme MAb malignant glioma Phase I Tusf/ A
Aastrom" Aastrom B Kciences cellular cancer immunosuppression/ Phase II CeU ProdocMn Aπ Abor.Ml therapy blood and immune system System recovery for patients receiving stem and progenitor ablative chemotherapy cell expansion from bone mamow and umbilical cord Wood
ActnnmuM* National Cancer Institute interferon colon, lung, ovarian, prostate Phase II interferon Bethesda.MD cancers, melanoma NCI TRIAL gamma-l Genentech
5. San Francisco. CA
AfP-Scm™ Immunomedics MAb extent of disease staging of liver Phased teehnetiuffl-99m- Moms Wains, NJ and germ cell cancers FAb' fragment (germctl allogeneic 5yStemix cellular advanced leukemia, rymphoma, Phase 1 hematopoietic Palo Alto, CA therapy rπyelodysplastic syndromes stem cell tran .plantation
Atovemιv-7 Vlcal gene therapy advanced metastatic melanoma, PhtMll
DNAlipid complex San Diego, CA norκesectable squamous cell encoding HLA-S7 carcinoma of me head and neck antigen
ALT Cellcor cellular metastatic renal cell carcinoma Phase III
(autolymphocyte Newton, MA therapy (kidney cancer) completed therapy) CYTOCEN Princeton, NJ
ALVAC-87.1 National Cancer Institute gene therapy melanoma Phase) Bdhesda,MD NCI TRIAL
ALVAC-CEA-B7.1 National Cancer Institute gene therapy advanced adenocarciπomas Phase I Beώesda,MD NCI TRIAL
ALVAC-CEA National Cancer Iπstlttαe vaccine advanced cancers Phase 1 vaccine Bethesd),MD NCI TKIAI
ALVAC-IL-12 National Cancer Institute vaccine melanoma Phase 1 vaccine Bettesda. D NCI TRIAL
Pasteur Merieux Conruught
Lyons, France
Ampfgeπ* Hemisphere Biopharma Interferon renal cancer Phase l/ll New York, NY (see also AIDSHIV, infectious diseases, other) ami-cancer T-cell Cell Cenesys gene therapy colon cancer Phase W gene therapy foster City. CA anti-idkxype Novartis Pharmaceuticals MAb cancer Phase 1 monoclonal East Hanover, NJ antibody TABLE A
CANCER AND RELATED CONDITIONS
Product Product Development
Name Company Category Indication Status anti-Ta Fv}-PE38 National Caπctr Institute MAb+tOxin leukemia, lymphoma Phase I knmunøtoxin Bethesda,MD NCI TRIAL anti-iransterrin National Cancer Institute MAb advanced, refractory solid tumors Phase! receptor Bethetda.MD NCI TRIAL
MAb ami-VECF Genentech MAb cancer Phase! humanized MAb S. San Francisco, CA autologous SyStemix cellular hematopoietic reconstrtution in Phase I/tl hematopoietic PahΛH,CA therapy patient, with multiple myeloma, stem cells for non-Hodgkin's lymphoma, autologous breast cancer hematopoietic transplantation autologous peptide- National Cancer Institute cellular advanced soG tumors Phacel specific activated Bethesd_,MD therapy NCI TRIAL lymphocytes autologDus National Cancer Institute gene therapy breast cancer, myeloma Phase! transduced CDJ*+ Bethesda,MD NCI TtlAL bone marrow and peripheral blood stem cells
Avickin* lanssen Pharmaceutica MAb cokxectai, lung, prostate cancers Phased
MAb conjugate Frtusvi/fe, NJ NeoRx Seattle, WA
Avicine™ AVI BioPhairna vaccine cokxectal, pancreatic cancers Phas
CTP-37 Po nd,OR
Avonex* Biogen interferon glioma Phased interferon beta-l Cambridge, MA (see also neurologic)
87 trartsfected National Cancer Institute vaccine melanoma Phase 1 allogeneic Bethesda,MD NCI TRIAL melanoma cell vaccine
BEC2, aπti-idiotype I Clone Systems vaccine melanoma, smaH-cell lung cancer Phase 1 MAb Scmetvitk, NJ
Bdaieron* National Cancer Institute interferon norwmall-cell lung cancer Phase III recombinant Beώesd_.MD (see also neurologic) NCI TRIAL beta inteneron-lb Berlex Laboratories Wayne. NJ bispecific Chiron MAb cancer Phasel antibody Emeryville. CA
C225, a tl-ECFR ImClone Systems MAb epidermal growth factor receptor Phased chimeric MAb So erville, NJ positive cancers
Campath 1 H LeukoSite MAb chronic lymphocytic leukemia in clinical CarrΛrw!je,A<A trial* TABLE A
CANCER AND RELATED CONDITIONS
Product Product Development Name Company Category Iπcficalion Status carcinoembryonic National Cancer Institute vaccine breast, gastrointestinal tract Phase! antigen peptide- 1 Be(hesda,MD lung cancers NCi TRIAL vaccine
CEAGde*" Immunomedics MAb eoloreαal cancer Phas humanized Morris Plains, N] anti-CEA antibody (hMN14)
OA-Scan™ Immunomedics MAb extent of disease staging of breast Phased technetium-99m- Moms Plains, NJ cancer arcitumomab
(breast)
CEΛ-Sαn™ Immunomedics MAb extent of disease staging of lung Phase III technetium-99m- Morris Plains, N) cancer arcitumomab
(lung)
CEAVac™ Titan Pharmaceuticals vaccine cotorectal cancer Phased anti-idiotype 5. San Francisco, CA antibody vaccine cell therapy CytoTherapeutics cellular cancer pain, uπtreaiabWunrelieved Phase Providence, Rl therapy by other forms of treatment
C port™ Alkermes recurrent malignant brain tumor Phase Id
(RMP-7) Cambridge, MA and carbσplatin chemomtrapy- Cenerix gene therapy treatment of cancer patients Phase HI resisnm Rye, NY requiring chemotherapy bone marrow chimericMAb National Cancer Institute MAb melanoma, neuroblastoma Phased 14.18 Bethetda.MD NCI TRIAL
CM 101 CarboMed cancer Phase 1/D 8rentwood,TN
CMA-676 Wyem-Λyerst Laboratories MAb relapsed acute myeiogenous Phase II/lll Philadelphia. PA leukemia
CMB-401 Wyeth-Ayerst Laboratories MAb ovarian cancer Phase l/ll Philadelphia, PA colon cancer Immune Response Corp. vacdne colon cancer Phase! cell line Carlsbad, CA vaccine Sidney Kimmel Cancer Center San Diego, CA
CP-358,774 OSI Pharmaceuticals cellular cancer Phase 1 Vntondaie, NY therapy Pfcer NewYαrfcNY -2S84 Cell Therapeutics ovarian, prostate cancer, Phase 1 Stack, WΛ sarcoma cytσslne deamlnase C-enVec gene therapy colon cancer Phase I gene-adeπαviral Rockville, MD vector TABLE A
CANCER AND RELATED CONDITIONS roduct Product Development Name Company Cateaory Indication
DA/Hu(gamma).4 Chiron Viagene gene therapy metastatic melanoma Phase 1
IhlFN^V)] San Diego, CA fUsroveαor1** hlFN-γretroviral vector
DAΗu(gamma}.15- Chiron Viagene gene therapy stage IV Phase! traitsduced San Diego, CA malignant melanoma autologous tumor ceils and interferon" gamma expressing transduced autologous tumor ceils (combination therapy)
DAHu.gamma).15- Chiron Viagene gene therapy disseminated Phase! iraruduced San Diego, CA malignant melanoma autologou* tumor cells; ITAT daniplestim Static growth factor mobilization of peripheral Phased! SkokictL blood stem ceib dendritic cell Denditon cellular advanced prostate cancer Phase 11/111 therapy Mountain Vew, CA therapy multiple myeloma Phase 1
E/A lipid complex Targeted Genetics gene therapy breast, head and neck, ovarian Phase! ItgDCC-feVA) Seattle, WA cancers
EGF fusion protein Seragen fusion protein non-smal ell lung cancer Phase Ml DAB^CF Hopkintαn, MA
EPWX* National Cancer Institute erythropoietin πeuroblastoma Phase 1! erythropoietin Beth_sda.MD NCI TRIAL Ortho Biotech Raritan,NJ
ERB-38 National Cancer Institute fusion protein advanced stage solid tumors Phase l immunotoxin Bethesda.MD NCI TRIAL fusion protein (recombinant)
Ewing's sarcoma National Cancer Institute vaccine sarcoma Phase! and alveolar Beώesda,MD NCI TRIAL rhabdσmyosarcoma peptide vaccine
FLT3 ligarx. National Cancer Institute growth factor melanoma, renal cell cancer Phase 1 Bethesda.MD NCI TRIAL Immuπex Seattle, WΛ
C3139 Centa antisense cancer Phase!
5*1 Diego, CA gamma interferon Chiron gene therapy cancer Phase 1 gene therapy Emeryville, CA TABLE A
CANCER AND RELATED CONDITIONS
Product Product d velopment
Name Company C tenary Indication
Cati immune™ Aphton vaccine olorectat, pancreatic stomach Phase 1/U neutralizing G17 Woodland, CA cancers hormone (see also digestive)
Genevan* Centocor vac ne colorectal cancer Phase! gene vaccine Malv_m,PA
CLI-328 Genetic Therapy gene therapy glioblasto a muhiforme Phase 1H Calthersburg, MD
GM-CSF cellular Pσwderject Vaccines vaccine melanoma, sarcoma Phase 1 cancer vaccine Madison, Wt
CM Bristol-Myers Squibb vaccine prevent recurrence following Surgery Phase III gangiiαside Princeton, N) to remove primary melanoma antigen Progenies Pharmaceuticals Taπγwwπ,NY gplOO denovirus National Cancer Insdtute vaccine melanoma Phase 1 vaccine Bethesda,MD NCI TRIAL Cenzyme Molecular O coksgy Cambridge, MA gpl 00 peptide National Cancer Institute a ant melanoma Phase 1 vaccine BeShesd_,MO NCI TRIAL
CVAXi" CellGenesys vaccine prostate, lung cancers, melanoma Phase l/li cancer vaccine Foster dry. CA
HER-2/πeu National Cancer Institute vaccine breast, colorectal, ovarian, Phase! peptide vaccine Bβhesda,MD prostate cancers NCI TRIAL
Herceptin™ Genentech MAb breast cancer Phase dl trastuzumab 5. San Francisco, CA completed (anti-HEK-2 humanized MAb)
HPV16,E6andE7 National Cancer institute vaccine cervical cancer Phase i peptide vaccine Beώesώ.MD NCI TRIAL
HPV E7 lipopeptide National Cancer Institute vaccine cervical cancer Phase 1 vaccine Beώesώ.MD NCI TRIAL
Cytel
San Diego, CA
HPV vaccine Medlmmune vaccine cervical cancer Phase 1 Gaithersburg,MD (see also infectious diseases) SmithKlirvt Beedum Philadelphia, PA
KSPPC-96 Antigenics heat shock melanoma, pancreatic, Phase! (autologous Ne yorfςNY protein renal cell cancers tumor derived) human growth Transkaryotic Therapies gene therapy cancer cachexia (musde wasring) Phasel hormone Cambridge, MA
IDEOInBB IDEC Pharmaceuticals MAb non-Hodgkir { B-cell lymphoma Phase VII San Diego, CA
IDEC-Y288 IDEC Pharmaceuticals MAb πon-Hodgldn's B-cell lymphoma Phase l/ll San Diego, CA TABLE A
CANCER AND RELATED CONDITIONS
Product Product Development
Name Company Category Indication S tus
Leucotrapin Cangene colony mobilization of peripheral blood Phase III
GM-CSF Mississauga. Ontario stimulating stem ceils In patients with factor adjuvant breast cancer
Leukine™ Immunex colony prophylaxis and treatment of application sargramosom Seatth, WA Stimulating chemotherapy-induced neutropenia, submitted
(GM SF) factor prophylaxis of chemotherapy-induced neutropenia in acute myelogenous leukemia
(see also AIDSHIV)
LeαvecSπ Vlcal gene therapy prostate cancer, renal cell carcinoma, Phasel
DNA/ϋpid complex San Diego, CA melanoma, sarcoma encoding IL-2
LP 2307 LIDAK Pharmaceuticals vaccine malignant melanoma Phase HI La folia, Cλ
LK-3001 Inex Pharmaceuticals antisense Phasel HaywantCΛ in accelerated phase or blast crisis lYM-1 Techniclone MAb lymphoma Phase IIIII Tustin.CA
Lyrnphodde'M immunomedics MAb non-Hoogkin's B-cell lymphoma Phase 1/11 antl-CD22 Morris Plains, NJ humanized MAb
LymphoScan™ Immunomedics MAb extent of disease staging of Phase III techπetium-99m- Morris trains, NJ non-Hodgx 's B-cell lymphoma, bectumomab detection of residual disease (lymphoma) following radiatiorVchemotherapy
MAb Glaxo Wellcome MAb lung, prostate cancers Phased Rsch. Triangle Park. NC
MΛRT-1 National Cancer Institute vaccine melanoma Phasel adenovirus Bethesά-.MD NCI TRIAL vaccine Genzyme Molecular Oncology Cambridge, MA
MART-1 National Cancer Institute vaccine metasatic melanoma Phasel melanoma Bethesda,MO NCI TRIAL vaccine
MDRxlT- Than Pharmaceuticals gene therapy enable hi^vdose chemotherapy Phasel 5. Sin Francisco, CA with reduced side effects
MDX-47 Medarex MAb head and neck, renal cancers Phase VII btspecific antibody Artnandafe, NJ
MDX-H210 Medarex MAb breast, colorectal, kidney, ovarian, Phase 1/11 btspecific antibody Annandale, NJ prostate cancers
Metadne* ibi ImmunoChem vaccine stage IV melanoma with interferon Phase III melanoma Hamilton. MT alpha completed rheracdne (therapeutic Ribi ImmunoChem vaccine stage II melanoma in patients with Phase III vaccine) Hamilton. MT no evidence of disease to revent Southwest Oncology Group recurrence following surgery to San Antonio, TX remove primary disease TABLE A
C A N C E R A N D R E L A T E D CO N D IT IO N S
Product Product Development Name Company Category Indication Status myeloid progenitor Human Genome Sciences interleukin chemoprotection Phase l inhibitory factor- 1 Rockville, MD myeloma-derived National Cancer Institute vaccine multiple myeloma Phase l idiotypic antigen Bethtsώ, MD NCI TRIAL vaccine
NEUPOOT Amgen colony acute myelogenoυs leukemia application
Filgrastim Thousand Oaks, CA stimulating (see also AIDS/HIV, respiratory) submitted
(rC-CSF) factoi
Oncaspar* Enzon first-line treatment of acute in clinical
PECU-asparagiπase Piscataway, NJ rymphobUstic leukemia (AH) trials Rhone-Poulenc Rorvr adult ALL πon-Hodgkin's lymphoma, TitusvMe, NJ chronic iymphocytic leukemia
Onceiyin* Technlclone MAb malignant glioma Phase l 7us.ι' CA
OncoRad* ra CYTOCEN MAb targeted radiotherapy for prostate Phase d CYT-356.Y.90 Princeton, NJ malignancies
OflcoScint* CYTOGEN MAb detection, staging and follow-up Phase d CR 7V Princeton, NJ of breast cancer satumomab pendetide
ONYX-01S Onyx Pharmaceuticals oneolytic p53 deficient cancers Phase 1/11 Richmond, CA virus therapy p53 and RAS National Cancer Institute vacdne solid tumors Phase l vaccine Bethesda, MD NCI TRIAL p53 tumor Schering-Plough gene therapy lung cancer Phase d Madison, NJ solid tumors that carry the Phase l p53 gene mutation or deletion
Patorex* Centocor MAb adjuvant therapy for post-operative Phase 111 edrecolomab Malvem, PA colorectal cancer peripheral blood National Cancer Institute gene therapy ovarian cancer Phase l lymphocytes Beάmda. MD N C I T R I A L transduced with a gene encoding a chimericT-ceϊl receptor
Proleuldn* Chiron interleukin acute myelogenous leukemia, Phase Mil aldesleukin Emeryville, CA non-Hodgkin's lymphoma (interleukin-.!) (see also AIDS HIV) promegapαietiπ Searle growth factor adjunctive hematopoietic therapy Phase l Skokie, IL following chemotherapy
PrusuraC Therion Biologies vaccine prostate cancer Phase 1/11 recombinant Cambridge, MA vaccinia vine TABLE A
CANCER AND RELATED CONDITIONS
Product Product Development Name Company Category Indication Status r
RΛS 5- 1 peptide National Cancer Institute vaccine solid tumors Phasel vaccine Bethesda.MD NCI TRIAI
ΓCEΛ Vacate Protein Sciences vaccine breast, colon cancers Phasel recombinant Maiden, CT carcinoembryonic antigen
Rebrf* Serono Laboratories interferon colorectal cancer Phase Ul recombinant Nσrwef/,Λ1A (see also infectious diseases, Interferon beta-1 a neurologic) non-small-cell lung cancer Phase W recombinant human Genetics Institute Interleukin cancer Phase VII interleukin-12 Cambridge, MA (see also infectious diseases)
(rhIL-12) WyetrμAyerst Laboratories Philadelphia, A retroviral vector Chiron gene therapy melanoma Phasel with tumor necrosis Emeryville. CA factor gene r -gplOO Therion Biologic vaccine melanoma Phasel (recombinant Cambridge, MA fowl pox virus) rf-MΛRT.l Therion Biologies vacdne melanoma Phasel (recombinant Cambridge, MA fowlpox virus)
RICScan*α 9 Neoprobe MAb colorectal cancer application
125l-cc49MΛb Dublin. OH submitted
Rituxan* National Cancer institute MAb leukemia, lymphoma Phased rimximab Bethesda,MD NCI TRIAL IDEC Pharmaceuticals San Diego, CA
Roferoπ*-A Hoffmann-La Roche interferon malignant melanoma adjuvant Phase III interferon alfa-2a, Nut y, NJ recombinant rV-gplOO Therion Biologies vaccine melanoma Phasel (recombinant Cambridge. MA vaccinia virus) rV-MART-1 Therion Biologies vaccine melanoma Phasel (recombinant Cambridge, MA vaccinia virus)
SejosJm'" Serono Laboratories human cancer cachexia Phase l/ll somatropm Norwell. MA growth (see also other) (rDNA origin) hormone for injection
Sigoslx* Ares-Serono and interleukin hematologkal conditions Phase l/H recombinant Serono Laboratories (rπyelodvsplastic syndromes, cancer) interleuklπ-6 Norwell, MA (r-IL-6) TABLE A
SMAim-MWS Protein Design Labs MAb acute myeWd leukemia Phase d/Id
HuM195 Mountain View, CA acute promyelocytic leukemia Phase advanced mydoid leukemia Phase l (with Bismuth-213) stem cell factor Amgen stem cell adjunct to chemotherapy application Thousand Oaks, CA factor submitted
SU101 SUCEN PDGF- malignant glioma Phase III Redwood Gry. CA receptor tyrosine prostate cancer Phase l kinase inhibitor solid tumors Phase!/!!
SU5416 SUCEN angiogenesls solid tumors Phas l Redwood Cty, CA inhibitor
TBC CEA Therion Biologies vacant colorectal and lung cancers Phase VII (vaccinia virus Cambridge. MA expressing carcinoembryonic antigen)
TCell-HOM Coulter Cellular Therapies cellular cancer Phase l Boston. M iherapy
Tneratope* Biomira vaccine breast cancer Phase d synthetic Edmonton. Alberta completed carbohydrate Chiron therapeutic Emeryville. CA vaccine thrombopoietiπ Genentech erythropoietin mrombσcytopenia related to αncer Phase d
5- San Francisco, CA treatment
Tπyrogen* Genzyme detection and treatment erf application recombinant human Cambridge, MA thyroid cancer metastases submitted thyroid-stimulating hormone
TNT Techrϋclαπe MAb non-Hodgkin's B-cell lymphoma Phase IHII Tusύn, CA solid tumors Phase l
TriAB™ Titan Pharmaceuticals vaccine breast cancer Phased anti-idiotype 5. San Frandsco, CA antibody vaccine
TπGHvJ™ Titan Phannaceuticals vaccine small-cell lung cancer, melanoma Phase l anti-idiotype SL San Francisco, CA antibody vaccine urate αxidase Sanolϊ recombinam prophylaxis for chemotherapy- Phase d! (recombinanrly- New York, NY emyme related hyperurice ia, tnatment produced enzyme) of cancer-related hyperuricemia TABLE A
CANCER AND RELATED CONDITIONS
Product Product Development
Name Company Calesjof Indication Status r vaccinia -CEA National Cancer Institute vaccine advanced colorectal cancer Phasel l∞KO Bethesda, MO NCI TRIAL vaccine Therion Biologies Cambridge. MA
Vaxid Vital vaccine B-<ell and mantle cell lymphorrias Phasel anti-idiotype DNA San Diego, CA vaccine
Xeiecept™ Neurobiotogical brain rumor edema Phased human Technologies corricotropin- Richmond. CA releasirtg factor
(hCRF)
Zeπapax* Hoffmann-La Roche MAb certain blood cancers Phase dadizumab Nuύey,NJ (see also eye, neurologic, skin,
Protein Design Labs transplantation)
Mountain View, CA
DIABETES AND RELATED CONDITIONS
Product _. Product _,. . Development Name Company Category Iπdtcahon Status
Beta fine Geπzyme Tissue Repair growth chronic diabetic foot ulcers Phased transforming growth Cambridge, MA factor factor-beta 2
BetaRx-H VivoRx cellular insulin-dependent diabetes Phasel encapsulated Santa Monica, CA therapy human isles
BetaRx-f VivoRx cellular insulin-dependent diabetes Phasel encapsulated Sam Monica, CA therapy porcine isles
Betafct-fr VivoRx cellular insulin-dependent diabetes Phasel encapsulated Santa Monica, CA therapy proliferated human Islets
Outage.™ Novo Nordisk recombinant h poglycemia Phase III recombinant human Pharmaceuticals human (see also digestive) glucagon Princeton, N] protein (protein) glucagon Eli Lilly recombinant to treat severe hypoglycemie events application for injection Indianapolis, IN human in patients with diabetes and to aid submitted (rONA origin) protein in gastrointestinal diayrøβflc procedures insuliπσtropin Sdos type 2 diabetes Phased
Mountain Vttw, CA memaπliπe Neurobϊσlogical painful diabetic neuropathy Phase U Technologies (see also AIDS/HIV) Richmond, CA nerve Cenentech growth diabetic peripheral neuropathy Phase III growth factor S. San Francisco. CA factor TABLE A
DIABETES AND RELATED CONDITIONS
Product Product Development Name Company Category Indication Status pimagediπe Alteon diabetic progressive kidney disease, Phase III
Ramsey, N) diabetic end-stage kidney disease
Genentech (see also neurologic)
S. San Frandsco, CA pramlmtide Amyi in Pharmaceuticals human improved metabolic control, Phase III San Diego, CA amylin which includes glucose, weight analog and lipid profiles in type 1 and insulin-using type 2 diabetes rDNA insulin Inhale Therapeutic Systems recombinant diabetes Phased P)b _\CA insulin
Tmvert1" Sensus human dlaberes-relaied illnesses Phased
Austin, TX growth (see also growth disorders) hormone
DIGESTIVE DISORDERS
Product Product Development Name Company Category Indication Status
Λvalάπe"* Centocor MAb Crohn's disease application chimeric aπti-TNF MaNem,PA (see also autoimmune) submitted antibody
Gastrimmune™ Aphton vaccine gastioesophageal reflux disease, Phase l/ll neutralizing Gl 7 Woodland, CA peptic and nonstetoidal hormone antf-fnflammatory drug ulcers (see also cancer)
Gluαgen™ Novo Nordisk recombinant gastrointestinal motilrty inhibition Phase III recombinant Pharmaceuticals human (see also diabetes) human glucagon Princeton, NJ protein (protein) interleukin-10 Schering-Plough interleukin Crohn's disease, ulcerative colitis Phased (11-10) Madison. NJ (see also AIDS/HIV, autoimmune, heart, neurologic respiratory, skin)
I51S2302 Isώ Pharmaceuticals antisense Crohn's disease, ulcerative colitis Phased Carlsbad. Cλ (see also autoimmune, skin, transplantation)
LDP-02 Genentech MAb inflammatory bowel disease Phased
S. San Francisco, CA teukoSitt
Cambridge, MA
LeukoSαn* Invnunomedtcs MAb inflammatory bowel disease Phased suleiomab Morris Plains, NJ (see also infectious diseases)
Neunwga* Genetics Institute interleukin Crohn's disease Phased recombinant human Cambridge. MA inttrltukin-TI recombinant ICOS pancreatitis Phase platelet activating BoΦell. WΛ (see also respiratory J factor- acetyβidrolase (rPAf-AM) TABLE A
EYE CONDITIONS
Product Product Development
Name Company Category Indication Status ^
BPD-MA QLT PhotoTherapeutk-s age-related macular degeneration Phase I vtrteporfin Vancouver, Brftlisrt Columbia
MDX-RA Medarex MAb prevention of secondary cataract Phase III immunotαxin AwandaJe, /
Zenapax* Hoffmann-la Roche MAb uveitts Phase IΛ1 dadizuroab Nυtley, NJ (see also cancer, neurologic skin, Protein Design Labs transplantation) Mountain View, CA
GENETIC DISORDERS
Product Product Development Name Company Category Indication
ΛAVCFTR Targeted Genetics gene therapy cystic fibrosis Phasel gene therapy Seattle, WΛ (see also respiratory)
CπTVadenovirus Genzyme gene therapy cystic fibrosis Phasel vector Cambridge, MA
CFTR/I'ipid Genzyme gene therapy cystic fibrosis Phasel vector Cambridge, MA ex vivo stem eel IV Genzyme gene therapy Gaυcher's disease Phasel rerrovirus vector Cambridge, MA
CR2134B7B Glaxo Wellcome gene therapy cystic fibrosis Phase Wl Rsck Triangle Park, NC Megabios Buriingame, CA
CV-10 GeπVec gene therapy cystic fibrosis Phasel Rockville, MD
HP-3 Milkhaus Laboratory signalling cystic fibrosis Phase!! Bσxfoπt MΛ
Nettprex*" XOMA recombinant cystic fibrosis exacerbations Phasel recombinant human Berkeley, CA human (see also infectious diseases, other) bactericidal/ protein permeability- increasing protein (rBPMD
Purmoiyroe* Genentech recombinant early intervention in cystic fixosis Phase I domase alpha, S. San Francisco, CA DNase recombinant x-galachosidase A Transkaryotic Therapies enzyme Fabns disease Phasel Cambridge, MA TABLE A
G R O WT H D I S O R D E R S
Product Product Development Name Company Category Indication Status pralmorelin Wyeth-Ayerst Laboratories human adult growth hormone deficiency Phase l (CPA-748) Philadelphia, PA growth hormone
PraLea_«* hCH Alketmes human growth hormone deficiency Phase III
Cambridge. MA growth in children
Genentech hormone
5. San Francisco, CA
Saizen* Serano Laboratories human management of adults with growth Phase ill somatropin NorweH A growth hormone disorder, imrauterine (rDNA origin) hormone growth retardation in children for injection (see also other)
Trovert™ Sensus human acTomegaly Phase d Ausϋn, TX growth (see also diabetes) hormone
H E A RT D I S E A S E
Product Product Development Name Company Category Indication Status
AouTect™ Diatide peptide detection of carotid thrombus Phase d
Tc-99m apcitide Londonderry, NH anri-CD18 Genentech MAb acute myocardial infarction Phase humanized MAb 5. San Francisco, CA
BioByPaβ™ GenVec gene therapy cardiovascular disease, Phase 1 therapeutic Rockville. MD including cardiac artery disease angiogenesis and peripheral vascular disease,
(VEC ) either as an adjunct or alternative to existing surgical approaches such as cardiac artery bypass grafts and angioplasty
Biαstent™ NeoRx reduction of restήiosis (vascular Phase l Seattle, WA remodeling) following balloon angioplasty
CapiSOirrt Centocor MAb atherosclerotic plaque Imaging Phase ! Matvem, PA agent
CorsevinT,,M Centocor MAb thrombolytic complications of Phase l 12D10-Fab Mahrem, PA percutaneous transkiminal
Corvas coronary angioplasty, coronary
San Diego, CA arterial starts, disseminates intravascular coagulation
CPC-1 11 Cypros Pharmaceuticals cellular coronary bypass surgery Phase C-risbad. CA therapy (see also blood) factor Vila Corvas deep vein thrombosis, pulmonary Phase l inhibitors San Diego, CA embolism, unstable angina, myocardial infarction
ΠBLAST* Sciαs growth peripheral vascular disease, Phase d trafermiπ Mountain View, CA factor coronary artery disease Wyeth-Ayerst Laboratories (see also neurologic) Philadelphia, PA TABLE A
H E A R T l D I S E A S E
Product Product Development Name Company Catesory Indication Status gene therapy Collateral Therapeutics gene therapy stable exertioπal angina Phase (til San Diego, CA growth factor Chiron growth coronary artery disease Phase l Emeryville. CA factor hSGl.l-SCFV Alexion Pharmaceuticals cardiopulmonary Phase d (recombinant) Ne Have CT bypass-associated inflammation Enzon using SCD* technology Plscaαway. NJ
Hu23F2G ICOS MAb myocardial infarction Phase d MAb Bothel WA (see also neurologic other) πlegiflh™ COR Therapeutics percutaneous trarαhiminal application eptifibatide S. San Francisco, CA coronary angioplasty. submitted (llh/llla platelet Schering-Plough unstable angina aggregation Madison, NJ inhibitor) acute myocardial infarction Phase!) inter leu kin-10 Schering-Prough interleukin ischemic reperfua'on injury Phase ! (IL-10! Madison, NJ (see also ΛIDVHIV, autoimmune, digestive, neurologic respiratory, skin) lanoteplase Bristol-Myers Squibb t-PΛ acute myocardial infarction Phase 111 ftmcefon, NJ
LR-32B0 Iπα Pharmaceuticals antisense cardiovascular resti osis Phase 11 Vancouver, BC Schwarz Pharma Milwaukee, wi
MHl-Fab' American Biogenetie MAb in vivo imaging agent for the Phase 1/11 imaging agent Sciences detection of cardiovascular
Boston, MA thrombosis
MP!*-C Rfci ImmunoChem prevention/ameliontion of Phased immunomodulator Hamilton, MT cardiac ischemia reperfusion injury
Natrecαr* BNP Seios acute congestive heart failure Phase III
Mountain View, CA completed/ application submitted cardiovascular pulmonary surgery Phase l
Novastan* Texas Biotechnology hepariπ-induced application argatroban Houston, TX thrombocytopenia submitted thrombosis syndrome
ReoPra* Centocor MAb unstable angina Phase id abcixππab Malven PΛ (see also neurologic) Eli Lilly Indianapolis, IN acute rnyocartfial infarction Phase II rhAntithrombin III Genzyme control of blood clotting during Phase d (recombinant) Cambridge, MA coronary artery bypass surgery completed
TNK Genentech t-PA acute rrryocardial mfarction Phase id
(second-generation 5. San Francisco. CA r-PA) TABLE A
HEART DISEASE
Product Product Development
Name Company S_*___ιι__ Indication Status
TP10 T Cell Sciences recombinant heart attack Phase I Needham,MA soluble (see also respiratory, transplantation) receptor
VfGF Genentech growth coronary artery disease Phasel
S. San Francisco, CA factor
VEG 121 Scios growth cardiovascular disorders Phasel (vascular Mountain View, CA factor endodietial growth factor)
XuHx™ Genentech acute coronary syndrome Phase ! sibratiban 5. S n Francisco, CA oral llb/Illa antagonist
INFECTIOUS DISEASES
Product Product Development Name Company Category Indication Status adefovir diprvoxil Ctlead Sciences πuctaotide hepatitis B Phasel! Foster Oty, CA analogue
AlfeπinNGel* Interferon Sciences interferon human papiliomavirus infections Phase II interferon alfa-n3 New Brunswick, NJ
Alreron N Interferon Sciences interferon chronic hepatitis C infections Phase 111 Injection* New Brunswick, NJ (see also AIDS/HIV) interferon arfa-n3 genital wans Phased
AmpBgen* Hemispherx Btopharma interferon hepatitis Phase 1/11 New York, NY (see also ΛlDSΗtV, oncer, other) anti-tumor necrosis Chiron MAb sepsis Phase 11/111 factor MAb Emeryville, CA
Campyiobaαer Anrex Biologies cellular traveler's diarrhea Phase vaccine Caithersbwg, MD vaccine {Campylobacter infections)
CMV vaccine Chiron vaccine cytomegalovirus infection Phas l! Emeryville, CA
DTaP vaccine Chiron vaccine diphtheria, tetanus, Phase III Emeryville, CA acel ilar pertussis epstein-Barr virus Λvifon recombinant prevention of Epsrem-Barr virus Phasel vaccine Mountain View, CA subun infection (cause of monorrucleosis SmrthKCra Beecham vacdne infection] Philadelphia, PA genital herpes Glaxo Wellcome vaccine genital herpes Phasel vaccine Rsώ.TιiangJe atk.NC
He/icobacfer Aπtex Biologies cellular peptic ulcers Phasel vaccine Caithesburg, MD vaccine {Helicobacter pylori infections) TABLE A
I N F E C T I O U S D I S E A S E S
Product Product Development Name Cnmpany Category Indication Status hepatitis A Chiron vaccine hepatitis A Phase Id vaccine Emeryville, CA hepatitis B DNA Powder Ject Vaccines DNA hepatitis B prevention Phase l vacdne Madison, Wl vaccine hepatitis 3 vaccine SmithKlrne Beecham vaccine treatment of hepatitis B Phase (recombinant) Philadelphia, PA herpes simplex SmtthKline Beecham vaccine prevention of herpes simplex Phase III vaccine Philadelphia, PA infection
(recombinant)
HPV vaccine Medmmuπe vacdne genital wans Phase l Caithersburg, MD (see also cancer: SmrrhKliπe Beecham Philadelphia. PA human Protein Design Labs MAb liver transplantation due to Phase I/ll ami-hepatitis B Mountain View. CA chronic hepatitis B infection completed antibody (05T577) tntron*A Schering-Plough rπterferon pediatric hepatitis B, setf-injectabie application interferon alfa-2b Madison. NJ dosing system for hepatitis C submitted (recombinant) (see also cancer! hepatitis C (PEG-lπtron A) Phase 111 lπtron* A Schering-Plough interferon relapsed hepatitis C application Xebetol™ Madison, NJ submitted interferon alfa-2b (recombinant)/ naive hepatitis C (not previously Phase III ribavirin treated with interferon) hepatitis C (PEG-tntron A/Rebetol) Phase l
LeukαScan* Immunomedics MAb diagnosis of osteomyelitis, application sulesomab Morris Plains, NJ infected prosthesis, appendicitis submitted (see also digestive)
Lyme borreliosis Pasteur Merieux Connaught vaccine Lyme disease Phase III protein vaccine Swiftwater, PA
Lyme disease SmrthfOine Beecham vaccine prevention of Lyme disease application vaccine Philadelphia, PA submitted
(recombinant)
MAK 19SF Knoll Pharmaceutical MAb sepsis Phase 111 Mr. Olive, NJ
MED 91 Medlmmune vaccine B 19 parvr_virus-induced Phase l parvovirus Caiώeπbυrg, MD miscarriages and anemia B 19 vaccine meningococcus C Chiron vaccine meningococcus C Phase II vaccine Emeryville, CA TABLE A
INFECTIOUS DISEASES
Product Product Develo men Name Company Category IndkatnM Status
TABLE A
I N F E R T I L I TY
Product Product Development Name Company Catep°ry Indication Status ^
Aa«eτ» Ares-Seronoand hormone- female infertility Phase l gonadotropLn Serono Laboratories releasing hormone-rdeasing Norwell, MA hormone hormone antagonist antagonist
(ChRHA)
Gonal-P* Serono Laboratories recombinant male infertility Phase 111 recombinant human Norwell, MA fertility follicle-stimulating hormone hormone (r-FSH)
LhADt* Ares-Serono and recombinam female infertility— foHicular support, Phase d/Ill recombinam Serono Laboratories fertility stimulation of follicular development human leuiinizing Norwel MA hormone hormone (r-hLH)
OvitW* Ares-Serono and recombinant female infertility Phase 111 recombinant Serono Laboratories gonadotropin (see also AiDS UV) human chorionic Norwell MA gonadotropin (r-hCG)
N E U R O L O G I C D I S O R D E R S
Product Product Development Nome Company Cateμocy Indfcatiuπ Status
Activate* Genentech t-PA acute ischemic stroke within Phase in arreplase, 5. Sin Francisco, CA 3 to S hours of symptom onset recombinant
Anet^X"*4λS Anergen functional multiple sclerosis Phase ! Redwood Oty. CΛ antigenics immuno- therapy
Antegren Alhena Neuroscienees MAb multiple sclerosis flares Phased natalbrumab S. San Francisco, CA
ATM0J7 T Cell Sciences MAb multiple sderosis Phase l humanized MAb Needhanx MA
Avoπex* Biogen interferon secondary, progressive Phase III interferon beta-la Cambridge, MA multiple sclerosis (see also cancer)
Bettttron* Berlex Laboratories interferon chronic progressive multiple sderosis Phase Id recombinant Wayne, NJ (see also cancer) interferon beta-lb Chiron Emeryville, CA brain-derived Λmgen growth airryotrophic lateral sderosis Phase l neurotrophic factor Thousand Ga CA factor
(BDNF) Regeneron Pharmaceuticals Tarrytown, NY TABLE A
N E U R O L O G I C D I S O R D E R S
Development
BBS* Product
Company Category Indication
CPC-211 Cypros Pharmaceuticals cellular bchemic stroke, traumatic brain Phase r! Carlsbad, CA therapy injury βntimomab Boehringer IngeJheim MAb stroke Phase n/lll (anti-ICAM-1 MAb) Pharmaceuticals (see also other) RidgefiekJ, CT
FIBIA5T* Sdos growth stroke Phase d/Ill trafermin Mountain View, CA factor bee a o heart) Wyeth-Ayerst Laboratories Philadelphia, PA
HU23F2G tcos MAb multiple sderosis, ischemic stroke Phase MAb Bothell VVA (see also heart, other) interlevkin-10 Sdiering-Plough interleukin multiple sclerosis Phase l (IL-1Q) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, respiratory, skin)
IR 20B Immune Response Cβφ. vaccine multiple sderosis Phase l therapeutic vaccine Carlsbad, CA
LDP-01 LeukoSite MAb stroke Phase 1/11 Cambridge, MA (see also transplantation)
MS-TCR Conneties vaccine multiple sderosis Phase 11! Pa/oΛAo, 0.
Myotmphin* Cephalon growth amyotrophic lateral sderosis application rhlGF-1 West Chester, PA factor submitted Chiron Emeryville, CA peripheral neuropathies Phase
NeuroCeI!τ"-fE Diacrin cellular focal epilepsy Phase l (cellular Char/estown, MA therapy transplantation therapy)
NeuroCeflf-HD Diacrin cellular Huntington's disease Phase l (cellular Charkstown, MA therapy completed transplantation Genzyme Tissue Repair therapy) Catribήdg-, A
Diacrin cellular Parkinson's disease Phase d
(cellular Charkstown, MA therapy transplantation Genzyme Tissue Repair • therapy) Cambridge, MA πeurotropnin-3 A gen growth enteric neuropathies Phase I/!!
Thousand Oate, CA factor
Regeneron PharmaceuticaLs
Tatrytσwn, NY pimagedine Alteon overt neuropathy Phase III
Ramsey, NJ (see also diabetes)
Genentech
S. San Francisco, CA prosaptide Myelos Neurαsdences growth neuropathic pain and peripheral Phase d
TX14(A) San Diego, CA factor neuropathy TABLE A
NEUROLOGIC DISORDERS
Product Product Development
Nome Company Catenory Indication
Rebif* Serono Laboratories interferon rdapsing, remitting multiple sclerosis; application recombinant Norwell MA transitional multiple sclerosis submitted Interferon beta-la (see also cancer, infectious diseases) teoftD* Centocor MAb stroke Phased abdximab Malven A (see also heart) Eli Lilly Indianapolis, IN
Spheπmine™ Titan Pharmaceuticals cellular Parkinson's disease Phasel S. San Francisco, CA iherapy
Zenapex* Hoffmann-La Roche MAb tropical spastic paraparetis Phase l/ll da izumab Nυtleγ.Nl (model for multiple sclerosis) Protein Design Labs (see also cancer, eye, skin, Mountain View, CA transplantation)
RESPIRATORY DISEASES
Product Product Development
Name Company Cattfiβry Indication Status
AAVCFTR Targeted Genetics gene therapy sinusitis Phasel gene therapy Seattle, W A (see also genetic) acelrύ r pertussis Chiron vacdne pePatriC pertussis application vaccine £meryv._fe, CA (whooping cough) submitted anti-lgE Genentech MAb allergic asthma Phase ! humanized MAb S- San Francisco, CA Novartis Pharmaceuticals allergic rhinitis Phase!! East Hanover, NJ Tanox Biosysrems Houston, TX
Influenza rHAO Protein Sdences vacdne prevention of influenza Phase n Vacdne Maiden, CT influenza vaccine influenza virus Aviroπ vacdne prevention of influenza Phase Id vaccine Mountain View, CA
(live, attenuated) interleukin-* imminex recombinant asthma Phasel receptor Seattle, WA soluble receptor intedeukin-lQ Schering-Plough interleukin acute lung injury Phasel (IL-10) Madison. N) (see also AJDS/HTV, autoimmune, digestive, heart, neurologic, skin) lisofylline Cell Therapeutics acute lung injury Phased Seattle, WA (see also other)
NCUPOCtN* A gen colony multilobar pneumonia, Phase IU
Filgrastim Thousand Oaks. CA stimulating pneumonia sepsis
(rG-CSF) (actor (see also Λ1DS/HIV, cancer) TABLE A
R E S P I R AT O R Y D I S E A S E S
Product Product Development
Name Company Category Indication Status
Oxsodiβl* Bio-Technology General dismutase bronchopulmonary dysplasia Phase d! rhCu2r super kelin, NJ in premature infants dismutase parairiAuero_a Aviron vacdne prevention of parainfluenza type-3 Phase d type-3 vacdne Mountain View, CA infection (cause of croup in infants) (live, attenuated bovine)
PIV vaccine, Vvyeth- derie continuous prevention of parainfluenza Phase l live, attenuated Vaccines & Pediatrics ceil line virus-mediated lower respiratory Philadelphia, PA vacdne disease in infants
Qufllmn_une-P Aqurla Biopharmaceuticals vacdne pneumococeti 'mfcctiOM in Phase d Worcester, MA the elderly recombinant ICOS acute respiratory distress syndrome, Phase platelet activating Bothell. WΛ asthma factor- (see also digestive) acetyfnydrotase IrPΛF-ΛH)
RSV subunit Wyeth-Lederla continuous prevention of respiratory syncytial Phase d vaccine Vacσπes & Pediatrics cell line virus-mediated lower respiratory Philadelphia, PA vacdne disease in the elderly and at-risk children
RSV vacdne, Wyttlvlederie continuous prevention of respiratory syncytial Phase ! live, attenuated Vacdnes & Pediatrics cell line virus-mediated lower respiratory Philadelphia, PA vacdne disease m infants soluble ICAM-1 Boehringer Ingdheim recombinant prevention and/or treatment of Phase d (S1RR ) Pharmaceuticals soluble rhinovinis-rnduced common cold Ridgeβeld, CT receptor
Syrβps,,M Medimmune MAb prevention of respiratory syncytial application MEDM93 Caithersbυrg, MD virus disease submitted humanized RSV MAb
TP10 T Cell Sciences recombinant acute respiratory distress syndrome Phase Needhar MA soluble (see also heart transplantation) receptor truncated ICAM Bayer adhesion rhinovlrus-associatεd Phase l Berkeley, CA molecule exacerbations of asthma
TABLE A
S K I N D I S O R D E R S
Product Product Drvciopment
Name Company Category indication ami -GDI la Genentech MAb moderate to severe psoriasis Phase humanized MAb 5. San Francisco, CA (hu1124) XOMA
Berkeley, CA
, gamma mterferoπ Coπnetics mterreioii keloids Phase d Palo Afro, CA
ICM3 ICOS MAb psoriasis Phase l Bαthell. WΛ
11-2 fusion protein Seragen fusion moderate to severe psoriasis Phase l/ll DABj^tL-2 Hopkmton, MA protein (see also autoimmune, cancer) interleukiπ-10 Schering-Plough interleukin psoriasis Phase l (IL-10) Madison. NJ (see also AIDS/HIV, autoimmune, digestive, heart neurologic, respiratory)
IR502 Immune Response Corp. vaccine psoriasis Phase d therapeutic Carlsbad, CA vaccine
ISIS 2302 Isis Pharmaceuticals antisense psoriasis Phase d Carlsbad, CA (see also autoimmune, digestive, transplantation) kεrattnoeytf Human Genome Sciences growth wound healing Phase ! growth factor-2 Rodeville. MD faαor (see also other) ( GF-2J
LFA3TΪP Biogen recombinant psoriasis Phase 11 Cambridge, MA T-eell inhibitor
Regranex™ Chiron growth pressure ulcers Phase d! becaplermiπ Emeryville. CA factor (see also other)
(recombinant R.W. Johnson human Pharmaceutical platelet-derived Research Institute growth faαor-BB) Raritan NJ
T4NS Uposome Applied Genetics protection against aαinic keratoses Phase in Lotion Freepoιt, NY In patients with xeroderma
T4 endonudease V prgmeπtosa encapsulated in liposomes
TGF-beta3 OSI Pharmaceuticals growth impaired wound hearing Phase d
Uniondale. NY factor (see also other) transforming Novartis Pharmaceuticals growth wound healing Phase l! growth East Hanover, NJ factor factor-beta-3
Ztaapax* Hd mann-La Roche MAb psoriasis Phase l/ll daclizumab Nυύey. Nj (see also cancer, eye, neurologic, Protein Design Labs transplantation) Mountain View, CA TABLE A
T R A N S P L A N T A T I O N
Product Product Development
Name Company CateBory Indication albgeneic SySte ix cellular correct genetic diseases by in utero Phase l hematopoietic Pah Alto, CA therapy transplantation of genetically stem cells unaffected CβHs from a sibling
receptor
HSD-Tk Genetic Therapy gene therapy treatment of graft versus host disease Phase l retroviral vector Caithersburg, MD in allogeneic hematopoietic Sy5temix stem cell transplantation Pa/ A/fo, CA
HSV-tk Chiron gene therapy graft versus host disease Phase l Emeryville, CA in bone marrow transplantation
IStS 2302 isis Pharmaceuticals antisense renal transplant rejection Phase d Carlsbad, CA (see also autoirnraurg, digestive, skin)
LDP-Q1 LeukoSite MAb kidney transplantation Phase l/ll Caπύridge, MA (see also neurologic)
MEDI-507 Medlmπuine MAb graft versus host disease Phase d
(humanized Caithersburg MD
MAb) BioTransplant acute kidney transplant rejection Phase l/ll Charfestowπ, MA
ORTHOCIONE Onho Biotech MAb prevention of organ transplant Phase d OKT4A Raritan, N] rejection (see also autoimmune)
Sάnuled Novartis Pharmaceuticals MAb transplantation application basiibamab East Hanover, NJ submitted
SMART" Aπt>^D3 Protdn Design Labs MAb organ transplantation Phase l HuM291 Mountain View. CA (see also autoimmune)
TP10 T Cell Soenees recombinant transplantation Phase l/ll Needhan\ MA soluble (see also heart respiratory) receptor
Zenapax* Hoffmann-La Roche MAb liver transplantation Phase d dadizumab Nutley, NJ (see also cancer, eye, neurologic, skin) Protein Design Labs Mountain View, CA pediatric kidney transplantation Phase l/i!
Zenapax* Hoffmann-la Roche MAb kidney transplant rejection, Phase l/ll dadizumab Nutley, NJ cydσspσrine elimination and Prote Design Labs
Cellctpt* Mountain View, CA TABLE A
O T H E R
Product Product Development
Name Company Category mdicatirKi Status *^
Recornbumifl Ceπteoπ exdpient use Phase l recombinant King of Pnissia, PA human albumin
Regranβx™ Chiron growth venous ulcers Phase III becapfermin Emeryville, CA factor (see also skin)
(recombinant R.W. Johnson human Pharmaceutical platdet-derived Research Institute growth fictor-BB) Raritan, NJ rhBMP-2 Genetics Institute growth bone and cartilage repair in clinical
Cambridge, MA factor trials
Sairen* Serono Laboratories human chronic renal failure in children Phase III somatropin Norwell, MA growth (see also growth disorders)
(rDNA originj hormone for injection post-operative recovery Phas d
Serosttm'" Serono Laboratories human metabolic conditions Phase d somatropin Norwell, MA growth (see also cancer)
(rDNA origin) hormone for injection
Sernatoiine* Cdtrix Pharmaceuticals growth hip fractures, severe acute bums Phase d recombinant Santa data. CA factor insulin-like growth faetor-V binding protein-3
TGP-bet_3 051 Pharmaceuticals growth oral mucositis Phase d
Uniondale, NY factor (see also skin)
The content of this < survey has been obtained through government and Industry sources based on the latest information.
Survey cur rt as of March 13, 199ft. The information may not be comprehensive. For more sperific information about a particular produ contact the individual company directly.
PhRMA Internet address: ht_p_Λvww.phτrna.org
Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association.
Copyright 01998 by the Pharmaceutical Research and Mantia urers of America. Permission lo reprint is awarded if proper credit is given.
In one aspect, particular benefit is obtained with this invention when used with biopharmaceuticals, which include, for example, any proteins, polypeptides, enzymes, irnmunoglobulins, polynucleic acids, and plasmids or other biopolymers. Specific examples of biopharmaceuticals to be included in the crystal formulations of the present invention include the following: insulin, glucagon, Glucagon-Like Peptide- 1 (7-37)OH (GLP-1), human growth hormone, leptin, follicle-stimulating hormone (FSH), ribozyme, and analogs thereof .
The API's useful with the present invention include those which themselves may form crystalline products, as well as those which do not. By way of example, any proteins can be prepared as microcrystalline suspension products, but the results have frequently been unsatisfactory using existing technology. However, inclusion of these biomolecules into a host crystal system in accordance with the present invention overcomes this limitation on crystallization. The invention further finds utility even with API's that are readily crystallized, such as insulin. The incorporation of such API's into a single crystal lattice can be used to enhance stability or provide means of delivery that have different characteristics. Solvents for preparation of the saturated and supersaturated crystal lattice component include, but are not limited to, water, alcohols (e.g., ethanol, isopropanol), other organic solvents, acids, bases, and buffers. The crystals of the present invention are prepared to have a predetermined amount of active pharmaceutical ingredient. The desired amount of active pharmaceutical ingredient will depend on typical considerations, such as the effective amount of API used for administering to a patient. The concentration of API in the crystal is controlled, such as by previously described means, to yield crystals which are readily used in preparing pharmaceutical formulations for administration. The active pharmaceutical ingredient can be incorporated into the crystals at any of a wide variety of molar or weight percentages. Preferred percentages can be easily selected by a skilled artisan taking into account the usual considerations for later formulation of the desired pharmaceutical compositions, depending on the application, route of delivery, and desired pharmacological profile. Preferred percentages include, for example, concentrations of 0.01 - 1 weight percent. As used herein, all weight percentages are given as the percent based on the weight of the crystal including the crystal lattice component, the active pharmaceutical ingredient and any other components included within the crystals, unless stated otherwise.
The crystals may be prepared at varying size distributions, similarly depending on the subsequent formulating to be done with the crystals, or on crystal growth parameters. The crystals may be harvested and then sorted directly to desired size ranges, or may first be processed, such as by grinding or milling, and then sorted such as by sieving. As will be appreciated, a desired amount of active pharmaceutical ingredient may be obtained simply by obtaining a determined weight of crystals containing the active pharmaceutical ingredient at a known weight concentration. The useful size or weight range of the crystals of the present invention accordingly varies widely, depending on such factors as the inclusion level of the active pharmaceutical ingredient, the dosage amount for the active pharmaceutical ingredient, and the method of delivery of the crystals. By way of example, suitable crystals may have an average size distribution of 1 μm to 1 mm . The crystals of the present invention will typically be used in a formulation comprising a large number of crystals. It is a feature of the present invention that the active pharmaceutical ingredient is included within the crystal lattice component in a predictable, oriented fashion. This leads to a uniform concentration of the active pharmaceutical ingredient as a molar, and therefore weight, percentage of the crystals. In one aspect of the present invention, there is provided a composition of crystals having a substantially uniform weight concentration of active pharmaceutical ingredient as between crystals. The term "substantially uniform weight concentration" refers to the fact that the weight concentration of active pharmaceutical ingredient in the various crystals is sufficiently uniform that an acceptably accurate weight of active pharmaceutical ingredient can be obtained based on the weight of the crystals and the average concentration of active pharmaceutical ingredient in such crystals. In one preferred embodiment, there is provided a composition of crystals in which the size distribution of active pharmaceutical ingredient does not vary between crystals by more than about 20 percent. However, alternate embodiments may be equally useful, including mixtures of different size crystals. A desired quantity of active pharmaceutical ingredient is then accurately obtained by measuring a weight amount of crystals which, given the concentration of active pharmaceutical ingredient, yields the selected weight of active pharmaceutical ingredient. The crystals and included API's are useful in the crystal form for both the stabilization and storage of the API and for the administration of the API to a patient. As used herein, it will be appreciated that the term patient refers to either humans or non-humans, depending on the nature of the active pharmaceutical ingredient. The crystals may be used as such, and in one aspect of the present invention the crystals consist essentially of simply the crystal lattice component and the API. Alternatively, the crystals include the crystal lattice component and the API in combination with other pharmaceutically-acceptable adjuvants also contained within the crystals.
The crystals of the present invention are preferably formulated as pharmaceutical materials for ultimate delivery in solid or liquid form. In such applications, the crystals are typically formulated with common, compatible, pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof. For purposes herein, the term "pharmaceutically-acceptable" refers in this context to the excipients, diluents or carriers, as well as coatings or other components referred to elsewhere, being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Examples of excipients, diluents, and carriers that are suitable for such dosage forms are well known in the art, and include the following: suspension additives such as tonicity modifiers, buffers, precipitants, and preservatives; fillers and extenders such as starch, lactose, dextrose, sucrose, sorbitol, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol and glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. Additionally, the adjuvant may comprise crystals of the crystal lattice component that are prepared without the included API.
The crystals may be coated to achieve various effects. In one approach, the crystals are coated with the same crystal lattice component which forms the underlying crystal, but without the included API. This assures that the coating and the underlying crystal have compatibility. The coating is then applied at a thickness which provides the desired effect, such as further protection of the active pharmaceutical ingredient, bulking of the crystal for handling, and/or effecting a sustained or delayed release of the active pharmaceutical ingredient. Alternatively, the same effects can be accomplished by coating the crystals with other compatible coating compositions, such as those which are well known in the pharmaceutical coating art. The crystals can also be coated so as to release the active pharmaceutical ingredient only or preferably in a particular part of the intestinal tract or other route of administration, possibly over a period of time. This is accomplished, in known fashion, using coatings, envelopes, and protective matrices made, for example, from polymeric substances or waxes.
It is a feature of one aspect of the present invention that the crystals and included API's may be packaged and administered to patients in discrete pharmaceutical dosage forms. The crystals may be used as such in solid form, or may be formulated into liquid solutions or suspensions prior to use. The compositions may accordingly be administered by various routes, for example, by the oral, rectal, vaginal, ocular, buccal, nasal, pulmonary, iontophoretic, topical or parenteral routes. Such compositions form part of the present invention and are prepared in manners well known in the pharmaceutical art. The API's of the present invention are effective over a varied dosage range.
Such dosages are readily accommodated by the present invention by permitting various sizes of crystals, concentrations of API, etc. It will be understood that the amount administered will be determined in light of the relevant circumstances, including the condition to be treated, the choice of API to be administered, the size of the patient being treated, and the chosen route of administration. Therefore, specific dosage ranges will differ accordingly, and are not limiting of the scope of the invention in any way. The compositions are formulated in one embodiment as a unit dosage form. The term "unit dosage form" refers to physically discrete units, such as tablets, capsules, and suspensions in vials or cartridge/pen systems suitable as unitary dosages, particularly as unitary daily dosages. Each discrete unit contains a predetermined quantity of active pharmaceutical material calculated to produce the desired effect, e.g., a prophylactic or therapeutic effect. The amount of active pharmaceutical ingredient contained in a given dosage unit can be varied depending on the manner of delivering the crystals. For example, a single dosage unit in tablet form may contain 1/4, 1/3, 1/2 or 1 times the unit dose for the active pharmaceutical ingredient, according to which 1 to 4 tablets would be administered to achieve a unit dose of the active pharmaceutical ingredient.
Therefore, in one aspect of the present invention, there is provided a pharmaceutical product in dosage form comprising a pharmaceutical delivery unit including a dosage amount of active pharmaceutical ingredient. The API is contained within the crystal lattice component, and a sufficient amount of crystals is included within the delivery unit to constitute the dosage amount of the API. It will be appreciated that the dosage amount of pharmaceutical may be obtained by provision of one or more crystals of the present invention. One form of the product consists essentially of a dosage amount of the crystals. In an alternative form, the pharmaceutical product consists of the dosage amount of the crystals. The ultimate delivery forms may include, for example, tablets, soft and hard gelatin capsules, pellets, granules, marumes, lozenges, sachets, cachets, elixirs, suspensions, ointments, suppositories, injection solutions and suspensions, nonpareils, spheres and sterile packaged powders. The crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants, including excipients, diluents and carriers, as already described. One preferred form of the pharmaceutical product consists essentially of the crystals, and an alternate form consists of the crystals and the pharmaceutically-acceptable adjuvants. The delivery forms are prepared by conventional techniques such as disclosed in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, PA (1995), which is incorporated herein by reference, or other treatises available to the skilled artisan. Compressed tablets, for example, are prepared by well-known means which are conventional in the art. The tablets may be prepared by wet or dry granulation methods or by direct compression, and may be produced by any of a wide variety of tabletting machines. Tablet formulations usually incorporate diluents, binders, lubricants and disintegrators, as well as the crystals with included API's. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
Certain solid pharmaceutical dosage forms of the present invention, most notably tablets, may be coated in conventional fashion with a wide variety of materials utilizing various processes. Typically, the products of the present invention may be sugar coated or film coated in accordance with well-known techniques. The coatings serve an aesthetic purpose as well as a practical one. Coatings can mask an unpleasant taste or odor, can increase ease of ingestion by the patient, and can serve to improve the ultimate appearance of the dosage form. Similarly, coatings can protect the product from the effects of air, moisture and light, can improve product identification, and can facilitate handling in packaging and fill lines during manufacture.
Various adjuvants may be included in the coating formulations as is well known in the art. These include, for example, permeability enhancers, plasticizers, antitacking agents and the like. A discussion of coating techniques and adjuvants is presented in United States Patent No. 5,015,480, issued to Childers et al. on May 14, 1991, the pertinent portions of which are hereby incorporated herein by reference. Further information pertinent to coating processes and equipment may be obtained from Remington's Pharmaceutical Sciences, supra. Tablets are often coated with sugar as a flavorant and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet. The compounds may also be formulated as chewable tablets by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well- established practice. Instantly dissolving tablet-like formulations are also now frequently used to assure that the subject consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some subjects. A lubricant is used in a tablet formulation to prevent the tablet and punches from sticking in the die of the tabletting machine. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
Tablet disintegrators are substances which swell when wetted to break up the tablet and release the crystals. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate. Enteric formulations are used to protect crystals and the included API's from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
The crystals with included API's may similarly be formulated into capsules for administration. Such capsules are prepared utilizing conventional encapsulating methods. A general method of manufacture involves preparing the crystals for use in capsules, such as by milling the crystals to a suitable size. The crystals are blended with desired excipients, diluents or carriers, and the resulting mixture is filled into suitably-sized capsules, typically hard gelatin capsules, using conventional capsule-filling machines. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
When it is desired to administer the crystal formulations as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to raise its melting point slightly. Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are also in wide use.
The crystals can also be similarly formulated as elixirs or suspensions for convenient oral administration or for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.
The inventive crystals enable the design of sustained-release formulations based upon various factors to yield both the desired amount of active pharmaceutical ingredient and the desired pharmacokinetic profile for delivery of the active pharmaceutical ingredient. Selectively incorporating the active pharmaceutical ingredient into the crystal lattice, e.g., into a specific crystal growth sector, modulates the release profiles and can therefore be used to effect desired pharmacological properties. The choice of the crystal component and the process used to grow the crystals of excipient host and guest active pharmaceutical ingredient can be selected and/or modified to adjust parameters such as the delivery rate of the active pharmaceutical ingredient upon use of the formulation. The active pharmaceutical ingredient is incorporated into the crystal matrix at a selected rate, typically as only a small weight percentage of the overall crystal. This permits moderate and uniform rates of release. Various approaches may be used to accomplish a delayed or sustained release of active pharmaceutical ingredient from the crystals. In a typical application the crystals of the desired size are combined with a compatible preservative and the mixture is injected subcutaneously or surgically implanted to provide a prolonged payout as the crystals dissolve as a result of contact with the surrounding body tissue and fluid. In one approach, the concentration of the active pharmaceutical ingredient in the crystals is reduced in order to effect a sustained release over time. Alternatively, larger crystals may be used to provide for more prolonged payout of the active pharmaceutical ingredient. In another approach, coatings on the crystals are used to affect the rate of release of the active pharmaceutical ingredient. Such coatings may comprise the same crystal lattice component but without the included active pharmaceutical ingredient, as well as other coating compositions useful for this purpose. In the alternative, the crystals of the present invention can be used to isolate and/or store the active pharmaceutical ingredient for later reconstitution into solution. The crystals may be stored for extended periods of time prior to reconstitution in view of the added stability accorded the API's by the encompassing crystal lattice component. The crystals are then combined with pharmaceutically-acceptable excipients, diluents or carriers to prepare the solutions for subsequent administration. The crystals are readily dissolved or suspended in appropriate diluents, which may be selected, for example, from the list previously provided with regard to diluents used to initially prepare the crystals. Such solutions of dissolved crystals provide the active pharmaceutical ingredient free of the previously encompassing crystal lattice component. The solutions are useful, for example, for oral administration, parenteral use, or as suppositories. For parenteral administration, for example, the crystals may be formulated in a pharmaceutically-acceptable diluent such as physiological saline (0.9%), 5% dextrose, Ringer's solution, and the like, along with other additives to reduce the solubility of the crystals in suspension.
The resulting pharmaceutical formulations provide an active pharmaceutical ingredient which is included within the host crystal and has enhanced stability and shelf-life. The present invention therefore satisfies the desire to provide certain pharmaceuticals having an acceptable, room-temperature shelf-life. Depending on the circumstances, particularly the API involved, the desired shelf-life can be as little as one month, or may be at least one year, two years or more. The pharmaceutical molecules are generally isolated from one another and from the environment by the surrounding crystal lattice. The containment of the API in the solid crystal lattice also fixes the conformational orientation. This eliminates most of the potential degradation mechanisms, such as polymerization, oxidation, deamidation and proteolysis, that could otherwise reduce the stability of the pharmaceutical.
Methods demonstrating stability include but are not limited to high- performance liquid chromatography for purity and potency, FT-IR for secondary structure, in-vitro and in-vivo bioassays, and pharmacokinetic profiles. The crystals of the present invention are readily prepared and are useful in containing the included API in an isolated, oriented position within the lattice. The utility of the present invention is demonstrated in the following examples, which are illustrative in nature, and are not to be considered limiting of the scope of the present invention.
Example 1
To demonstrate the potential kinetic stabilization of proteins, green fluorescent protein (GFP) was incorporated into deionized α-lactose monohydrate.
GFP was selected because it is known to fluoresce only in its native conformation. Upon denaturation, the interior of the β-barrel of the molecule is exposed and the fluorescence of the p-hydroxybenzylideneimidazolinone chromophore is rapidly quenched. Typical crystal growth conditions involved the addition of 8 volumes of an approximately 1 mg/mL (approximately 37 μmole) solution of GFP in 10 mM tris-HCl, pH8 and 10 mM EDTA to 100 volumes of a supersaturated aqueous solution (approximately 1.15 M) of deionized α-lactose monohydrate. The mixed solution was allowed to stand for 3-4 days at room temperature in a 24-well plate. Crystals were harvested between 1-3 days and displayed a hatchet morphology as shown in Figure 1 with a broad base (010) further bounded by { 100} , { 110}, { 1- 10}, and {0-11 }. Small (0-10) and { 1-50} faces are also occasionally present. When illuminated with a long wavelength UV lamp, the crystals exhibited a bright green fluorescence localized within a sharply defined pyramid corresponding to the (010) growth sector. This indicates that GFP is selectively recognized and overgrown by the (010) face in preference to the others. More importantly, it is evidence that the GFP is in its native conformation. The level of GFP to lactose is approximately 0.008% (w/w).
GFP fluorescence intensity was measured as a function of time and temperature in three environments: saturated aqueous α-lactose solution, lyophilized α-lactose, and crystalline α-lactose monohydrate. As shown in Figure 2, both the solution and lyophilized preparations lost nearly half of the fluorescence intensity at 333°K within one hour. The crystal showed no change at 333°K or even 343°K. Example 2 To investigate the potential for incorporation of a biopharmaceutical into crystals of biocompatible excipients, studies were conducted using rhodamine- labeled glandular glucagon and lactose. As in the previous studies, the rhodamine label was used to facilitate the visualization of glucagon in the host crystals. Typical crystal growth conditions involved the addition of 5 volumes of a supersaturated solution of deionized α-lactose monohydrate to 1 volume of an approximately 1.5 mg/mL (approximately 300 to 400 μmole) of rhodamine-labeled glucagon in purified water. The mixed solution was allowed to stand at room temperature in a 24-well plate. Crystals were harvested between 1-3 days and displayed a hatchet morphology with a broad base. With the rhodamine label, glucagon inclusion was visible in the crystals as a well-defined pyramid corresponding to the (010) growth sector. The level of inclusion was determined to be approximately 0.1% (w/w). In-vitro dissolution experiments were performed on the glucagon/lactose crystals to evaluate potential for in-vivo, sustained-release pharmacokinetics. The release of rhodamine-labeled glucagon into solution was followed by fluorescence spectroscopy. In a typical experiment, 1-2 crystals were added to 100 microliters of phophate buffered saline solution at room temperature and the increase in fluorescence of the solution was monitored over time. The release of glucagon from the dissolving crystals was generally complete after 24-48 hours depending on crystal size and was linear until the last few hours of dissolution. Additional details are contained in the article entitled "Stabilization of Proteins in Single Crystal Hosts: Green Fluorescent Protein and α-Lactose Monohydrate," M. Kurimoto, P. Subramony, R. Gurney, S. Lovell, J.A. Chmielewski, B. Kahr, J. Am. Chem. Soc. 1999, 121, 6952-6953, which article is hereby incorporated herein by reference.
Example 3 To demonstrate the universality of this technology for incorporation of a diversity of biopharmaceuticals into crystals of biocompatible excipients, studies were conducted using biosynthetic human insulin and insulin analogs, V8-GLP-l(7-37)OH, a glucagon-like insulinotropic peptide- 1 analog, exendin, and human growth hormone in deionized α-lactose monohydrate or phthalic acid. Information regarding V8-GLP is available in United States Patent No. 5,705,483, issued to Galloway and Hoffman on January 6, 1998, which patent is hereby incorporated herein in its entirety. For information regarding exendin, see, e.g., R. Goke, H.C. Fehmann, T. Linn, H. Schmidt, M. Krause, J. Eng, B. Goke, "Exendin- 4 is a High Potency Agonist and Truncated Exendin-(9-39)-amide an Antagonist at the Glucagon-like Peptide l-(7-36)-amide Receptor of Insulin-secreting Beta- cells," J. Biol. Chem. 1993, Sep 15, 268(26), pp. 19650-5, which reference is hereby incorporated herein in its entirety.
Typical crystal growth conditions involved the addition of 1 volume of an approximately 10 mg/mL rhodamine- or Texas red-labeled peptide or protein in 0.1M phosphate-buffered saline solution (PBS, pH7.4) to 10 volumes of a supersaturated α-lactose solution or phthalic acid solution. Supersaturated solutions of purified α-lactose were obtained by adding 0.41 grams of α-lactose to 1 mL of purified water, allowing to dissolve in a 50-70°C water bath, and cooling to room temperature. Supersaturated solutions of phthalic acid were prepared by adding 0.05 grams of phthalic acid to 1 mL of either 70/30 (v/v) water/acetonitrile or 90/10 water/ethanol, allowing to dissolve in a 50-70°C water bath, and cooling to room temperature. Larger volumes of supersaturated solutions are obtained by using the same solute-to-solvent ratio.
The solutions of labeled peptide or protein with the supersaturated α- lactose or phthalic acid were mixed by swirling, transferred to a 24-well crystallization plate or other suitable glass or polypropylene container, and allowed to stand at room temperature. Crystals were harvested in 4-5 days and rinsed with hexanes, ethanol, or methanol. All preparations yielded crystals with dye-labeled protein inclusions as determined by microscopic examination using an Olympus SZ-40 microscope with a CCD vision camera.
The shape of the crystals formed was dependent on the solvent system used for the phthalic acid. The crystals formed with phthalic acid in water/ethanol were long, petal-shaped clusters. The crystals formed with water/ethanol were smaller and rhombic. Crystals of labeled-insulin/lactose were dissolved in PBS and analyzed by HPLC. The level of insulin inclusion was determined to be approximately 0.1%. This process is scalable from 100 μL to several liters. The larger volume crystallizations were performed using glass beakers, or other appropriate large containers, covered with watch glasses.
Using the same process, unlabeled insulin and exendin have also been incorporated into α-lactose monohydrate and phthalic acid crystals. Upon dissolution of the crystals with 0.01N HC1, purified water and/or methanol, the level of peptide included in these hosts was determined by analysis of the sample solutions with an HPLC system in the flow-injection analysis mode using a chemiluminescent nitrogen-specific detector (CLND). The level of peptide inclusions ranged from approximately 0.1% to 10% (w/w). These data demonstrate that the level of inclusion can be manipulated by appropriate choice of guest and host molecules in addition to crystallization conditions. See also the following references which are hereby incorporated herein in their entirety: M. Windholz, (editor). Merck Index, 10th edition, p. 769; R.A. Visser, Neth. Milk Dairy Journal, 34, 1980, pp. 255-275; J. Chmielewski, et al., JACS, 119, 43, pp. 105665-10566.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising: a single crystal of a pharmaceutically-acceptable crystal lattice component; and an active pharmaceutical ingredient different from and included within the crystal in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure.
2. A pharmaceutical material comprising: a mixture of single crystals, each crystal comprising a pharmaceutically- acceptable crystal lattice component and an active pharmaceutical ingredient different from and included within the crystal in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure.
3. The pharmaceutical material of claim 2 in which the crystals comprise at least two crystal lattice components, the first crystal lattice component being characterized by first pharmacokinetics and the second crystal lattice component being characterized by second pharmacokinetics.
4. The pharmaceutical material of claim 2 in which said mixture comprises a mixture of two different types of said crystals, the first type of the crystals comprising a first crystal lattice component and the second type of the crystals comprising at least one crystal lattice component different from the first crystal lattice component.
5. The pharmaceutical material of any of claims 2 to 4 in which the active pharmaceutical ingredient comprises discrete units and the units are included within the crystals in isolation from one another.
6. The pharmaceutical material of any of claims 2 to 5 in which the active pharmaceutical ingredient is included within the crystal at a concentration of about 0.001 to 1 weight percent based on the weight of the crystal including the active pharmaceutical ingredient.
7. A method of preparing a pharmaceutical product which comprises: including an active pharmaceutical ingredient into single crystals of a pharmaceutically-acceptable crystal lattice component, the including being conducted under pharmaceutically-acceptable conditions to provide the active pharmaceutical ingredient in the crystals in a growth-sector specific orientation; and harvesting the single crystals.
8. The method of claim 7 and which further includes dissolving the harvested crystals into a pharmaceutically-acceptable diluent to form a solution containing the pharmaceutical free of the crystals.
9. A method of stabilizing an active pharmaceutical ingredient which comprises including the active pharmaceutical ingredient into single crystals of a pharmaceutically-acceptable crystal lattice component, the including being conducted under pharmaceutically-acceptable conditions to provide the active pharmaceutical ingredient in the crystals in a growth-sector specific orientation, the active pharmaceutical ingredient comprising discrete units and the units being included in the crystals in isolation from one another.
10. A method of administering an active pharmaceutical ingredient which comprises administering to a patient a pharmaceutical composition comprising single crystals of a pharmaceutically-acceptable crystal lattice component and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure.
11. The invention of any of claims 1 to 10 in which, for each crystal, the active pharmaceutical ingredient is included within the crystal in a growth- sector specific orientation.
12. The invention of any of claims 1 to 11 and further comprising a pharmaceutically-acceptable adjuvant selected from the group consisting of excipients, diluents, carriers and mixtures thereof.
13. The invention of any of claims 1 to 12 in which the active pharmaceutical ingredient is a biopharmaceutical.
14. The invention of any of claims 1 to 13 in which the crystal lattice component is selected from the group consisting of: sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, potassium citrate, zinc, calcium, and any derivatives, salt forms, or mixtures thereof.
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AU2007212021B2 (en) 2006-02-07 2013-06-06 Takeda Pharmaceutical Company Limited Stabilized compositions of proteins having a free thiol moiety
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US5075291A (en) * 1989-11-22 1991-12-24 Ici Americas Inc. Crystalline sugar alcohol containing uniformly dispersed particulate pharmaceutical compound
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