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Rapid acting and long acting insulin combination formulations

A combined rapid acting-long acting insulin formulation has been developed wherein the pH of the rapid acting insulin is adjusted so that the long acting glargine remains soluble when they are mixed together. In the preferred embodiment, this injectable basal bolus insulin is administered before breakfast, provides adequate bolus insulin levels to cover the meal, does not produce hypoglycemia after the meal and provides adequate basal insulin for 24 hours. Lunch and dinner can be covered by two bolus injections of a fast acting, or a rapid acting or a very rapid acting insulin. As a result, a patient using intensive insulin therapy should only inject three, rather than four, times a day. Experiments have been performed to demonstrate, the importance of the addition of specific acids to hexameric insulin to enhance speed and amount of absorption and preserve bioactivity following dissociation into the monomeric form by addition of a chelator such as EDTA. As shown by the examples, the preferred acids are aspartic, maleic, succinic, glutamic and citric acid. These are added in addition to a chelator, preferably ethylenediaminetetraacetic acid (EDTA). The results show that the citric acid formulation was more effective at dropping the blood glucose rapidly than the identical rapid acting formulation prepared with HCl in swine. Charge masking by the polyacid appears to be responsible for rapid insulin absorption. EDTA was not effective when used with adipic acid, oxalic acid or HCl at hastening the absorption of insulin. These results confirm the results seen in clinical subjects and patients with diabetes treated with the rapid acting insulin in combination with citric acid and EDTA.
Owner:ELI LILLY & CO

Rapid Acting and Long Acting Insulin Combination Formulations

A combined rapid acting-long acting insulin formulation has been developed wherein the pH of the rapid acting insulin is decreased so that the long acting glargine remains soluble when they are mixed together. In the preferred embodiment, this injectable basal bolus insulin is administered before breakfast, provides adequate bolus insulin levels to cover the meal, does not produce hypoglycemia after the meal and provides adequate basal insulin for 24 hours. Lunch and dinner can be covered by two bolus injections of a fast acting, or a rapid acting or a very rapid acting insulin. As a result, a patient using intensive insulin therapy should only inject three, rather than four, times a day. Experiments have been performed to demonstrate the importance of the addition of specific acids to hexameric insulin to enhance speed and amount of absorption and preserve bioactivity following dissociation into the monomeric form by addition of a chelator such as EDTA. As shown by the examples, the preferred acids are aspartic, glutamic and citric acid. These are added in addition to a chelator, preferably ethylenediaminetetraacetic acid (EDTA). The results show that the citric acid formulation was more effective at dropping the blood glucose rapidly than the identical rapid acting formulation prepared with HCl in swine. Charge masking by the polyacid appears to be responsible for rapid insulin absorption. EDTA was not effective when used with adipic acid, oxalic acid or HCl at hastening the absorption of insulin. These results confirm the results seen in clinical subjects and patients with diabetes treated with the rapid acting insulin in combination with citric acid and EDTA.
Owner:ELI LILLY & CO

Microlithography reduction objective and projection exposure apparatus

A projection objective formed from six mirrors arranged in a light path between an object plane and an image plane is provided. The projection objective, in some examples, is characterized by having a physical distance between the vertexes of adjacent mirrors that is large enough to allow for the six mirrors to have sufficient thickness and stability properties to prevent surface deformations due to high layer tensions. In some embodiments, mirror thickness are such that surface deformations are prevented with mirrors having layer tensions lower than 350 MPa. Mirror surfaces may comprise multilayer systems of Mo/Be or Mo/Si layer pairs. In some examples, the physical distance between a vertex of the third mirror and a vertex of the sixth mirror (S3S6) satisfies the following relationship: 0.3×(a used diameter of the third mirror S3+a used diameter of the sixth mirror S6)<S3S6. In some examples, a ratio of a physical distance between a vertex of the first mirror and a vertex of the third mirror (S1S3) to a physical distance between the vertex of the first mirror and a vertex of the second mirror (S1S2) is within the range of: 0.5<S1S3/S1S2<2. In some examples, the physical mirror surfaces of the mirrors have a rotational symmetry with respect to a principal axis (PA). In some examples, all physical mirror surfaces are aspherical. In some examples, at most five physical mirror surfaces are aspherical. Other examples are provided, along with microlithography projection exposure apparatuses and processes for producing a microelectronic device.
Owner:CARL ZEISS STIFTUNG

Projection system for EUV lithography

An EUV optical projection system includes at least six reflecting surfaces for imaging an object (OB) on an image (IM). The system is preferably configured to form an intermediate image (IMI) along an optical path from the object (OB) to the image (IM) between a secondary mirror (M2) and a tertiary mirror (M3), such that a primary mirror (M1) and the secondary mirror (M2) form a first optical group (G1) and the tertiary mirror (M3), a fourth mirror (M4), a fifth mirror (M5) and a sixth mirror (M6) form a second optical group (G2). The system also preferably includes an aperture stop (APE) located along the optical path from the object (OB) to the image (IM) between the primary mirror (M1) and the secondary mirror (M2). The secondary mirror (M2) is preferably concave, and the tertiary mirror (M3) is preferably convex. Each of the six reflecting surfaces preferably receives a chief ray (CR) from a central field point at an incidence angle of less than substantially 15°. The system preferably has a numerical aperture greater than 0.18 at the image (IM). The system is preferably configured such that a chief ray (CR) converges toward the optical axis (OA) while propagating between the secondary mirror (M2) and the tertiary mirror (M3).
Owner:CARL ZEISS SMT GMBH
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