Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-22
2003-07-01
Jones, Dwayne C. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S514000, C514S450000, C544S106000
Reexamination Certificate
active
06586407
ABSTRACT:
This invention relates to new injectable pharmaceutical formulations containing partricin derivatives as the active ingredient. In particular, the new pharmaceutical formulations enclose at least one derivative of partricin in the form of a free base, or a pharmaceutically acceptable water-soluble salt of it, in a solubilizing/dispersing medium made up of a lipid and/or phospholipid emulsion in water.
In patent applications EP-A-0434943 (equivalent to U.S. Pat. No. 5,296,597) and EP-A-0489308 (equivalent to U.S. Pat. No. 5,298,495) several derivatives of partricin A and/or B (henceforth “partricin”) are described, wherein the carboxyl in position C-18 of the macrolidic ring is in the form of an ester or of a neutral amide or of an amide containing a basic nitrogen group in the side chain and where the primary amino group of mycosamine can optionally form an amide bond with the carboxyl of an acid, it too containing a basic nitrogen group in the chain.
The afore-said documents also describe the preparation of their salts with acids, acceptable from a pharmacological and pharmaceutical point of view, and report that such salts are unusually water-soluble.
It has already been ascertained that the partricin derivatives, described in the afore-said European patent applications, can also be used in clinical practice, for human and veterinary application as drugs for treatment of several pathologies sensitive to the partricin derivatives; in particular, injectable formulations may be prepared enclosing such derivatives, evidencing the advantages deriving from the water-solubility of the said partricin derivatives. These formulations may permit, for instance, using a derivative of partricin's as the active ingredient (e.g., N-dimethylaminoacetyl-partricin A 2-dimethylamino-ethylamide diascorbate—code name SPA-S-843) for instance with the addition of ascorbic acid, as antioxidant, and of lactose as excipient. The freeze-dried product is normally dissolved in 5% glucose solution at the time of use and administered by slow intravenous infusion.
Even though this formulation can be of concrete utility in the clinical practice, it was however found that such aqueous formulations of partricin derivatives, specially when repeatedly administered and with daily frequency, can cause local vascular damage with considerable pain at the site of injection, tissue irritation, edema formation and thickening of vasal epithelium, leading in the end, to massive formation of thrombi and onset of frank thrombophlebitic forms.
It has now been surprisingly found that these side effects involving the vascular system, brought about by intravenous injections of known formulations of the partricin derivatives, can be considerably limited, or even avoided, by the use of new formulations wherein the partricin derivative is enclosed in a lipid and/or phospholipid emulsion in water.
One of the subjects of the present invention is in fact an injectable pharmaceutical formulation enclosing at least one partricin derivative in the form of free base—or of water-soluble pharmaceutically acceptable salt thereof, with acids that are acceptable from a pharmaceutical and pharmacological point of view—in a solubilizing/dispersing medium made up of a lipid and/or phospholipid emulsion in water such that the resulting emulsion be iso-osmotic.
In the present invention the expression “partricin derivative” indicates the derivatives of partricin described in patent applications EP-A-0434943, EP-A-0489308, GB-A-1359473 (equivalent to U.S. Pat. No. 3,780,173) and GB-A-1046774 (equivalent to U.S. Pat. No. 3,961,047). In particular, preferred formulations are those wherein the partricin derivative is a derivative of partricin A and/or B presenting the carboxyl in position C18 of the macrolidic ring in the form of ester or of neutral amide or of amide containing a basic nitrogen group in the side chain, and those wherein the derivative is further substituted, on the primary amino group of mycosamine in the form of amide with an acid containing a basic nitrogen group in the side chain. A partricin derivative specially preferred for the formulations of the invention is N-dimethylaminoacetyl-partricin A 2-dimethylamino-ethylamide. When the formulations of the invention enclose a partricin derivative in the form of a free base, the addition of a surfactant and/or a co-solvent is preferred in order to avoid any eventual problem of active ingredient solubilization before its inclusion in the lipid emulsion; alternatively, this trouble can be avoided by sonication of the particles, elevation of the system temperature e.g., from room temperature to 40-50° C., and etc.
In the case the formulations of the invention enclosed a pharmaceutically acceptable salt of the partricin derivative, these salts are preferably formed with at least one, preferably two, acid equivalents, preferably ascorbic or aspartic acid; the salt preferred for the formulations of the invention is N-dimethylaminoacetyl-partricin A 2-dimethylamino-ethylamide diascorbate, as such or as its free base.
The formulations of the invention comprise a pharmaceutically effective quantity of the partricin derivative; the dose of partricin derivative per unit to be administered remains substantially equal to that of the traditional formulations. In particular, the quantity ranges from 1 to 100 mg, preferably 10 to 50 mg.
The partricin derivative enclosed in the formulations of the invention is, preferably, in the form of solution, of micellar pseudosolution, of encapsulated inclusion compound, or of suspension of sub-micronized particles, their size being smaller than 5 &mgr;m. preferably smaller or equal to 3 &mgr;m, to avert the risk of pulmonary embolism; following sterilization (by sterilizing filtration or other suitable method), the partricin derivative can directly be added to the lipid emulsion or, preferably, stored in the dry state, following suitable processing (e.g., through freeze-drying), to improve long-term stability and be added to the lipid emulsion just prior to its therapeutic use by parenteral injection, particularly intravasal and, preferably, intravenous route.
In the formulation of the invention, the solubilizing/dispersing medium, is a lipid emulsion, preferably oil-in-water, containing lipids and/or phospholipids, in the form of droplets, vesicles, nanospheres, etc.
The lipids and/or phospholipids used in the formulations of the present invention can be from different origin, that is, animal and/or vegetable and/or synthetic and/or semisynthetic origin (hydrogenated fats and the like).
The lipids are preferably taken from the group of the mono-, di- or triglycerides; specially triglycerides; when of vegetable origin preferably from olives, for instance triolein, or from soybeans, when of animal origin preferably fish oils.
The phospholipids, in particular the phosphatidylcholines, when of vegetable origin are typically soybean lecithins, when of animal origin are selected preferably from egg yolk lecithins.
Other phospholipids, preferred for the formulations of the invention, are those selected from the group of the distearoilphosphatidyl-choline, dimyristoilphosphatidylcholine, dimyristoilphosphatidylglycerol, phosphatidyl-ethanolamine, phosphatidylserine, phosphatidyl-inositol.
Hydrogenate lipids and/or phospholipids too can be used in the formulations of the invention.
When phospholipids are used alone, they can be in the form of multilamellar or unilamellar, large or small vesicles, optionally containing sterols. In other cases, lipids and/or phospholipids can be present in the form of lipid nanospheres able to encapsulate the partricin derivative.
The concentration of the lipids eventually present in the formulations of the invention varies from 1 to 25%, being it usually 10-20% while the concentration of the phospholipids eventually present can vary from 0.05% to 5%.
The formulations of the invention can also enclose an excipient and/or a pharmaceutically acceptable adjuvant, such as those commonly used in the formulations intended for injectable us
Bruzzese Tiberio
Ferrari Valerio Maria
Jones Dwayne C.
Quatex N.V.
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